Phase II study of a neutrophil elastase inhibitor (AZD9668) in patients with bronchiectasis

SummaryNeutrophil elastase (NE) activity is increased in bronchiectasis and may play a role in this condition. We wished to determine the effect of AZD9668, a selective oral inhibitor of NE.Efficacy and safety of AZD9668 60 mg twice daily over 4 weeks were evaluated in a randomised, double-blind, placebo-controlled, parallel-group, Phase II, signal-searching study in patients with bronchiectasis. Outcome measures included: waking and post-waking sputum neutrophil counts; lung function tests; 24-h sputum weight; BronkoTest® diary card data; St George's Respiratory Questionnaire for COPD patients (SGRQ-C); sputum NE activity; inflammatory biomarker levels; desmosine levels; adverse events, safety haematology and biochemistry. AZD9668 levels in plasma and sputum were measured to confirm exposure.Thirty-eight patients were randomised: 16 to placebo and 22 to AZD9668. There was no change in sputum neutrophils with AZD9668. Forced expiratory volume in 1 s improved by 100 mL in the AZD9668 group compared with placebo (p = 0.006). Significant changes (defined a priori as p < 0.1) in favour of AZD9668 were also seen in slow vital capacity, plasma interleukin-8, and post-waking sputum interleukin-6 and Regulated on Activation, Normal T-cell Expressed and Secreted levels. Non-significant changes in favour of AZD9668 were seen in other lung function tests, sputum weight and the SGRQ-C. AZD9668 was well tolerated.In this small signal-searching study, 4 weeks' treatment with AZD9668 improved lung function in patients with bronchiectasis and there were trends for reductions in sputum inflammatory biomarkers. Larger studies of longer duration would be needed to confirm the potential benefits of this agent in bronchiectasis.Registration: NCT00769119

Cloning, characterization and immunolocalization of human ameloblastin

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93555/1/j.1600-0722.2000.108004303.x.pd

Quantitative high-performance liquid chromatography-tandem mass spectrometry method for the analysis of free desmosines in plasma and urine

A rapid method for the determination of the sum of free desmosine and isodesmosine in human plasma and urine is described. Efficient sample clean-up prior to LC-MS/MS analysis is mandatory for detection of free desmosines in plasma samples. The combination of ultra-filtration and a two-step solid phase extraction minimizes the sample complexity and ion suppression effects. The flow through from the ultra filtration is passed through a C18 resin and then the target analytes are trapped and enriched on a mixed mode solid phase extraction material. The combination of these three orthogonal sample preparation steps allows detection of endogenous free desmosines in plasma from healthy individuals. An analytical column packed with porous graphitic carbon material enables the retention of the polar desmosine analytes, which are measured by electrospray ionization tandem mass spectrometry. Deuterium labeled isodesmosine is added as internal standard and a linear calibration curve was constructed in the range of 0.1-2.0 nmol/L for plasma samples and 5-200 nmol/L for urine samples. These results demonstrate that the described LC-MS/MS method provides sensitive, repeatable and accurate quantification of free desmosines in plasma and urine samples. (C) 2013 Elsevier B.V. All rights reserved

Blood biomarkers and measures of pulmonary function-A study from the Swedish twin registry.

OBJECTIVE: There is great need of biomarkers for research and clinical purposes in COPD. This study explored the relationships between ten putative plasma biomarkers of COPD and physiological measures of reduced lung function. METHODS: FEV(1), FVC, residual volume/total lung capacity (RV/TLC) and CO diffusion capacity (D(L)CO) were assessed in 357 subjects from the Swedish Twin Registry. The lung function measures were studied in relation to plasma levels of desmosines, C-reactive protein (CRP), plasminogen inhibitor activator (PAI-1) concentration and activity, tissue inhibitor of metalloproteinase (TIMP-1), clara cell protein 16 (CC16), surfactant protein D (SPD), matrix metalloproteinase 9 (MMP-9), hepatocyte growth factor (HGF) and interleukin (IL)-8. RESULTS: After adjustments for age, sex, height, BMI and smoking, FEV(1) was significantly associated with PAI-1 activity and desmosines. RV/TLC was significantly associated with CC16, PAI-1 concentration and PAI-1 activity, and D(L)CO was significantly associated with desmosines, TIMP-1 and CRP. When the multivariate analysis was restricted to subjects with COPD (i.e., FEV(1)/FVC < 0.70), CRP and desmosines were inversely associated with lung function. CONCLUSION: Several biomarkers were associated with lung function in this cross-sectional study. Especially CRP and desmosines could be useful markers to assess disease severity in subjects with COPD

Twins studies as a model for studies on the interaction between smoking and genetic factors in the development of chronic bronchitis

Smoking is the main risk factor for COPD (chronic obstructive pulmonary disease) but genetic factors are of importance, since only a subset of smokers develops the disease. Sex differences have been suggested both in disease prevalence and response to environmental exposures. Furthermore, it has been shown that acquisition of 'addiction' to smoking is partly genetically mediated. Disease cases and smoking habits were identified in 44919 twins aged > 40 years from the Swedish Twin Registry. Disease was defined as self-reported chronic bronchitis or emphysema, or recurrent cough with phlegm. The results showed that chronic bronchitis seems to be more prevalent among females, and that the heritability estimate for chronic bronchitis was a moderate 40% and only 14% of the genetic influences were shared by smoking. In addition, 392 twins have been invited to a clinical investigation to evaluate: (i) to what extent genetic factors contribute to individual differences (variation) in FEV1 (forced expiratory volume in 1 s), vital capacity and l (diffusion capacity), taking sex into consideration, and (ii) whether smoking behaviour and respiratory symptoms influence these estimates