Circadian Rhythms in the Pharmacokinetics and Clinical Effects of Beta-agonist, Theophylline, and Anticholinergic Medications in the Treatment of Nocturnal Asthma

Published asthma consensus reports now acknowledge that asthma is a nocturnal disease in as many as 75% of those afflicted by this medical condition. Nonetheless, the treatment of this chronic obstructive pulmonary disease in the clinic continues to be based primarily on homeostatic considerations in that it relies on long-acting bronchodilator and other therapies formulated and scheduled to ensure constant or near-constant levels of medication during the 24h. The need of asthma patients prone to nighttime attacks is not the same during the day and night; the therapeutic requirements of patients who experience nocturnal asthma, especially ones with the more severe forms of the disease, are often not satisfied by conventional medications. The therapeutic response and patient tolerance to bronchodilator medications can be improved markedly when the medications are proportioned during the 24h as a chronotherapy, that is, when more medication is delivered during nighttime sleep than daytime activity, as verified by numerous studies. This article reviews how the body's circadian rhythms influence the pharmacokinetics and effects of commonly prescribed asthma therapies and addresses why and how they must be taken into consideration to increase the effectiveness of asthma treatment.     

Neuropsychological Outcomes of Nocturnal Asthma

In spite of frequent reports that nocturnal asthma results in fatigue and impaired cognitive performance, there exists little objective evidence as to the daytime consequences of this disorder. Treatment studies have established that the symptoms of nocturnal asthma improve with medication intervention, but performance does not. Studies of obstructive sleep apnea (OSA), a source of generally more severe sleep fragmentation, have demonstrated that measurement of sleep-deprivation effects is limited to tasks requiring heightened alertness and rapid information processing, and that the degree of score change is related to the degree of sleep disruption. Studies of normal, but sleep-deprived, subjects indicate that (1) utilization of repetitive measures sustained for long duration can potentiate motivation to overcome the effects of fatigue in the laboratory, and (2) even when average scores do not change significantly, performance becomes more irregular. These collective findings about the measurement of performance impairment secondary to sleep deprivation can be used to guide new studies of nocturnal asthma. Finally, children must be included in future investigations because they may be at even greater risk for daytime consequences of nocturnal asthma than adults.     

清热化痰、宣肺解痉法治疗支气管哮喘的临床疗效及对气道呼吸参数、生活质量的影响

摘要 目的：探讨清热化痰、宣肺解痉法治疗支气管哮喘的临床疗效及对气道呼吸参数、生活质量的影响。方法：选取我院2019年10月到2021年9月收治的60例支气管哮喘患者作为研究对象,分为观察组与对照组,每组30例。对照组予吸入布地奈德福莫特罗粉吸入剂,观察组在对照组基础上增加清热化痰宣肺解痉法治疗,对比两组患者临床疗效,治疗前与治疗1个月后的中医证候积分变化,气道呼吸参数变化,炎症因子以及生活质量变化。结果：观察组总有效率较对照组高（P<0.05）;两组患者治疗前中医证候积分对比无差异（P＞0.05）,治疗后降低,且观察组低于对照组（P＜0.05）;两组患者治疗前第1秒用力呼气容积（FEV₁）、用力肺活量（FVC）、第1s用力呼气量/用力肺活量（FEV₁/FVC）最大呼气流速（PEF）对比无明显差异（P＞0.05）,治疗后两组患者FVC、FEV₁、FEV₁/ FVC、PEF均有提升,且观察组高于对照组（P＜0.05）;两组患者治疗前肿瘤坏死因子-α（TNF-α）、转化生长因子-β1（TGF-β1）、基质金属蛋白-9（MMP-9）、血管内皮生长因子（VEGF）、干扰素-γ（IFN-γ）、白细胞介素-4（IL-4）水平对比无明显差异（P＞0.05）,治疗后两组患者TNF-α、TGF-β1、MMP-9、VEGF、IFN-γ、IL-4水平均明显降低,且观察组低于对照组（P＜0.05）;两组患者治疗前生活质量评分对比无差异（P＞0.05）,治疗后1个月生活质量相关评分均降低,且观察组较对照组低（P＜0.05）。结论：支气管哮喘患者在常规西医治疗基础上增加清热化痰宣肺解痉法治疗可减轻患者症状。另外可改善患者呼吸功能,降低炎症因子反应,提升患者生活质量。     

