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Biomedical subjects

U Beyer

Publications and source records attributed to U Beyer.

At least 19 recordsLinked to original sources
PubMed2003

Calibration of the viscometric glucose sensor before its use in physiological liquids--compensation for the colloid-osmotic effect.

The function of the recently described viscometric affinity sensor (VAS), which measures glucose due to its strong effect on the viscosity of a sensitive liquid containing Concanavalin A (ConA) and dextran, was analysed for osmotic and colloid-osmotic effects on the glucose reading. The suction of low- and high-molecular weight osmotica on the membrane of the microdialysis fibre was measured using a membrane osmometer built from the microdialysis probe of the VAS. The reduction of the sensor read-out in blood plasma can be completely explained by a change in small osmotic volume fluxes through the dialysis membrane, which affect the ConA concentration and the viscosity after the flow of the sensitive liquid through the dialysis probe. The measuring error could be prevented by the presence of the polyethylene glycol 6000 at an isotonic concentration in the glucose standard solutions used for sensor calibration.

Biosensing Techniques↗
PubMed2003

Ring-shaped vortex domain in type-II superconductors.

We present results of experiments in superconducting niobium and numerical simulations showing the creation of a metastable ring-shaped vortex domain by heating. Such vortex rings, if pinned by structural defects, can exist forever.

Journal Article↗
PubMed2001

Recording of subcutaneous glucose dynamics by a viscometric affinity sensor.

AIMS/HYPOTHESIS: To provide a nonenzymatic sensor for glucose monitoring in subcutaneous tissue. METHODS: A continuously working affinity sensor based on the glucose-dependent viscosity of a sensitive liquid containing dextran and concanavalin A has been designed by arranging a microdialysis probe, two flow-resisting capillaries and two pressure transducers in a linear flow system. It allows synchronous processing of the viscosity of the sensitive liquid at the standard glucose concentration and the glucose concentration to be measured. In preliminary human trials the sensor was implanted into the subcutaneous tissue of the forearm and its read-out was compared with capillary blood concentrations. RESULTS: In vitro, the viscometric sensor shows a linear and long-term stable dependence on the glucose concentration without detectable drift. At the applied flow rate of the sensitive liquid (about 5 microliters/h) the technical delay is 5 to 10 min. The read-out of the implanted sensor followed the dynamics of the capillary blood glucose concentrations with a time-shift of 10 to 15 min but showed a systematic error when based on precalibration with polymer-free glucose solutions. After appropriate in vivo calibration, the read-out was in good or acceptable coincidence with capillary blood concentrations according to the error grid method and did not show any detectable reduction of sensitivity during the periods of measurement (up to 44 h). CONCLUSION/INTERPRETION: The viscometric-affinity sensor is an efficient tool for current research on glucose monitoring in the subcutaneous tissue and can potentially be further developed for routine clinical use.

Blood Glucose↗
PubMed2001

Differences in the intracellular distribution of acid-sensitive doxorubicin-protein conjugates in comparison to free and liposomal formulated doxorubicin as shown by confocal microscopy.

PURPOSE: To investigate differences in the cellular uptake and intracellular distribution of protein-bound doxorubicin in comparison to free doxorubicin and a liposomal formulation (CAELYX) METHODS: LXFL 529 lung carcinoma cells were incubated with an acid-sensitive transferrin and albumin conjugate of doxorubicin, a stable albumin doxorubicin conjugate, and free and liposomal doxorubicin for up to 24 h. The uptake of doxorubicin was detected with confocal laser scanning microscopy (CLSM). To investigate the intracellular localization of the anticancer drug, lysosomes, Golgi apparatus, and mitochondria were also stained by various organelle-specific fluorescent markers. In vitro efficacy of the doxorubicin derivatives was examined with the BrdU incorporation assay. RESULTS: The acid-sensitive albumin and transferrin doxorubicin conjugates showed enhanced cytotoxicity in comparison to liposomal doxorubicin, whereas the stable albumin-doxorubicin conjugate showed only marginal activity. Of all compounds tested, doxorubicin showed the highest cytotoxicity. CLSM studies with specific markers for lysosomes, mitochondria, and the Golgi apparatus demonstrated that protein-bound doxorubicin or liberated doxorubicin was accumulated in the mitochondria and Golgi compartments, but not in the lysosomes after 24 h. Free doxorubicin showed a time-dependent intracellular shift from the nucleus to the mitochondria and Golgi apparatus. Fluorescence resulting from incubation with CAELYX was primarily detected in the nucleus. CONCLUSIONS: Our results indicate that other organelles in addition to the cell nucleus are important sites of accumulation and interaction for protein-bound doxorubicin or intracellularly released doxorubicin as well as for free doxorubicin.

