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Biomedical subjects

Tobias Welte

Publications and source records attributed to Tobias Welte.

At least 19 recordsLinked to original sources
PubMed2007

Does beta-blocker treatment influence central sleep apnoea?

UNLABELLED: Chronic severe heart failure is frequently associated with disturbances in the central control of breathing. During wakefulness, central breathing disorders could be ameliorated with beta-blocker treatment, but nothing is known about the effects of beta-blockers on the control of breathing during sleep. This study intends to determinate the prevalence and severity of nocturnal apnoeas and hypopnoeas in heart failure patients treated with or without metoprolol or carvedilol. Fifty consecutive patients with dilated cardiomyopathy in NYHA class II-IV with a left ventricular ejection fraction (LVEF) of 35% or below were studied with full polysomnography over one night. The mean Apnoea-Hypopnoea Index of beta-blocker free patients was 19.8+/-14.2 versus 7.4+/-8.5 (p<0.05) and 8.7+/-8.1 (p<0.05) in patients treated with metoprolol or carvedilol, respectively. The arousal index, sleep quality, and daytime sleepiness were improved in similar magnitude. CONCLUSION: Long-term treatment of patients with advanced chronic heart failure with sufficient doses of metoprolol or carvedilol is associated with a lower prevalence and severity of central sleep apnoea (CSA).

Adrenergic beta-Antagonists↗
PubMed2006

Ertapenem in critically ill patients with early-onset ventilator-associated pneumonia: pharmacokinetics with special consideration of free-drug concentration.

OBJECTIVES: Most information about pharmacokinetics of antimicrobial agents is obtained from studies in healthy volunteers. However, antibiotics are therapeutically used in infected patients with very different pharmacokinetic properties compared with healthy individuals. PATIENTS AND METHODS: In a single-centre, prospective, open-label study, 17 adult critically ill patients with early-onset ventilator-associated pneumonia (VAP) were treated with 1 g of ertapenem infusion once a day. Blood and urine samples were collected before and at different time-points up to 24 h after medication on day 1. Concentrations of ertapenem in plasma were determined with a validated HPLC method. Free-drug concentrations were estimated using a two-class binding site equation. RESULTS: The overall clinical success rate of the assessable cases was 66.7% (12/16). Pharmacokinetic parameters of ertapenem in our critically ill patients were clearly different when compared to those reported in the literature for healthy volunteers. The enhanced V(z) (17 vs. 8 L) and CL(TOT) (43 vs. 20 mL/min) with resulting lower C(max) (90 vs. 253 mg/L) and AUC(0-infinity) (418 vs. 817 mg x h/L) values were mainly related to hypoalbuminaemia (range 9.2-25.6 g/L) in our patient population. A population pharmacokinetic analysis using the NONMEM program indicated creatinine clearance as a significant covariate for explaining the between-subject variability of ertapenem in the patient population. Estimated free plasma concentrations of ertapenem exceeded a MIC(90) of 2 mg/L only for 6 h (25%) after infusion. CONCLUSIONS: For an adequate dose adjustment of highly protein-bound drugs like ertapenem, knowledge of actual albumin concentrations is necessary. A shortening of the dosage interval or continuous infusion of ertapenem should be considered to ensure optimal free concentrations in critically ill patients with severe hypoalbuminaemia and normal renal function.

Adult↗
PubMed2006

[Pathomechanisms in chronic obstructive pulmonary disease (COPD)].

Chronic obstructive pulmonary disease (COPD) is one of the most common chronic diseases worldwide, and its morbidity and mortality are still increasing. Thus, it is expected that, globally, COPD will be the third most common cause of death by 2020. Moreover, COPD leads to enormous health-economic costs (i. e., outpatient and inpatient treatment, inability to work). Nevertheless, the prevalence of COPD is underestimated also in Germany. This is partly because often, the disease is symptomatic only in its advanced stages and as a result it is not diagnosed until late. In addition, the therapeutic effects on the long-term course and the progression of the disease are limited. Therefore, a much deeper understanding of the manifold and complex pathomechanisms of this pathomorphologically varied disease is needed before new therapeutic strategies can be developed. The aim of this review is to discuss current concepts of the pathophysiology of COPD and their scientific bases. The authors will concentrate mainly on a differentiated description of the pathomechanisms which cause chronic obstructive bronchiolitis and obstructive pulmonary emphysema.

