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Neutrophil elastase inhibitors: recent advances in the development of mechanism-based and nonelectrophilic inhibitors.

Due to its implication in pathologies of prevalent diseases such as chronic obstructive pulmonary disease, fibrosis, bronchiectasis and ARDS, the serine protease, human neutrophil elastase, has been in focus for drug-development efforts over the last two decades.

In recent years, continued efforts to identify and optimize novel mechanism-based inhibitors have led to a number of new inhibitors being reported. These compounds show promising potency and selectivity profiles, although their use is still limited by their inherent stability. Recently, two novel classes of potent and selective, synthetic, nonelectrophilic human neutrophil elastase inhibitors that display improved stability and overall drug-like properties have been reported.

The most advanced compound from these classes, AZD9668, has been reported to show significant effects on relevant biomarkers in bronchiectasis and cystic fibrosis patient populations.

Effect of Bronchial Colonisation on Airway and Systemic Inflammation in Stable COPD.

The recovery of potentially pathogenic microorganisms (PPMs) from bronchial secretions is associated with a local inflammatory response in COPD patients. The objective of this study was to determine the relationships between bronchial colonisation and both bronchial and systemic inflammation in stable COPD.

In COPD patients recruited on first admission for an exacerbation, bacterial sputum cultures, interleukin (IL)-1β, IL-6 and IL-8 levels, and blood C-reactive protein (CRP) were measured in stable condition. Bronchial colonisation was found in 39 of the 133 (29%) patients and was significantly related to higher sputum IL-1β (median [percentile 25-75]; 462 [121-993] vs. 154 [41-477] pg/ml, p = 0.002), IL-6 (147 [71-424] vs. 109 [50-197] pg/ml, p = 0.047) and IL-8 values (15 [9-19] vs. 8 [3-15] (×103) pg/ml, p = 0.002). Patients with positive cultures also showed significantly elevated levels of serum CRP (6.5 [2.5-8.5] vs. 3.5 [1.7-5.4] mg/l, p = 0.016). Bronchial colonisation by Haemophilus influenzae was associated with higher levels of IL-1β and IL-8 and clinically significant worse scores on the activity and impact domains of the St. George's Respiratory Questionnaire.

In conclusion, bronchial colonisation is associated with bronchial inflammation and high blood CRP levels in stable COPD patients, being Haemophilus influenzae related to a more severe inflammatory response and impairment in health-related quality of life.

Substantial need for early diagnosis, rehabilitation and treatment of chronic obstructive pulmonary disease.

Our goal was to estimate the number of individuals with chronic obstructive pulmonary disease (COPD) in the Capital Region of Denmark and the need of resources required to implement the regional management programme for COPD.

MATERIAL AND METHODS: We examined a total of 45,970 participants from the Copenhagen General Population Study (CGPS) using spirometry and a questionnaire.

RESULTS: The prevalence of spirometrically defined COPD among individuals older than 40 years of age was 15%, corresponding to 120,000 citizens in the Region. The number of individuals with moderate COPD (forced expiratory volume in one second (FEV1): 50-80% of predicted value) was estimated to approx. 51,000 (6.4%), whereas at least 10,000 (1.3%) were expected to have severe or very severe COPD (FEV1 < 50% of predicted value). Our estimates indicate that more than 26,000 individuals with moderate, severe or very severe COPD in the Region are smokers and that more than 19,000 qualify for physical training. We estimated that approx. 4,000 individuals with severe COPD were not treated with any inhaled medication.

CONCLUSION: The Capital Region of Denmark needs to allocate substantial resources into early detection, rehabilitation and medical treatment of individuals with COPD in order to comply with the intentions of the Region's own management programme for COPD.
FUNDING: The present analyses were sponsored by a grant from the Danish Ministry of Health. The CGPS was supported by the Copenhagen County Foundation, the Danish Medical Research Council and the Boserup Foundation.

Vitamin D status is associated with bone mineral density and functional exercise capacity in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is associated with several extrapulmonary effects that contribute to the severity of the disease. Vitamin D is suggested to play a role in COPD and its related extrapulmonary effects.

Aims. To determine the prevalence of vitamin D deficiency and its relation with bone density, muscle strength, and exercise capacity in patients with COPD.

Methods. Our cross-sectional study included patients with moderate to very severe COPD. We collected data on lung function, body composition, bone density, quadriceps muscle strength, 6-minute walking distance, and plasma 25-hydroxyvitamin D (25(OH)D) concentration. Vitamin D deficiency was defined as plasma 25(OH)D concentration below 50 nmol/L.

Results. In total, 151 COPD patients were included; 87 patients (58%) had vitamin D deficiency. Plasma 25(OH)D concentration was positively associated with bone density (P = 0.005) and 6-minute walking distance (P < 0.001) after adjustment for potential confounders. Plasma 25(OH)D concentration was not associated with quadriceps muscle strength.

Conclusions. The majority of COPD patients had vitamin D deficiency. Plasma 25(OH)D concentration was positively associated with bone density and exercise capacity. Intervention studies are necessary to determine whether vitamin D supplementation is of benefit in the prevention or treatment of osteoporosis and poor exercise capacity in patients with COPD.

Determination of inflammatory biomarkers in patients with COPD: A comparison of different assays.

Chronic obstructive pulmonary disease (COPD) is an inflammatory pulmonary disorder with systemic inflammatory manifestations that are mediated by circulating acute-phase reactants. This study compared an enzyme-linked immunosorbent assay (ELISA) to a nephelometric technique for the measurement of serum C-reactive protein (CRP) and serum amyloid A (SAA) and investigated how the choice of assay influenced the estimation of inflammation in patients with stable COPD.

METHODS: CRP and SAA concentrations measured by ELISA and nephelometry in 88 patients with COPD and 45 control subjects were used to evaluate the performance of these methods in a clinical setting.

RESULTS: With both assays, the concentrations of CRP and SAA were higher in COPD patients than in controls after adjustment for age and sex. There was a moderate correlation between the values measured by ELISA and those measured by nephelometry (logCRP: r = 0.55, p < 0.001; logSAA: r = 0.40, p < 0.001). However, the concentrations of biomarkers determined by nephelometry were significantly higher than those obtained with ELISA for CRP (mean difference = 2.7 (9.4) mg/L) and SAA (mean difference = 0.31 (14.3) mg/L).

CONCLUSION: Although the serum CRP and SAA concentrations measured by ELISA and nephelometry correlated well in COPD patients, the ELISA values tended to be lower for CRP and SAA when compared with nephelometric measurements. International standardization of commercial kits is required before the predictive validity of inflammatory markers for patients with COPD can be effectively assessed in clinical practice.

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