Larry C. Lands

Background Progressive lung damage causes most deaths in cystic fibrosis. Non‐steroidal anti‐inflammatory drugs (such as ibuprofen) may prevent progressive pulmonary deterioration and morbidity in cystic fibrosis. This is an update of a previously published review. Objectives To assess the effectiveness of treatment with oral non‐steroidal anti‐inflammatory drugs in cystic fibrosis. Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, hand searches of relevant journals and abstract books of conference proceedings. We contacted manufacturers of non‐steroidal anti‐inflammatory drugs and searched online trials registries. Latest search of the Group's Trials Register: 21 November 2018. Selection criteria Randomized controlled trials comparing oral non‐steroidal anti‐inflammatory drugs, at any dose for at least two months, to placebo in people with cystic fibrosis. Data collection and analysis Two authors independently assessed trials for inclusion the review and their potential risk of bias. Two authors independently rated the quality of the evidence for each outcome using the GRADE guidelines. Main results The searches identified 17 trials; four are included (287 participants aged five to 39 years; maximum follow‐up of four years) and one is currently awaiting classification pending publication of the full trial report and two are ongoing. Three trials compared ibuprofen to placebo (two from the same center with some of the same participants); one trial assessed piroxicam versus placebo. The three ibuprofen trials were deemed to have good or adequate methodological quality, but used various outcomes and summary measures. Reviewers considered measures of lung function, nutritional status, radiological assessment of pulmonary involvement, intravenous antibiotic usage, hospital admissions, survival and adverse effects. Combined data from the two largest ibuprofen trials showed a lower annual rate of decline for lung function, % predicted forced expiratory volume in one second (FEV₁), mean difference (MD) 1.32 (95% confidence interval (CI) 0.21 to 2.42) (moderate‐quality evidence); forced vital capacity (FVC), MD 1.27 (95% CI 0.26 to 2.28) (moderate‐quality evidence); forced expiratory flow (FEF_25%‐75%), MD 1.80 (95% CI 0.15 to 3.45). The post hoc analysis of data from two trials split by age showed a slower rate of annual decline of FEV₁ % predicted and FVC in the ibuprofen group in younger children, MD 1.41% (95% CI 0.03 to 2.80) (moderate‐quality evidence) and MD 1.32% (95% CI 0.04 to 2.60) (moderate‐quality evidence) respectively. Data from four trials demonstrated the proportion of participants with at least one hospitalization may be slightly lower in the ibuprofen group compared to placebo, Peto odds ratio 0.61 (95% CI 0.37 to 1.01) (moderate‐quality evidence). In one trial, long‐term use of high‐dose ibuprofen was associated with reduced intravenous antibiotic usage, improved nutritional and radiological pulmonary status. No major adverse effects were reported, but the power of the trials to identify clinically important differences in the incidence of adverse effects was low. We did not have any concerns with regards to risk of bias for the trial comparing piroxicam to placebo. However, the trial did not report many data in a form that we could analyze in this review. No data were available for the review's primary outcome of lung function; available data for hospital admissions showed no difference between the groups. No analyzable data were available for any other review outcome. Authors' conclusions High‐dose ibuprofen can slow the progression of lung disease in people with cystic fibrosis, especially in children, which suggests that strategies to modulate lung inflammation can be beneficial for people with cystic fibrosis.

