Efficacy of the pan-selectin antagonist Bimosiamose on ozone-induced airway inflammation in healthy subjects--a double blind, randomized, placebo-controlled, cross-over clinical trial.

Selectins, a family of cell adhesion molecules, are involved in the activation and extravasation of leukocytes in inflammatory diseases. Inhalation of ozone induces an inflammation of the airways, which is dominated by neutrophils. We investigated the effect of repeated inhalations of the pan-selectin antagonist Bimosiamose on ozone-induced airway inflammation in healthy volunteers. In a double-blind, placebo-controlled, randomized, cross-over study Bimosiamose (10 mg bid) was inhaled via a breath actuated nebulizer (AKITA2 APIXNEB(®)) for 4 days. Treatment was followed by inhalation of ozone (250 ppb) for 3 h with intermittent exercise. Induced sputum was collected 3 h post ozone challenge for analysis of cellular and non-cellular composition. 18 subjects were randomized and completed the study. All treatments were safe and well tolerated. Compared to placebo Bimosiamose reduced the numbers of sputum neutrophils by 40% (p = 0.068) and concentrations of interleukin-8 and matrix-metalloproteinase-9 in sputum supernatant by 35% (p = 0.004) and 46% (p = 0.022), respectively. Inhalation of Bimosiamose showed favourable anti-inflammatory effects on ozone-induced airway inflammation in healthy volunteers. Further studies have to proof and translate this anti-inflammatory effect of Bimosiamose into a clinical benefit in patients with chronic obstructive pulmonary disease. (ClinTrialgov Ident: NCT01108913).

Pharmacokinetics of Nintedanib in Subjects With Hepatic Impairment.

Nintedanib is an intracellular inhibitor of tyrosine kinases used in the treatment of non-small cell lung cancer and idiopathic pulmonary fibrosis (IPF). This phase 1 open-label study investigated the influence of mild and moderate hepatic impairment on the pharmacokinetics (PK), safety, and tolerability of nintedanib following oral administration of a single 100-mg dose. Subjects with hepatic impairment classified as Child-Pugh A (mild hepatic impairment) or Child-Pugh B (moderate hepatic impairment) were eligible. The control group comprised healthy matched subjects. Primary end points were Cmax and AUC0-∞ of nintedanib. Thirty-three subjects received nintedanib (8 in each of the Child-Pugh A and Child-Pugh B groups and 17 controls). The shape of the plasma concentration-time curve for nintedanib was similar between Child-Pugh A or B and healthy subjects. Nintedanib exposure was ∼2-fold higher in Child-Pugh A subjects and ∼8-fold higher in Child-Pugh B subjects than in healthy subjects. Adverse events were reported in 3 Child-Pugh B subjects (37.5%), no Child-Pugh A subjects, and 3 healthy subjects (17.6%). In conclusion, exposure to nintedanib was higher in Child-Pugh A and B subjects than in matched healthy subjects. A single dose of nintedanib 100 mg had an acceptable safety and tolerability profile in subjects with hepatic impairment. Results of this dedicated phase 1 study are in line with exploratory investigations into the PK of nintedanib in patients with advanced solid tumors or IPF and hepatic impairment.

Decreasing cardiac chamber sizes and associated heart dysfunction in COPD: role of hyperinflation.

BACKGROUND: Little is known about the role of abnormal lung function in heart size and heart dysfunction in patients with COPD. We studied the relationship of lung function with heart size and heart dysfunction and associated consequences for 6-min walk distance (6MWD) in patients with COPD of different severitites. METHODS: In 138 patients with COPD (Global Initiative for Obstructive Lung Disease [GOLD] I-IV), we measured the size of all cardiac chambers, left ventricular diastolic dysfunction (relaxation and filling), and global right ventricular dysfunction (Tei-index) by echocardiography. We also measured lung function (spirometry, body plethysmography, and diffusion capacity) and 6MWD. RESULTS: The size of all cardiac chambers decreased with increasing GOLD stage. Overall, moderate relationships existed between variables of lung function and cardiac chamber sizes. Static hyperinflation (inspiratory-to-total lung capacity ratio [IC/TLC], functional residual capacity, and residual volume) showed stronger associations with cardiac chamber sizes than airway obstruction or diffusion capacity. IC/TLC correlated best with cardiac chamber sizes and was an independent predictor of cardiac chamber sizes after adjustment for body surface area. Patients with an IC/TLC < or = 0.25 had a significantly impaired left ventricular diastolic filling pattern and a significantly impaired Tei-index compared with patients with an IC/TLC > 0.25. An impaired left ventricular diastolic filling pattern was independently associated with a reduced 6MWD. CONCLUSIONS: An increasing rate of COPD severity is associated with a decreasing heart size. Hyperinflation could play an important role regarding heart size and heart dysfunction in patients with COPD.

The metabolic syndrome in patients with chronic bronchitis and COPD: frequency and associated consequences for systemic inflammation and physical inactivity.

BACKGROUND: The metabolic syndrome is a condition frequently found among individuals > 60 years of age. It predisposes affected individuals to systemic inflammation and physical inactivity. Systemic inflammation and physical inactivity are relevant extrapulmonary markers of morbidity and mortality in patients with COPD. Here, we studied the following: (1) the frequency of the coexisting metabolic syndrome in patients with chronic bronchitis (CB) and COPD of different severities; and (2) its association with systemic inflammation and physical inactivity. METHODS: In 30 patients with CB (normal spirometry finding) and in 170 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages I to IV), we measured the characteristics of the metabolic syndrome, systemic inflammation (high-sensitivity C-reactive protein [hs-CRP], interleukin-6, fibrinogen), and the physical activity level. RESULTS: The frequencies of the metabolic syndrome in patients with CB, GOLD stages I, II, III, and IV, were 53%, 50%, 53%, 37%, and 44%, respectively (average, 47.5%). The levels of hs-CRP and interleukin-6 were significantly increased in patients with the metabolic syndrome, while the physical activity level was significantly decreased. Multivariate linear regression analyses revealed metabolic syndrome, physical activity level, and CB/GOLD stages to be independent predictors of hs-CRP and interleukin-6 levels, and physical activity level to be a predictor of fibrinogen levels. CONCLUSIONS: In our study, almost one-half of the patients with CB/COPD had coexisting metabolic syndrome, with a slightly lower frequency in patients with severe COPD. The coexisting metabolic syndrome is associated with an increase in the levels of some systemic inflammatory markers and physical inactivity, independent of lung function impairment.