Antioxidants↗
PubMed2006

Ultrastructural types of alveolar macrophages in bronchoalveolar lavages from patients with pulmonary sarcoidosis.

By routine applied quantitative BAL methods are particularly helpful for the diagnosis of pulmonary sarcoidosis. Here the morphology of the alveolar cells does not play a role. However, morphological and especially electron microscopic investigations might contribute to the clarification of the aetiology of this disease. In a prospective study we investigated the bronchoalveolar lavages (BALs) from 10 patients with recently histologically diagnosed, untreated pulmonary sarcoidosis. Commonly applied cytological and immunological BAL diagnostic techniques were accompanied by morphological investigations of alveolar cells, especially alveolar macrophages, using light and electron microscopy. All patients showed lymphocytic alveolitis with an increased number of CD4 positive lymphocytes as well as an increased CD4/CD8 ratio. A striking light microscopic finding was the great morphological variety of the alveolar macrophages. Electron microscopy revealed typical lymphocytes, neutrophils, and eosinophils as well as three different types of alveolar macrophages in all 10 patients: type I (approx. 30%) with a normal macrophage morphology, a vacuole-rich type II (approx. 30%) with myelin-like structures and type III (approx. 40%) with electron-dense inclusions. The occurrence of intracellular myelin figures in type II macrophages is a hint for increased phagocytotic processes of surfactant with or without its overproduction in the sense of a secondary alveolar proteinosis. Numerous electron-dense inclusions in type III also indicate an increased macrophage activity that leads to an increased release of cytokines, which in turn can trigger an inflammatory reaction.

Adult↗
PubMed2006

Mediator responses of alveolar macrophages and kinetics of mononuclear phagocyte subset recruitment during acute primary and secondary mycobacterial infections in the lungs of mice.

Little is known about the activation programme induced in alveolar macrophages upon phagocytosis of mycobacteria and the concomitant mononuclear phagocyte migratory responses that shape the acute phase of mycobacterial infection. Using high-speed cell sorting in conjunction with real-time RT-PCR analysis, we show that sorted alveolar macrophages of transgenic CX3CR1+/GFP mice infected with red fluorescent-labelled Mycobacterium bovis BCG exhibited weak transcriptional changes of lysosomal cathepsins B, L, D, K and S, whereas antimicrobial cathepsin G was strongly induced upon infection. Moreover, mRNA levels of pattern recognition receptors TLR2, TLR4 and NOD2 were downregulated as were neutrophil chemoattractants KC, MIP-2 and IP-10, whereas highly upregulated mRNA levels of the monocyte chemoattractant CCL2 were observed. M. bovis BCG infection of the mice elicited the alveolar accumulation of highly CX3CR1-positive alveolar dendritic cells but not neutrophils within the alveolar compartment, whereas no increased accumulation of CX3CR1high lung parenchymal dendritic cells (lung DC) or CX3CR1neg lung macrophages compared with controls was noted. In contrast, CX3CR1+/GFP mice previously immunized with M. bovis BCG rapidly responded with increased accumulations of both CX3CR1high alveolar and lung parenchymal DC and CX3CR1neg lung macrophages upon intratracheal M. bovis BCG challenge. Moreover, alveolar and lung macrophages and lung DC were found to contribute to early uptake of M. bovis BCG. Together, acute mycobacterial infection triggers both rapid changes in gene expression profiles in infected alveolar macrophages and a compartment-specific accumulation of mononuclear phagocyte subsets contributing to M. bovis BCG uptake in vivo.

Animals↗
PubMed2006

Antibiotic treatment of community acquired pneumonia varies widely across Germany.