Rationale: Cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in human skeletal muscle cells. Variations of CFTR dysfunction among patients with cystic fibrosis may be an important determinant of maximal exercise capacity in cystic fibrosis. Previous studies on the relationship between CFTR genotype and maximal exercise capacity are scarce and contradictory. Objectives: This study was designed to explore factors influencing maximal exercise capacity, expressed as peak oxygen uptake (V. o2peak), with a specific focus on CFTR genotype in children and adults with cystic fibrosis. Methods: In an international, multicenter, cross-sectional study, we collected data on CFTR genotype and cardiopulmonary exercise tests in patients with cystic fibrosis who were ages 8 years and older. CFTR mutations were classified into functional classes I–V. Results: The final analysis included 726 patients (45% females; age range, 8–61 yr; forced expiratory volume in 1 s, 16 to 123% predicted) from 17 cystic fibrosis centers in North America, Europe, Australia, and Asia, all of whom had both valid maximal cardiopulmonary exercise tests and complete CFTR genotype data. Overall, patients exhibited exercise intolerance (V. o2peak, 77.3 ± 19.1% predicted), but values were comparable among different CFTR classes. We did not detect an association between CFTR genotype functional classes I–III and either V. o2peak (percent predicted) (adjusted β = −0.95; 95% CI, −4.18 to 2.29; P = 0.57) or maximum work rate (Wattmax) (adjusted β = −1.38; 95% CI, −5.04 to 2.27; P = 0.46) compared with classes IV–V. Those with at least one copy of a F508del-CFTR mutation and one copy of a class V mutation had a significantly lower V. o2peak (β = −8.24%; 95% CI, −14.53 to −2.99; P = 0.003) and lower Wattmax (adjusted β = −7.59%; 95% CI, −14.21 to −0.95; P = 0.025) than those with two copies of a class II mutation. On the basis of linear regression analysis adjusted for relevant confounders, lung function and body mass index were associated with V. o2peak. Conclusions: CFTR functional genotype class was not associated with maximal exercise capacity in patients with cystic fibrosis overall, but those with at least one copy of a F508del-CFTR mutation and a single class V mutation had lower maximal exercise capacity.

Progressive lung damage causes most deaths in cystic fibrosis. Non-steroidal anti-inflammatory drugs (such as ibuprofen) may prevent progressive pulmonary deterioration and morbidity in cystic fibrosis. To assess the effectiveness of treatment with non-steroidal anti-inflammatory drugs in cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, hand searches of relevant journals and abstract books of conference proceedings. We contacted manufacturers of non-steroidal anti-inflammatory drugs. Latest search of the Group's Trials Register: 04 February 2016. Randomized controlled trials comparing oral non-steroidal anti-inflammatory drugs, at any dose for at least two months, to placebo in people with cystic fibrosis. Two authors independently assessed trials for inclusion the review and their potential risk of bias. The searches identified 10 trials; four are included (287 participants aged five to 39 years; maximum follow up of four years) and one is currently awaiting classification pending publication of the full trial report. Three trials compared ibuprofen to placebo (two from the same centre with some of the same participants); one trial assessed piroxicam versus placebo. The three ibuprofen trials were deemed to have good or adequate methodological quality, but used various outcomes and summary measures. Reviewers considered measures of lung function, nutritional status, radiological assessment of pulmonary involvement, intravenous antibiotic usage, hospital admissions, survival and adverse effects. Combined data from the two largest ibuprofen trials showed a significantly lower annual rate of decline for lung function, percent predicted forced expiratory volume in one second mean difference 1.32 (95% confidence interval 0.21 to 2.42); forced vital capacity mean difference 1.27 (95% confidence interval 0.26 to 2.28); forced expiratory flow (25-75%) mean difference 1.80 (95% confidence interval 0.15 to 3.45). The post-hoc analysis of data from two trials split by age showed a statistically significant slower rate of annual decline of percent predicted forced expiratory volume in one second and forced vital capacity in the ibuprofen group in younger children, mean difference 1.41% (95% confidence interval 0.03 to 2.80) and mean difference 1.32% (95% confidence interval 0.04 to 2.60) respectively. In one trial, long-term use of high-dose ibuprofen was associated with reduced intravenous antibiotic usage, improved nutritional and radiological pulmonary status. No major adverse effects were reported, but the power of the trials to identify clinically important differences in the incidence of adverse effects was low. We did not have any concerns with regards to risk of bias for the trial comparing piroxicam to placebo. However, the trial did not report many data in a form that we could analyse in this review. No data were available for the review's primary outcome of lung function; available data for hospital admissions showed no difference between the groups. No analysable data were available for any other review outcome. High-dose ibuprofen can slow the progression of lung disease in people with cystic fibrosis, especially in children, which suggests that strategies to modulate lung inflammation can be beneficial for people with cystic fibrosis. 口服非甾体抗炎药物治疗囊性纤维化肺病 进行性肺损伤导致大多数囊性纤维化患者死亡。非甾体抗炎药(如布洛芬)可以防止进行性肺囊性纤维化恶化和发病率。 评估非甾体抗炎药治疗囊性纤维化的有效性。 我们搜查了Cochrane囊性纤维化和遗传疾病组试验注册库，包括引用识别综合电子数据库搜索试验注册,及手动搜索相关的期刊和会议论文集摘要。我们联系了非甾体抗炎药的制造商。 最新检索截止日期为2016年2月4日。 比较口服非甾体抗炎药与安慰剂对照的随机对照试验。剂量：任何剂量，疗程：至少两个月,纳入患者：囊性纤维化患者。 两位作者独立筛选试验并评价其潜在偏倚。 本系统综述筛选了10个试验；其中4个试验为(5到39岁，287名参与者，最大跟进四年)，1个试验还未被分类，需要等到完整数据报告公布之后再做判断。三个试验比较布洛芬与安慰剂(两个来自同一中心，涉及一些相同的参与者)；一个试验评估了吡罗昔康对比安慰剂。 三个布洛芬试验被认为方法学质量很好，但使用不同的结果和总结措施。我们将肺功能指标、营养状态、放射性肺参与评估、静脉注射抗生素使用情况、住院、生存和不利影响纳入为结局指标。两个最大的布洛芬试验的合并数据显示，布洛芬组年肺功能下降率显著降低，预计在1秒钟用力呼气量百分比平均差1.32(95%可信区间0.21到2.42)；最大肺活量均差1.27(95%可信区间0.26到2.28),用力呼气流量(25-75%)均差为1.80(95%可信区间0.15到3.45)。两个试验的数据年龄分割的因果分析显示统计上显著的年度百分比下降的速度较慢,预计在1秒钟用力呼气量和最大肺活量在年幼的儿童,布洛芬组平均差1.41%(95%可信区间0.03到2.80)和平均差分别为1.32%(95%可信区间0.04到2.60)。一个试验显示，长期使用高剂量的布洛芬可减少静脉注射抗生素的使用，改善营养和放射性肺的影像。没有主要的不良反应报告，但临床试验尚不能确定此药物副作用发生率很低。 我们没有任何关于比较吡罗昔康和安慰剂偏倚。但是，试验没有报告很多可被我们分析的数据。没有可用的检查肺功能的主要结果数据；数据显示两组住院率没有区别。没有可以用于其他综述结局分析的数据。...