IL-13在支气管哮喘中的作用机制及治疗靶位

支气管哮喘是由多种细胞包括气道炎性细胞、结构细胞和多种细胞组分参与的气道慢性炎症性疾病。其发病原因复杂,以反复发作的呼吸困难、气道的高反应性和慢性炎症为特点。细胞因子作为免疫活性细胞中的效应分子,具有的免疫调节作用,诸多学者认为白介素-13(interleukin-13,IL-13)在哮喘发病中扮演重要角色,其拮抗剂有望成为哮喘治疗的新方法,本文欲将IL-13的生物学功能、IL-13在支气管哮喘中的作用机制及干预治疗靶位加以综述,为制定哮喘防治策略、开发新治疗技术提供新思路。     

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。     

Ad-sTNFRI-IgGFc腺病毒载体的构建及其转染人气道平滑肌细胞

TNF-a是一种具有广泛生物学活性的前炎症细胞因子, 参与哮喘整个病理生理过程。可溶性肿瘤坏死因子受体(sTNFR)可以拮抗肿瘤坏死因子活性, 已被用来治疗与TNF相关的炎性疾病。将sTNFRI-IgGFc基因插入腺病毒穿梭质粒pDC316, 与辅助质粒pBHGloxΔE1, 3Cre共转染HEK293细胞, 重组产生Ad-sTNFRI-IgGFc, PCR鉴定毒种正确后, 进行扩增、纯化和滴度测定, 转染人气道平滑肌细胞, 利用RT-PCR、免疫组化方法, 流式细胞仪, ELISA检测转染后细胞中sTNFRI-IgGFc的转录和表达。实验结果证明成功构建了Ad-sTNFRI-IgGFc腺病毒载体, 感染性滴度达3×1010 TCID50/mL, 200 moi转染气道平滑肌细胞阳性率达99.32%, 转染后气道平滑肌细胞在mRNA和蛋白水平均有sTNFRI-IgGFc表达。转染上清稀释64倍后仍对TNF有拮抗活性。为将表达sTNFRI-IgGFc腺病毒基因治疗哮喘的实验研究提供了基础。     

Relationship between African dust carried in the Atlantic trade winds and surges in pediatric asthma attendances in the Caribbean

Asthma is epidemic in developed and developing countries including those in the Caribbean where it is widely believed that African dust, transported in high concentrations in the Trade Winds every year, is a major causative factor. The link between asthma and dust in the Caribbean is based largely on anecdotal evidence that associates sharp increases in the occurrence of asthma symptoms with hazy conditions often caused by dust. Here we report on a 2-year study of the relationship between the daily concentrations of dust measured in on-shore Trade Winds at Barbados and pediatric asthma attendance rates at Queen Elizabeth Hospital (QEH). We looked for large increases in QEH daily attendances in relation to daily dust concentrations as previously suggested by anecdotal observations. We could not find any obvious relationship although there may be more subtle linkages between dust and asthma. Our measurements show, however, that the concentration of dust in the size range under 2.5 μm diameter is sufficiently high as to challenge United States Environmental Protection Agency air quality standards for respirable particles. Thus, African dust may constitute a health threat of a different nature, producing symptoms less obvious than those of asthma.     

