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Köln, Germany

Walterspacher S.,University Hospital Freiburg | Walker D.J.,University Hospital Freiburg | Kabitz H.-J.,University Hospital Freiburg | Windisch W.,Lungenklinik Merheim | Dreher M.,University Hospital Freiburg
COPD: Journal of Chronic Obstructive Pulmonary Disease | Year: 2013

Stair climbing is associated with dynamic pulmonary hyperinflation and the development of severe dyspnea in patients with chronic obstructive pulmonary disease (COPD). This study aimed to assess whether (i) continuous positive airway pressure (CPAP) applied during stair climbing prevents dynamic hyperinflation and thereby reduces exercise-induced dyspnea in oxygen-dependent COPD-patients, and (ii) the CPAP-device and oxygen tank can be carried in a hip belt. In a randomised cross-over design, oxygen-dependent COPD patients performed two stair-climbing tests (44 steps): with supplemental oxygen only, then with the addition of CPAP (7 mbar). The oxygen tank and CPAP-device were carried in a hip belt during both trials. Eighteen COPD patients were included in the study. Although all patients could tolerate stair climbing with oxygen alone, 4 patients were unable to perform stair climbing while using CPAP. Fourteen COPD patients (mean FEV1 36 ± 14% pred.) completed the trial and were analyzed. The mean flow rate of supplemental oxygen was 3 ± 2 l/min during stair climbing. Lung hyperinflation, deoxygenation, hypoventilation, blood lactate production, dyspnea and the time needed to manage stair climbing were not improved by the application of CPAP (all p > 0.05). However, in comparison to climbing with oxygen alone, limb discomfort was reduced when oxygen was supplemented with CPAP (p = 0.008). In conclusion, very severe COPD patients are able to carry supporting devices such as oxygen tanks or CPAP-devices in a hip belt during stair climbing. However, the application of CPAP in addition to supplemental oxygen during stair climbing prevents neither exercise-induced dynamic hyperinflation, nor dyspnea. © 2013 Informa Healthcare USA, Inc. Source


Kasper B.,University of Heidelberg | Scharrenbroich I.,Lungenklinik Merheim | Schmitt T.,University of Heidelberg | Wuchter P.,University of Heidelberg | And 3 more authors.
Bone Marrow Transplantation | Year: 2010

Prognosis of patients with metastatic soft tissue sarcoma remains poor. Whether high-dose chemotherapy with stem cell support improves the long-term outcome for these patients is debatable. We present a prospective, single-institutional phase II study that enrolled 34 soft tissue sarcoma patients with advanced and/or metastatic disease. After four courses of chemotherapy consisting of doxorubicin and ifosfamide, responding patients in at least partial response (PR) were treated with high-dose chemotherapy (n9); all other patients continued chemotherapy for two more cycles. After standard chemotherapy, PR (n10), stable disease (SD, n6) and progressive disease (PD, n14) were attained for the evaluable patients. Twenty-nine patients died and five are alive with the disease. Median PFS was 11.6 months (range 8-15) for patients treated with high-dose chemotherapy (n9) vs 5.6 months (range 0-19) for patients treated with standard chemotherapy. Median OS was 23.7 months (range 12-34) vs 10.8 months (range 0-39), respectively. The subgroup of patients treated with high-dose chemotherapy gained significant survival benefit. Nevertheless, high-dose chemotherapy as a possible consolidation strategy remains highly investigational. © 2010 Macmillan Publishers Limited All rights reserved. Source


Knobloch J.,University of Cologne | Sibbing B.,University of Cologne | Jungck D.,University of Cologne | Lin Y.,University of Cologne | And 4 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

Chronic obstructive pulmonary disease (COPD) therapy is complicated by corticosteroid resistance of the interleukin 8 (IL-8)-dependent and granulocyte macrophage-colony stimulating factor (GM-CSF)-dependent chronic airway inflammation, for whose establishment human airway smooth muscle cells (HASMCs) might be crucial. It is unclear whether the release of inflammatory mediators from HASMCs is modulated by cigarette smoking and is refractory to corticosteroids in COPD. Resveratrol, an antiaging drug with protective effects against lung cancer, might be an alternative to corticosteroids in COPD therapy. Vascular endothelial growth factor (VEGF) might offer protection from developing emphysema. We tested the following hypotheses for HASMCs: 1) smoking with or without airway obstruction modulates IL-8, GM-CSF, and VEGF release; and 2) corticosteroids, but not resveratrol, fail to inhibit cytokine release in COPD. Cytokine release from HASMCs exposed to tumor necrosis factor α (TNFα), dexamethasone, and/or resveratrol was measured via enzyme-linked immunosorbent assay and compared between nonsmokers (NS), smokers without COPD (S), and smokers with COPD (all n = 10). In response to TNFα, IL-8 release was increased, but GM-CSF and VEGF release was decreased in S and COPD compared with NS. Dexamethasone and resveratrol inhibited concentration-dependently TNFα-induced IL-8, GM-CSF, and VEGF release. For IL-8 and GM-CSF efficiency of dexamethasone was NS > S > COPD. That of resveratrol was NS=S=COPD for IL-8 and NS= S < COPD for GM-CSF. For VEGF the efficiency of dexamethasone was NS = S = COPD, and that of resveratrol was NS = S > COPD. All resveratrol effects were partially based on p38 mitogen-activated protein kinase blockade. In conclusion, smoking modulates cytokine release from HASMCs. Corticosteroid refractoriness of HASMCs in COPD is cytokine-dependent. Resveratrol might be superior to corticosteroids in COPD therapy, because it more efficiently reduces the release of inflammatory mediators and has limited effects on VEGF in COPD. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics. Source