Whey protein (WP) from cow’s milk is a rich source of essential and branched chain amino acids. Whey protein isolates (WPI) has been demonstrated to support muscle accretion, antioxidant activity, and immune modulation. However, whey is not readily digestible due to its tight conformational structure. Treatment of WPI with hyperbaric pressure results in protein unfolding. This enhances protein digestion, and results in an altered spectrum of released peptides, and greater release of essential and branched chain amino acids. Pressurized whey protein isolates (pWPI), through a series of cell culture, animal models and clinical studies, have been demonstrated to enhance muscle accretion, reduce inflammation, improve immunity, and decrease fatigue. It is also conceivable that pWPI would be more accessible to digestive enzymes, which would allow for a more rapid proteolysis of the proteins and an increased or altered release of small bioactive peptides. The altered profile of peptides released from WP digestion could thus play a role in the modulation of the immune response and tissue glutathione (GSH) concentrations. The research to date presents potentially interesting applications for the development of new functional foods based on hyperbaric treatment of WPI to produce products with more potent nutritional and nutraceutical properties.

Whey proteins have well-established antioxidant and anti-inflammatory bioactivities. High hydrostatic pressure processing of whey protein isolates increases their in vitro digestibility resulting in enhanced antioxidant and anti-inflammatory effects. This study compared the effects of different digestion protocols on the digestibility of pressurized (pWPI) and native (nWPI) whey protein isolates and the antioxidant and anti-inflammatory properties of the hydrolysates. The pepsin-pancreatin digestion protocol was modified to better simulate human digestion by adjusting temperature and pH conditions, incubation times, enzymes utilized, enzyme-to-substrate ratio and ultrafiltration membrane molecular weight cut-off. pWPI showed a significantly greater proteolysis rate and rate of peptide appearance regardless of digestion protocol. Both digestion methods generated a greater relative abundance of eluting peptides and the appearance of new peptide peaks in association with pWPI digestion in comparison to nWPI hydrolysates. Hydrolysates of pWPI from both digestion conditions showed enhanced ferric-reducing antioxidant power relative to nWPI hydrolysates. Likewise, pWPI hydrolysates from both digestion protocols showed similar enhanced antioxidant and anti-inflammatory effects in a respiratory epithelial cell line as compared to nWPI hydrolysates. These findings indicate that regardless of considerable variations of in vitro digestion protocols, pressurization of WPI leads to more efficient digestion that improves its antioxidant and anti-inflammatory properties.