呼吸道合胞病毒感染促进豚鼠产生气道高反应性及其机制研究

目的：通过检测气道反应性和M2受体功能,研究呼吸道合胞病毒（RSV）感染与哮喘发病的关系及机制。方法：34只豚鼠随机分为4组：Hep-2滴鼻＋生理盐水雾化（Hep-2／NS,A）组,RSV滴鼻＋生理盐水雾化（RSV／NS,B）组,Hep-2滴鼻＋鸡卵蛋白（OVA）雾化（Hep-2／OVA,C）组和RSV滴鼻＋OVA雾化（RSV／OVA,D）组,其中A和B纽各9只,C和D组各8只,以A组为对照组。21d通过电刺激迷走神经检测各组气道反应性和M2受体功能,行嗜酸性粒细胞计数以及病理学观察。结果：B组气道内压力（mmH2O）与A组无明显差异（P〉0．05）,给予匹罗卡品,IP下降幅度高于A组,但差别无显著性（P〉0．05）。C组IP明显高于A且（P〈0．05）,且给予匹罗卡品,IP下降幅度明显低于A组,差别有显著性（P〈0．05）。D组IP明显高于C组（P〈0．05）,给予匹罗卡品后IP下降幅度明显低于C组（P〈0．05）。结论：RSV感染可促进过敏原引起的M2R功能障碍,从而促进AHR发生。     

Glutathione S-transferase mu 1 (GSTM1) and theta 1 (GSTT1) genetic polymorphisms and atopic asthma in children from Southeastern Brazil

Xenobiotics can trigger degranulation of eosinophils and mast cells. In this process, the cells release several substances leading to bronchial hyperactivity, the main feature of atopic asthma (AA). GSTM1 and GSTT1 genes encode enzymes involved in the inactivation of these compounds. Both genes are polymorphic in humans and have a null variant genotype in which both the gene and corresponding enzyme are absent. An increased risk for disease in individuals with the null GST genotypes is therefore, but this issue is controversial. The aim of this study was to investigate the influence of the GSTM1 and GSTT1 genotypes on the occurrence of AA, as well as on its clinical manifestations. Genomic DNA from 86 patients and 258 controls was analyzed by polymerase chain reaction. The frequency of the GSTM1 null genotype in patients was higher than that found in controls (60.5% versus 40.3%, p = 0.002). In individuals with the GSTM1 null genotype the risk of manifested AA was 2.3-fold higher (95%CI: 1.4-3.7) than for others. In contrast, similar frequencies of GSTT1 null and combined GSTM1 plus GSTT1 null genotypes were seen in both groups. No differences in genotype frequencies were perceived in patients stratified by age, gender, ethnic origin, and severity of the disease. These results suggest that the inherited absence of the GSTM1 metabolic pathway may alter the risk of AA in southeastern Brazilian children, although this must be confirmed by further studies with a larger cohort of patients and age-matched controls from the distinct regions of the country.     

X-ray structures of free and leupeptin-complexed human alphaI-tryptase mutants: indication for an alpha-->beta-tryptase transition

Tryptases alpha and beta are trypsin-like serine proteinases expressed in large amounts by mast cells. Beta-tryptase is a tetramer that has enzymatic activity, but requires heparin binding to maintain functional and structural stability, whereas alpha-tryptase has little, if any, enzymatic activity but is a stable tetramer in the absence of heparin. As shown previously, these differences can be mainly attributed to the different conformations of the 214-220 segment. Interestingly, the replacement of Asp216 by Gly, which is present in beta-tryptase, results in enzymatically active but less stable alpha-tryptase mutants. We have solved the crystal structures of both the single (D216G) and the double (K192Q/D216G) mutant forms of recombinant human alphaI-tryptase in complex with the peptide inhibitor leupeptin, as well as the structure of the non-inhibited single mutant. The inhibited mutants exhibited an open functional substrate binding site, while in the absence of an inhibitor, the open (beta-tryptase-like) and the closed (alpha-tryptase-like) conformations were present simultaneously. This shows that both forms are in a two-state equilibrium, which is influenced by the residues in the vicinity of the active site and by inhibitor/substrate binding. Novel insights regarding the observed stability differences as well as a potential proteolytic activity of wild-type alpha-tryptase, which may possess a cryptic active site, are discussed.