Antineoplastic Agents↗
PubMed1999

Acid-sensitive polyethylene glycol conjugates of doxorubicin: preparation, in vitro efficacy and intracellular distribution.

Coupling anticancer drugs to synthetic polymers is a promising approach of enhancing the antitumor efficacy and reducing the side-effects of these agents. Doxorubicin maleimide derivatives containing an amide or acid-sensitive hydrazone linker were therefore coupled to alpha-methoxy-poly(ethylene glycol)-thiopropionic acid amide (MW 20000 Da), alpha,omega-bis-thiopropionic acid amide poly(ethylene glycol) (MW 20000 Da) or alpha-tert-butoxy-poly(ethylene glycol)-thiopropionic acid amide (MW 70000 Da) and the resulting polyethylene glycol (PEG) conjugates isolated through size-exclusion chromatography. The polymer drug derivatives were designed as to release doxorubicin inside the tumor cell by acid-cleavage of the hydrazone bond after uptake of the conjugate by endocytosis. The acid-sensitive PEG conjugates containing the carboxylic hydrazone bonds exhibited in vitro activity against human BXF T24 bladder carcinoma and LXFL 529L lung cancer cells with IC70 values in the range 0.02-1.5 microm (cell culture assay: propidium iodide fluorescence or colony forming assay). In contrast, PEG doxorubicin conjugates containing an amide bond between the drug and the polymer showed no in vitro activity. Fluorescence microscopy studies in LXFL 529 lung cancer cells revealed that free doxorubicin accumulates in the cell nucleus whereas doxorubicin of the acid-sensitive PEG doxorubicin conjugates is primarily localized in the cytoplasm. Nevertheless, the acid-sensitive PEG doxorubicin conjugates retain their ability to bind to calf thymus DNA as shown by fluorescence and visible spectroscopy studies. Results regarding the effect of an acid-sensitive PEG conjugate of molecular weight 20000 in the chorioallantoic membrane (CAM) assay indicate that this conjugate is significantly less embryotoxic than free doxorubicin although antiangiogenic effects were not observed.

Animals↗
PubMed1999

Drug-polymer conjugates containing acid-cleavable bonds.

Drug-polymer conjugates are potential candidates for the selective delivery of anticancer agents to tumor tissue. Incorporating acid-sensitive bonds between the drug and the polymer is an attractive approach because it ensures effective release of the polymer-bound drug at the tumor site. This release is either extracellular, resulting from the slightly acidic pH in tumor tissue, or intracellular, in acidic endosomes or lysosomes after cellular uptake of the drug-polymer conjugate. This paper reviews acid-sensitive drug-polymer conjugates developed during the past 20 years and outlines aspects for further development in this research field.

Alkylating Agents↗
PubMed1998

Synthesis and in vitro efficacy of transferrin conjugates of the anticancer drug chlorambucil.