UNLABELLED: Community Acquired Pneumonia (CAP) is a frequent and potentially fatal infectious disease which, in the majority of cases, needs an antibiotic intervention. OBJECTIVES: Aim was to evaluate antibiotic treatment patterns regarding all types of mono- and combination-therapy throughout the local clinical centres (LCCs) represented in the German competence network CAPNETZ (=Community Acquired Pneumonia Network) and to identify clinical indicators for regional differences. METHODS: We analysed outpatients and inpatients recruited between March 2003 and April 2005. Patient and treatment details were registered online using standardised data entry forms. A logistic regression model was issued for the 4 most frequently applied antibiotics, adjusting for potentially relevant confounders. RESULTS: The study sample consisted of 3221 patients at the age of 18 to 102 years. Overall, aminopenicillins plus betalactamase inhibitor (20.4%), fluoroquinolone (17.0%), macrolides combined with cephalosporins third generation (10.6%) and cephalosporins third generation (8.9%) were most frequently prescribed. After control for potential confounders, significant treatment differences remained between study sites. Regional variability of antibiotic CAP-treatment could not be attributed to a number of clinical or sociodemographic factors. CONCLUSIONS: The presented treatment variability ranges within given guidelines, but indicates the need for an ongoing implementation of evidence-based guidelines in order to avoid potential negative clinical or economic consequences.

Adolescent↗
PubMed2006

Once-daily tobramycin in cystic fibrosis: better for clinical outcome than thrice-daily tobramycin but more resistance development?

OBJECTIVES: Once-daily administration of aminoglycosides in cystic fibrosis (CF) patients is considered equally efficacious and potentially less nephrotoxic than dosing three times a day. However, the choice of the most suitable PK/PD index (C(max)/MIC versus AUC(24)/MIC) to ensure optimum clinical outcome in this patient population is not clear. PATIENTS AND METHODS: In a single-centre, open, randomized, controlled, non-blinded study 33 adult CF patients (20 females, 19-37 years) were treated with intravenous tobramycin (10 mg/kg/day) for 14 days given either as single dose once a day (Q24; 17 patients) or divided into three equal doses every 8 h (Q8; 16 patients). Tobramycin serum concentrations and MICs for Pseudomonas aeruginosa were determined on days 1 and 14. The clinical outcome parameter, correlated to PK/PD indices, was the percentage predicted forced expiratory volume in 1 s (FEV(1)% pred.). RESULTS: FEV(1)% pred. improved significantly for both treatments. There was a log-linear relationship between C(max)/MIC and FEV(1)% pred. and AUC/MIC and FEV(1)% pred. for both treatments. For equal values of AUC24/MIC, however, Q24 treatment provided better improvement in lung function than Q8 dosing, whereas C(max)/MIC did not show any dosing interval dependence. A statistically significant increase was observed for MIC (day 1) versus MIC (day 14) for Q24 treatment, however, no such difference was observed for Q8 treatment. CONCLUSIONS: The most important PK/PD parameter for clinical outcome in CF patients was C(max)/MIC. Outcome prediction of AUC(24)/MIC was dependent on the regimen. The increase of P. aeruginosa resistance after once-daily administration is linked to a long dosing interval. More and larger studies are needed to optimize the dosing regimen for maximum clinical outcome with minimum resistance development.

Adult↗
PubMed2006

Impact of the suctioning system (open vs. closed) on the incidence of ventilation-associated pneumonia: Meta-analysis of randomized controlled trials.

OBJECTIVE: Ventilation-associated pneumonia (VAP) is a serious complication of patients in intensive care units (ICU) who require mechanical ventilation. The choice of suctioning system (open vs. closed) remains unresolved in evidence-based guidelines. This meta-analysis was carried out to analyze the effect of the type of suctioning system on the incidence of VAP. DESIGN: A search of the literature was used to identify randomized controlled trials addressing this question. A meta-analysis was then performed to calculate the relative risk of ventilation-associated pneumonia acquisition with the two suctioning systems. RESULTS: Nine trials were included, with 648 patients in the open suctioning group and 644 in the closed suctioning group. VAP occurred in 128 (20%) of the open suctioning group and in 120 (19%) in the closed suctioning group (relative risk 0.95). CONCLUSIONS: At a given pneumonia prevalence of 20% in ICU patients there was no significant advantage for the use of either suctioning system in this meta-analysis. The choice of suctioning system should therefore be based on handling, cost, and individual patient's disease until more data are available.

Cross Infection↗
PubMed2006

Analysis of airway secretions in a model of sulfur dioxide induced chronic obstructive pulmonary disease (COPD).

