黏液调节/抗氧化剂预防慢性阻塞性肺疾病急性加重的荟萃分析

目的 评价长期口服黏液调节/抗氧化剂预防慢性阻塞性肺疾病(慢阻肺)急性加重的有效性及安全性,并探讨药物剂量及合并使用吸入糖皮质激素(ICS)对疗效的影响.方法 对慢阻肺患者规律口服黏液调节/抗氧化剂超过3个月的临床随机对照试验(RCT)进行系统检索,检索Medline和Google Scholar数据库中已发表的文献,对纳入文献逐个进行质量评价和资料提取.进行统计学分析时,计数资料采用相对危险度(RR);计量资料采用加权均数差(WMD)或标准均数差(SMD).采用Stata 11.0软件对数据进行合并统计分析.结果 共纳入10篇文献,共3 434例患者,平均研究时长11.3个月.口服黏液调节/抗氧化剂组急性加重次数较对照组降低0.36次/人年(WMD=-0.36,95％ CI为-0.47～-0.26,z=6.97,P＜0.001).未合用ICS的亚组分析显示治疗组急性加重次数较对照组下降0.58次/人年(WMD=-0.58,95％ CI为-0.89～-0.27,z=3.62,P＜0.001).对不同剂量N-乙酰半胱胺酸(NAC)的疗效分析显示,高剂量时治疗组急性加重次数较对照组减低0.39次/人年(WMD=-0.39,95％ CI为-0.61 ～-0.16,z=3.33,P=0.001);低剂量NAC仅在合用ICS比例较低时才显示出降低慢阻肺急性加重的作用(WMD=-1.25,95％ CI为-1.99～-0.51,z=3.32,P=0.001),当合用ICS比例较高时,两组之间无统计学差异(WMD=-0.06,95％ CI为-0.29～-0.17,z=0.5,P=0.617).研究期间黏液调节/抗氧化剂组FEV1较对照组无明显改善(SMD=0.03,95％ CI为-0.09 ～0.15,z=0.49,P=0.626),而用力呼出气量为25％ ～75％肺活量时的平均流量(FEF 25％～75％)改善有统计学意义(SMD=0.41,95％ CI为0.13 ～0.68,z=2.90,P=0.004).与对照组相比,黏液调节/抗氧化剂组的副作用发生率未见明显增加(RR=1.08,95％ CI为0.92 ～ 1.27,z=0.92,P=0.356).结论 长期口服黏液调节/抗氧化剂可以在不增加副作用的前提下降低稳定期慢阻肺患者的急性加重频次,这一作用可能在未合用ICS患者中更为明显.高剂量NAC预防慢阻肺急性加重的作用较低剂量明确,低剂量仅在合用ICS比例较低时显示出相应的作用.     

Usefulness of serum biopterin as a predictive biomarker for childhood asthma control: A prospective cohort study

Background

Pteridines are metabolites of tetrahydrobiopterin, which serves as co-enzyme of nitric oxide synthase. We sought to investigate the usefulness of pteridines as biomarkers for childhood asthma control.

聚焦慢性阻塞性肺病治疗药物

慢性阻塞性肺病（COPD）是肺部进行性疾病,需长期治疗。预计到2020年,每年COPD将会导致全球600多万人死亡。尽管对新型药物开发投资不断增加,但该领域的治疗仍以缓解症状的支气管扩张吸入剂为主,而不是治愈性疗法,故应对COPD的创新药的研发仍困难重重。与乳腺癌等疾病领域相比,呼吸系统药物的研发成功率不到50％,但每种获批药物的研发成本却翻倍。因此,制药公司致力于药品生命周期的管理,在当前治疗的基础上进一步改进。其策略包括不同种类药物联用、开发新配方和各种剂量剂型．改善疗效,方便给药。其中以长效β受体激动剂（LABA）／长效毒蕈碱拮抗剂（LAMA）的定量复方药的需求增长最多。领导市场的GSK公司的LABA沙美特罗和吸入型皮质类固醇（ICS）氟替卡松的复方药Advair,就是应用以上方法的典型。虽已出现潜在新型靶标．但这些药物还处于早期开发阶段。吸入型LABA／ICS定量复方药短期内仍是COPD治疗领域的主力军。     

Risk of Severe Cardiovascular Events From Add-On Tiotropium in Chronic Obstructive Pulmonary Disease

Objective

To examine the risk of cardiovascular disease (CVD) from tiotropium added to inhaled long-acting β₂ agonists (LABAs) and inhaled corticosteroids (ICSs) in a nationwide population with chronic obstructive pulmonary disease (COPD).