Kabitz H.-J.,University Hospital Freiburg | Bremer H.-C.,Schwarzwald Baar Klinikum Donaueschingen | Schwoerer A.,University Hospital Freiburg | Sonntag F.,University Hospital Freiburg | And 6 more authors.
Lung | Year: 2014

Purpose: Increased dyspnea and reduced exercise capacity in pulmonary arterial hypertension (PAH) can be partly attributed to impaired respiratory muscle function. This prospective study was designed to assess the impact of exercise and respiratory training on respiratory muscle strength and 6-min walking distance (6MWD) in PAH patients. Methods: Patients with invasively confirmed PAH underwent 3 weeks of in-hospital exercise and respiratory training, which was continued at home for another 12 weeks. Medication remained constant during the study period. Blinded observers assessed efficacy parameters at baseline (I) and after 3 (II) and 15 weeks (III). Respiratory muscle function was assessed by twitch mouth pressure (TwPmo) during nonvolitional supramaximal magnetic phrenic nerve stimulation. Results: Seven PAH patients (4 women; mean pulmonary artery pressure 45 ± 11 mmHg, median WHO functional class 3.1 ± 0.4, idiopathic/associated PAH n = 5/2) were included. The training program was feasible and well tolerated by all patients with excellent compliance. TwPmo was I: 0.86 ± 0.37 kPa, II: 1.04 ± 0.29 kPa, and III: 1.27 ± 0.44 kPa, respectively. 6MWD was I: 417 ± 51 m, II: 509 ± 39 m, and III: 498 ± 39 m, respectively. Both TwPmo (+0.41 ± 0.34 kPa, +56 ± 39 %) and 6MWD (+81 ± 30 m, +20 ± 9 %) increased significantly in the period between baseline and the final assessment (pairwise comparison: p = 0.012/<0.001; RM-ANOVA considering I, II, III: p = 0.037/<0.001). Conclusions: Exercise and respiratory training as an adjunct to medical therapy may be effective in patients with PAH to improve respiratory muscle strength and exercise capacity. Future, randomized, controlled trials should be carried out to further investigate these findings. © 2013 Springer Science+Business Media. Source


Knobloch J.,University Hospital Bergmannsheil | Feldmann M.,University Hospital Bergmannsheil | Wahl C.,University Hospital Bergmannsheil | Jungck D.,University Hospital Bergmannsheil | And 3 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

Bacterial infections induce exacerbations in chronic lung diseases, e.g., chronic obstructive pulmonary disease (COPD), by enhancing airway inflammation. Exacerbations are frequently associated with right heart decompensation and accelerate disease progression. Endothelin receptor antagonists (ERAs) might have therapeutic potential as pulmonary vasodilators and anti-inflammatory agents, but utility in exacerbations of chronic lung diseases is unknown. We hypothesized that cytokine releases induced by lipopolysaccharide (LPS), the major bacterial trigger of inflammation, are reduced by ERAs in pulmonary vascular smooth muscle cells (PVSMCs). Ex vivo cultivated human PVSMCs were preincubated with the endothelin-A-receptor selective inhibitor ambrisentan, with the endothelin-B-receptor selective inhibitor BQ788 [sodium (2R)-2- {[(2S)-2-({[(2R,6S)-2,6-dimethyl-1-piperidinyl]carbonyl}amino)- 4,4-dimethylpentanoyl][1-(methoxycarbonyl)-D-tryptophyl]amino} hexanoate], or with the dual blocker bosentan before stimulation with smooth LPS (S-LPS), rough LPS (Re-LPS), or a mixture of long and short forms (M-LPS). Expression of cytokines and LPS receptors (TLR4, CD14) were analyzed via enzyme-linked immunosorbent assay (ELISA) and/or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). All LPS forms induced interleukin (IL)-6-, IL-8-, and granulocyte macrophage- colony stimulating factor (GM-CSF) release. Bosentan and BQ788 inhibited M-LPS-induced release of all cytokines and soluble CD14 (sCD14) but not TLR4 expression. Ambrisentan blocked M-LPS-induced IL-6 release but not IL-8, GM-CSF, or LPS receptors. IL-8 release induced by S-LPS, which requires CD14 to activate TLR4, was blocked by bosentan and BQ788. IL-8 release induced by Re-LPS, which does not require CD14 to activate TLR4, was insensitive to both bosentan and BQ788. In conclusion, PVSMCs contribute to inflammation in bacteriainduced exacerbations of chronic lung diseases. Inhibition of the endothelin-B receptor suppresses cytokine release induced by long/smooth LPS attributable to sCD14 downregulation. ERAs, particularly when targeting the endothelin-B receptor, might have therapeutic utility in exacerbations of chronic lung diseases. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics. Source

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