Hypersecretion and chronic phlegm are major symptoms of chronic obstructive pulmonary disease (COPD) but animal models of COPD with a defined functional hypersecretion have not been established so far. To identify an animal model of combined morphological signs of airway inflammation and functional hypersecretion, rats were continuously exposed to different levels of sulfur dioxide (SO2, 5 ppm, 10 ppm, 20 ppm, 40 ppm, 80 ppm) for 3 (short-term) or 20-25 (long-term) days. Histology revealed a dose-dependent increase in edema formation and inflammatory cell infiltration in short-term-exposed animals. The submucosal edema was replaced by fibrosis after long-term-exposure. The basal secretory activity was only significantly increased in the 20 ppm group. Also, stimulated secretion was significantly increased only after exposure to 20 ppm. BrdU-assays and AgNOR-analysis demonstrated cellular metaplasia and glandular hypertrophy rather than hyperplasia as the underlying morphological correlate of the hypersecretion. In summary, SO2-exposure can lead to characteristic airway remodeling and changes in mucus secretion in rats. As only long-term exposure to 20 ppm leads to a combination of hypersecretion and airway inflammation, only this mode of exposure should be used to mimic human COPD. Concentrations less or higher than 20 ppm or short term exposure do not induce the respiratory symptom of hypersecretion. The present model may be used to characterize the effects of new compounds on mucus secretion in the background of experimental COPD.

Journal Article↗
PubMed2006

[What is new in the treatment of community-acquired pneumonia?].

Community-acquired pneumonia (CAP) is the most important infectious disease in Germany. After 3 years of data recording, the country-wide competence network CAPNETZ presents reliable data on etiology and course of the disease, based on more than 3,500 prospectively observed patients. In the acute phase, lethality is as high as nearly 10%, and in the 6-month follow-up period after the acute infection, lethality is > 15%. A reliable detection of the underlying pathogen is possible in less than half of all patients studied. The most frequent pathogens are Streptococcus pneumoniae (40%), Haemophilus influenzae, and Mycoplasma pneumoniae (8% each). Legionella (3%) and Chlamydia pneumoniae (< 1%) are rarely found, and gram-negative enterobacteriaceae (< 5%) are restricted to high-risk patient groups (nursing home, multimorbidity). CAPs due to pneumococci, legionella or enterobacteriaceae were associated with increased lethality. Problems with resistances had not been found in Germany, except for a decreasing susceptibility of S. pneumoniae to macrolides. Viruses could be detected in nearly 15% of all pneumonia patients. The CRB-65 score allows a reliable discrimination between patients with a high and low risk of dying. The new S3 guideline for diagnosis and treatment of CAP recommends a risk-adapted treatment. Low-risk patients shall receive a monotherapy with, e. g., amoxicillin, high-risk patients should be treated with a broad-spectrum combination therapy (beta-lactam and macrolide).

Age Factors↗
PubMed2006

Asthma and COPD.

The two obstructive airway diseases bronchial asthma and chronic obstructive pulmonary disease (COPD) represent major global causes of disability and death, and COPD is estimated to become the third most common cause of death by 2020. The structural and pathophysiologic findings in both diseases appear to be easily differentiated in the extremes of clinical presentation. However, a significant overlap may exist in individual patients regarding features such as airway wall thickening on computer tomography or reversibility and airway hyperresponsiveness in lung function tests. Airway inflammation differs between the two diseases. In bronchial asthma, airway inflammation is characterized in most cases by an increased number of activated T-lymphocytes, particularly CD4+ Th2 cells, and sometimes eosinophils and mast cells. The most notable difference of chronic severe asthma compared with mild to moderate asthma is an increased number of neutrophils. In stable COPD, airway inflammation is characterized by an increased number of T-lymphocytes, particularly CD8+ T cells, macrophages and neutrophils. With the progression of the disease severity, macrophage and neutrophil numbers increase. Although there may be a partial overlap between asthma and COPD in some patients, the differences in functional, structural and pharmacological features clearly demonstrate the consensus that asthma and COPD are different diseases along all their stages of severity.

Animals↗
PubMed2006

Novel strategies of aerosolic pharmacotherapy.

