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BACKGROUND: Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with reduced biventricular end-diastolic volumes and increased morbidity and mortality. The combination of a long-acting beta agonist (LABA) and a muscarinic antagonist (LAMA) is more effective in reducing hyperinflation than LABA-inhaled corticosteroid combination therapy but whether dual bronchodilation improves cardiac function is unknown. METHODS: We did a double-blind, randomised, two-period crossover, placebo-controlled, single-centre study (CLAIM) at the Fraunhofer Institute of Toxicology and Experimental Medicine (Hannover, Germany), a specialty clinic. Eligible participants were patients aged at least 40 years with COPD, pulmonary hyperinflation (defined by a baseline residual volume >135% of predicted), a smoking history of at least ten pack-years, and airflow limitation (FEV1

Einleitung: Kardiovaskuläre Erkrankungen sind bedeutende Komorbiditäten der COPD mit einem signifikanten Einfluss auf Morbidität und Mortalität. Dabei ist insbesondere Lungenüberblähung mit verminderten kardialen Volumina und reduziertem Herzzeitvolumen assoziiert. Die CLAIM Studie untersucht den Einfluss der Entblähung der Lunge mit dem dualen Bronchodilatator Indacaterol/Glycopyrronium (IND/GLY) auf die kardiale Funktion bei COPD Patienten mit erhöhtem Residualvolumen. Methoden: CLAIM ist eine monozentrische, randomisierte, doppelt-blinde, Placebo-kontrollierte cross-over Studie. COPD Patienten mit erhöhtem Residualvolumen und ohne klinisch signifikante kardiovaskuläre Erkrankungen wurden auf eine von zwei möglichen Behandlungssequenzen (IND/GLY 110/50 µg inhalativ q.d. gefolgt von Placebo oder umgekehrt) randomisiert. Primärer Endpunkt war die Veränderung im linksventrikulären enddiastolischen Volumen (LVEDV) gemessen mittels MRI nach 14-tägiger Behandlung. Ergebnisse: Von 62 randomisierten Patienten mit symptomatischer COPD und erhöhtem Residualvolumen durchliefen 57 beide Behandlungsphasen. IND/GLY führte zu einer klinisch relevanten und statistisch signifikanten Verbesserung der Lungenfunktion und des Residualvolumens (-0.75 L [95% CI: -0,93 bis -0,58; p

Rationale Cardiovascular diseases such as heart failure are common comorbidities of chronic obstructive pulmonary disease (COPD) and have a significant impact on morbidity and mortality. Lung hyperinflation detrimentally affects cardiac function in COPD patients and pharmacological deflation of the lung improves lung function and cardiac end-diastolic volumes. Here we show the effect of lung deflation and subsequent improvement of cardiac function on patient reported outcomes such as health status and symptoms in hyperinflated COPD patients. Methods In this randomized, double-blind, single-center, placebo-controlled, 2 period cross-over trial, COPD patients with increased residual volume (RV > 135 % pred.) and without relevant cardiovascular disease were enrolled. Primary outcome was the change in left-ventricular end-diastolic volume (LVEDV) measured with MRI after 14 days of treatment with indacaterol/glycopyrronium (IND/GLY, 110/50 µg q.d.) or placebo. Health status was assessed using the COPD assessment test (CAT) score and dyspnea was assessed with the baseline/transition dyspnea index (BDI/TDI) score. Results 62 patients were randomized, of which 57 completed both treatment periods. Treatment with IND/GLY significantly increased cardiac end-diastolic volumes, cardiac output and lung function measures vs. placebo. Improvement of end-diastolic volumes and lung function was associated with a statistical significant and clinically relevant increase in CAT and TDI scores. Changes in both scores remarkably exceeded the minimal clinically important difference after 14 days of treatment with LS means treatment differences versus placebo of -3.6 points (95% CI: -5.1, -2.2; P

GC-MS and GC-MS/MS methods were developed and validated for the quantitative determination of ibuprofen (do-ibuprofen), a non-steroidal anti-inflammatory drug (NSAID), in human plasma using alpha-methyl-H-2(3)-4-(isobutyl)phenylacetic acid (d(3)-ibuprofen) as internal standard. Plasma (10 mu L) was diluted with acetate buffer (80 mu L, 1 M, pH 4.9) and d(0)- and d(3)-ibuprofen were extracted with ethyl acetate (2 x 500 mu L). After solvent evaporation and d(0)- d(3)-ibuprofen were derivatized in anhydrous acetonitrile by using pentafluorobenzyl (PFB) bromide and N,N-diisopropylethylamine as the base catalyst. Under electron-capture negative-ion chemical ionization (ECNICI), the PFB esters of d(0)- and d(3)-ibuprofen readily ionize to form their carboxylate anions [M-PFB](-) at m/z 205 and m/z 208, respectively. Collision-induced dissociation (CID) of m/z 205 and m/z 208 resulted in the formation of the anions at m/z 161 and m/z 164, respectively, due to neutral loss of CO2 (44 Da). A collision energy-dependent H/D isotope effect was observed, which involves abstraction/elimination of H- from d(0)-ibuprofen and D- from d(3)-ibuprofen and is minimum at a CE value of 5 eV. Quantitative GC-MS determination was performed by selected-ion monitoring of m/z 205 and m/z 208. Quantitative GC-MS/MS determination was performed by selected-reaction monitoring of the mass transitions m/z 205 to m/z 161 for d(0)-ibuprofen and m/z 208 to m/z 164 for d(3)-ibuprofen. In a therapeutically relevant concentration range (0-1000 mu M) d(0)-ibuprofen added to human plasma was determined with accuracy (recovery, %) and imprecision (relative standard deviation, %) ranging between 93.7 and 110%, and between 0.8 and 4.9%, respectively. GC-MS (y) and GC-MS/MS (x) yielded almost identical results (y = 4.00 + 0.988x, r(2) = 0.9991). In incubation mixtures of arachidonic acid (10 mu M), d(3)-ibuprofen (10 mu M) or d(0)-ibuprofen (10 mu M) with ovine cyclooxygenase (COX) isoforms 1 and 2, the concentration of d(3)-ibuprofen and d(0)-ibuprofen did not change upon incubation at 37 degrees C up to 60 min. The trough pharmacokinetics of an inhaled arginine-containing ibuprofen preparation in mice was studied after once-daily treatment (0.0, 0.07, 0.4 and 2.5 mg/kg body weight) for three days. A linear relationship between ibuprofen concentration in serum (10 mu L) and administered dose 24h after the last drug administration was observed.