Vaccine Adjuvant Systems containing monophosphoryl lipid A and QS-21 induce strong humoral and cellular immune responses against hepatitis B surface antigen which persist for at least 4 years after vaccination

BackgroundRecombinant hepatitis B surface antigen (HBsAg) was used as a model antigen to evaluate persistence of cellular and humoral immune responses when formulated with three different Adjuvant Systems containing 3-O-desacyl-4′-monophosphoryl lipid A (MPL) and QS-21, in an oil-in-water emulsion (AS02_B and AS02_V), or with liposomes (AS01_B).MethodsThis is an open, 4-year follow-up of a previous randomised, double-blind study. Healthy subjects aged 18–40 years received three vaccine doses on a month 0, 1, 10 schedule and were initially followed for 18 months. A total of 93 subjects (AS02_B: n = 30; AS02_V: n = 28; AS01_B: n = 35) were enrolled in this follow-up and had an additional blood sample taken at Year 4 (NCT02153320). The primary endpoint was the frequency of HBsAg-specific CD4⁺ and CD8⁺ T-cells expressing cytokines upon short-term in vitro stimulation of peripheral blood mononuclear cells with HBsAg-derived peptides. Secondary endpoints were anti-HBs antibody titres and frequency of HBsAg-specific memory B-cells.ResultsA strong and persistent specific CD4⁺ T-cell response was observed at Year 4 in all groups. HBsAg-specific CD4⁺ T-cells expressed mainly CD40L and IL-2, and to a lesser extent TNF-α and IFN-γ. HBsAg-specific CD8⁺ T-cells were not detected in any group. A high, persistent HBsAg-specific humoral immune response was observed in all groups, with all subjects seroprotected (antibody titre ≥10 mIU/mL) at Year 4. The geometric mean antibody titre at Year 4 was above 100,000 mIU/mL in all groups. A strong memory B-cell response was observed post-dose 2, which tended to increase post-dose 3 and persisted at Year 4 in all groups.ConclusionThe MPL/QS-21/HBsAg vaccine formulations induced persistent immune responses up to 4 years after first vaccination. These Adjuvant Systems offer potential for combination with recombinant, synthetic or highly purified subunit vaccines, particularly for vaccination against challenging diseases, or in specific populations, although additional studies are needed.     

Modulation of the CD4+ T cell response after acellular pertussis vaccination in the presence of TLR4 ligation

Whole cell pertussis (wP) vaccines are gradually being replaced by aluminum salt-adjuvanted acellular pertussis (aP) vaccines. These promote CD4⁺ T cell responses with a non-protective Th2 component, while protective immune mechanisms to B. pertussis may rather involve long-lived Th1/Th17 type CD4⁺ T cells. Here we asked whether addition of a non-toxic meningococcal LPS derivative, LpxL1, as adjuvant can favorably modulate the aP-induced pertussis-specific CD4⁺ T cell response in mice. To assess the effect of TLR4 ligation, Th type, quantity, and memory potential of pertussis-specific CD4⁺ T cells were determined at the single-cell level after aP and aP+LpxL1 vaccination using intracellular cytokine staining and MHC class II tetramers. Adding LpxL1 to the aP vaccine weakened the Th2 component and strengthened the Th1/Th17 component of the specific CD4⁺ T cell response. Notably, LpxL1 addition also induced higher frequencies of tetramer positive CD4⁺ T cells in draining lymph nodes or blood, depending on the phase after vaccination. Moreover, there was a net profit in the number of CD4⁺ T cells with a central memory phenotype, preferred for long-term immunity. Thus, adding a TLR4 ligand as adjuvant to a current aP vaccine was associated with a more favorable pertussis-specific CD4⁺ T cell response.     

TRANSVAC research infrastructure – Results and lessons learned from the European network of vaccine research and development

TRANSVAC was a collaborative infrastructure project aimed at enhancing European translational vaccine research and training. The objective of this four year project (2009–2013), funded under the European Commission's (EC) seventh framework programme (FP7), was to support European collaboration in the vaccine field, principally through the provision of transnational access (TNA) to critical vaccine research and development (R&D) infrastructures, as well as by improving and harmonising the services provided by these infrastructures through joint research activities (JRA). The project successfully provided all available services to advance 29 projects and, through engaging all vaccine stakeholders, successfully laid down the blueprint for the implementation of a permanent research infrastructure for early vaccine R&D in Europe.     

Can ‘extrafine’ dry powder aerosols improve lung deposition?

There is increasing interest in the use of so-called ‘extrafine’ aerosols to target the small airways in the management of asthma and COPD. Using previously presented deposition data, we assessed whether submicron (<1 μm) particles can improve central and deep lung deposition. Our data show instead that particles in the range 1–3 μm are much more relevant in this respect. Based on this finding the Symbicort Turbuhaler, Seretide Diskus, Rolenium Elpenhaler and Foster (Fostair) NEXThaler ICS/LABA combination DPIs were tested in vitro as a function of the pressure drop (2, 4 and 6 kPa) across the inhaler. Obtained fine particle fractions (FPFs) <5 μm (as percent of label claim) were divided into subfractions <1, 1–3 and 3–5 μm. Differences of up to a factor of 4 were found between the best (Turbuhaler) and worst performing DPI (Elpenhaler), particularly for the FPF in the size range 1–3 μm. The NEXThaler, described as delivering ‘extrafine’ particles, did not appear to be superior in this size range. The marked differences in amount and size distribution of the aerosols between the devices in this study must cause significant differences in the total lung dose and drug distribution over the airways.