The pulmonary administration of drugs plays a crucial role in the management of various respiratory and systemic diseases. While the cellular properties of airway epithelial cells offer a great potential to deliver drugs into the lungs or the circulation, only little is known about the exact transport pathways. Recently, the high-affinity proton-coupled drug and peptide transporter PEPT2 was identified in the human respiratory tract. The expression of transporter mRNA and protein was localized to the airway epithelium and alveolar type II pneumocytes. In addition, transport studies revealed transporter-mediated uptake of substrates into epithelial cells indicating that the transporter is the molecular basis for the transport of peptides and peptidomimetic drugs in pulmonary epithelial cells. Since genotype analysis revealed no significant differences amongst different transporter genotypes concerning expression and function, the transporter displays an interesting novel target for pulmonary delivery of drugs.

Administration, Inhalation↗
PubMed2006

Resident alveolar macrophages are replaced by recruited monocytes in response to endotoxin-induced lung inflammation.

In the acute respiratory distress syndrome, recruitment of peripheral blood monocytes results in expansion of the total pool of resident alveolar macrophages. The fate of resident macrophages, or whether recruited monocytes are selectively eliminated from the alveolar airspace or differentiate into resident alveolar macrophages during the resolving phase of inflammation, has not been determined. Here, we analyzed the kinetics of resident and recruited macrophage turnover within the alveolar airspace of untreated and LPS-challenged mice. Using bone marrow chimeric CD45.2 mice that were generated by lethal irradiation of CD45.2 alloantigen-expressing recipient mice and bone marrow transplantation from CD45.1 alloantigen-expressing donor mice, we employed a flow cytometric approach to distinguish recipient from donor-type macrophages in bronchoalveolar lavage fluids. Our data show that resident alveolar macrophages of untreated chimeric CD45.2 mice are very slowly replaced by constitutively immigrating CD45.1 positive monocytes, resulting in a replacement rate of approximately 40% by 1 yr. In contrast, more than 85% of the resident CD45.2 positive alveolar and lung homogenate macrophages were exchanged by donor CD45.1-expressing macrophages within 2 mo after treatment with Escherichia coli endotoxin (LPS). Importantly, fluorescence-activated cell sorter analysis of increased annexin V binding to both recipient and donor-type macrophages revealed increased apoptotic events to underlie this endotoxin-driven inflammatory macrophage turnover. Collectively, the data show that under baseline conditions the alveolar macrophage turnover exhibits very slow kinetics, whereas acute lung inflammation in response to treatment with LPS triggers a brisk acceleration of recruitment of monocytes that replace the resident alveolar macrophage population.

Animals↗
PubMed2006

Fibroblasts of recipient origin contribute to bronchiolitis obliterans in human lung transplants.

RATIONALE: The participation of circulating precursor cells in the development of experimental pulmonary fibrosing lesions in mice has been recently demonstrated. OBJECTIVES: This study analyzes whether circulating, bone marrow-derived, fibroblastic precursor cells contribute to the development of fibrosing lesions in human lungs, especially bronchiolitis obliterans. METHODS: The occurrence of in situ microchimerism in bronchiolitis obliterans lesions of human lung allografts (n = 12) as well as of autologous lung tissue from patients post-bone marrow transplantation (n = 2) was analyzed using laser-assisted microdissection after immunohistochemical labeling of leukocytes followed by short tandem repeat-polymerase chain reaction-based genotyping. Combined immunofluorescence and fluorescence in situ hybridization for sex chromosomes was performed for independent confirmation in cases with appropriate sex mismatch (n = 2). MEASUREMENTS AND MAIN RESULTS: The bronchiolitis obliterans lesions of all 12 lung transplant patients contained considerable numbers of recipient-derived fibroblasts (mean, 32%). The fibrosing pulmonary lesions of the two bone marrow-transplanted patients also displayed clear in situ microchimerism. The in situ detection methodology confirmed these results, although to a lower degree (6-16%). CONCLUSIONS: These data clearly demonstrate the involvement of circulating fibroblastic precursor cells in the development of human fibrosing lung lesions and provide evidence that these cells are most probably bone marrow derived. These results may open new venues regarding the prevention of fibrosis in lung transplants and potentially in other organs.

Adult↗
PubMed2006

A new simple HPLC assay for the quantification of ertapenem in human plasma, lung tissue, and broncho-alveolar lavage fluid.

Ertapenem is an important newer broad-spectrum carbapenem antibiotic covering various infections caused by common gram-positive and -negative aerobes and anaerobes. Due to its physicochemical peculiarities, pharmacokinetic data of other carbapenems are of limited value in predicting ertapenem distribution into particular compartments of the body. This raises demand for detailed pharmacokinetic studies and, as a consequence, rapid and specific ways of analysis. The HPLC assays for the quantification of ertapenem in biological matrices reported so far are based on columns of 4.6mm I.D. and involve pre-concentration by use of column-switching. However, automated column-switching technique is not standard equipment with all analytical laboratories. Furthermore, signal-to-noise ratios are likely not to be sufficient for quantification of specimens of low concentration. Therefore, a new HPLC/UV method based on narrow-bore column design using sample pre-cleaning by liquid-liquid extraction has been developed. The assay is rapid for specimen concentrations > or =1 mg/l and is easily tuned to achieve low quantification limits at high chromatographic resolution for lower concentrated samples. The method has been successfully applied to plasma, serum, lung tissue or cell homogenates, and broncho-alveolar lavage fluid with lower limits of quantification of 40 and 20 microg/l, respectively. It was also used for the pharmacokinetic monitoring of ertapenem in humans.

Bronchoalveolar Lavage Fluid↗
PubMed2006

Endotoxin induced peritonitis elicits monocyte immigration into the lung: implications on alveolar space inflammatory responsiveness.

BACKGROUND: Acute peritonitis developing in response to gram-negative bacterial infection is known to act as a trigger for the development of acute lung injury which is often complicated by the development of nosocomial pneumonia. We hypothesized that endotoxin-induced peritonitis provokes recruitment of monocytes into the lungs, which amplifies lung inflammatory responses to a second hit intra-alveolar challenge with endotoxin. METHODS: Serum and lavage cytokines as well as bronchoalveolar lavage fluid cells were analyzed at different time points after intraperitoneal or intratracheal application of LPS. RESULTS: We observed that mice challenged with intraperitoneal endotoxin developed rapidly increasing serum and bronchoalveolar lavage fluid (BALF) cytokine and chemokine levels (TNFalpha, MIP-2, CCL2) and a nearly two-fold expansion of the alveolar macrophage population by 96 h, but this was not associated with the development of neutrophilic alveolitis. In contrast, expansion of the alveolar macrophage pool was not observed in CCR2-deficient mice and in wild-type mice systemically pretreated with the anti-CD18 antibody GAME-46. An intentional two-fold expansion of alveolar macrophage numbers by intratracheal CCL2 following intraperitoneal endotoxin did not exacerbate the development of acute lung inflammation in response to intratracheal endotoxin compared to mice challenged only with intratracheal endotoxin. CONCLUSION: These data, taken together, show that intraperitoneal endotoxin triggers a CCR2-dependent de novo recruitment of monocytes into the lungs of mice but this does not result in an accentuation of neutrophilic lung inflammation. This finding represents a previously unrecognized novel inflammatory component of lung inflammation that results from endotoxin-induced peritonitis.

Animals↗
PubMed2006

Nanomedicine for respiratory diseases.

Nanotechnology provides new materials in the nanometer range with many potential applications in clinical medicine and research. Due to their unique size-dependent properties nanomaterial such as nanoparticles offer the possibility to develop both new therapeutic and diagnostic tools. Thus, applied nanotechnology to medical problems--nanomedicine--can offer new concepts that are reviewed. The ability to incorporate drugs into nanosystems displays a new paradigm in pharmacotherapy that could be used for cell-targeted drug delivery. Nontargeted nanosystems such as nanocarriers that are coated with polymers or albumin and solid lipid particles have been used as transporter in vivo. However, nowadays drugs can be coupled to nanocarriers that are specific for cells and/or organs. Thus, drugs that are either trapped within the carriers or deposited in subsurface oil layers could be specifically delivered to organs, tumors and cells. These strategies can be used to concentrate drugs in selected target tissues thus minimizing systemic side effects and toxicity. In addition to these therapeutic options, nanoparticle-based "molecular" imaging displays a field in which this new technology has set the stage for an evolutionary leap in diagnostic imaging. Based on the recent progress in nanobiotechnology there is potential for nanoparticles and -systems to become useful tools as therapeutic and diagnostic tools in the near future.

Animals↗