One strategy for improving the selectivity and toxicity profile of antitumor agents is to design drug carrier systems employing soluble macromolecules or carrier proteins. Thus, five maleimide derivatives of chlorambucil were bound to thiolated human serum transferrin which differ in the stability of the chemical link between drug and spacer. The maleimide ester derivatives 1 and 2 were prepared by reacting 2-hydroxyethylmaleimide or 3-maleimidophenol with the carboxyl group of chlorambucil, and the carboxylic hydrazone derivatives 5-7 were obtained through reaction of 2-maleimidoacetaldehyde, 3-maleimidoacetophenone, or 3-maleimidobenzaldehyde with the carboxylic acid hydrazide derivative of chlorambucil. The alkylating activity of transferrin-bound chlorambucil was determined with the aid of 4-(4-nitrobenzyl)pyridine (NBP) demonstrating that on average 3 equivalents were protein-bound. Evaluation of the cytotoxicity of free chlorambucil and the respective transferrin conjugates in the MCF7 mammary carcinoma and MOLT4 leukemia cell line employing a propidium iodide fluorescence assay demonstrated that the conjugates in which chlorambucil was bound to transferrin through non-acid-sensitive linkers, i.e., an ester or benzaldehyde carboxylic hydrazone bond, were not, on the whole, as active as chlorambucil. In contrast, the two conjugates in which chlorambucil was bound to transferrin through acid-sensitive carboxylic hydrazone bonds were as active as or more active than chlorambucil in both cell lines. Especially, the conjugate in which chlorambucil was bound to transferrin through an acetaldehyde carboxylic hydrazone bond exhibited IC50 values which were approximately 3-18-fold lower than those of chlorambucil. Preliminary toxicity studies in mice showed that this conjugate can be administered at higher doses in comparison to unbound chlorambucil. The structure-activity relationships of the transferrin conjugates are discussed with respect to their pH-dependent acid sensitivity, their serum stability, and their cytotoxicity.

Animals↗
PubMed1998

Albumin conjugates of the anticancer drug chlorambucil: synthesis, characterization, and in vitro efficacy.

In our efforts to improve the selectivity and toxicity profile of antitumor agents, four maleimide derivatives of chlorambucil (1-4) were bound to thiolated human serum albumin which differ in the stability of the chemical link between drug and spacer. 1 is an aliphatic maleimide ester derivative of chlorambucil, whereas 2-4 are acetaldehyde, acetophenone, and benzaldehyde carboxylic hydrazone derivatives. HPLC stability studies at pH 5.0 with the related model compounds 5, 7, 8, and 9, in which chlorambucil was substituted by 4-phenylbutyric acid, demonstrated that the carboxylic hydrazone derivatives have acid-sensitive properties; the acid lability of 7 was particular prominent with a half-life of only a few hours. The alkylating activity of albumin-bound chlorambucil was determined with the aid of 4-(4-nitrobenzyl)-pyridine (NBP), demonstrating that on average three equivalents were protein-bound. Evaluation of the cytotoxicity of free chlorambucil and the respective albumin conjugates in the MCF7 mamma carcinoma and MOLT4 leukemia cell line employing a propidium iodide fluorescence assay demonstrated that the conjugate in which chlorambucil was bound to albumin through an ester bond was not as active as chlorambucil. In contrast, the conjugates in which chlorambucil was bound to albumin through carboxylic hydrazone bonds were as or more active than chlorambucil in both cell lines. In particular, the conjugate in which chlorambucil was bound to albumin through an acetaldehyde carboxylic hydrazone bond exhibited IC50 values which were approximately 4-fold (MCF7) to 13-fold (MOLT4) lower than those of chlorambucil. Preliminary toxicity studies in mice showed that this conjugate can be administered at higher doses in comparison to unbound chlorambucil.

Animals↗
PubMed1998

Transferrin conjugates of doxorubicin: synthesis, characterization, cellular uptake, and in vitro efficacy.

One strategy for improving the antitumor selectivity and toxicity profile of antitumor agents is to design drug carrier systems employing suitable carrier proteins. Thus, thiolated human serum transferrin was conjugated with four maleimide derivatives of doxorubicin that differed in the stability of the chemical link between drug and spacer. Of the maleimide derivatives, 3-maleimidobenzoic or 4-maleimidophenylacetic acid was bound to the 3'-amino position of doxorubicin through a benzoyl or phenylacetyl amide bond, and 3-maleimidobenzoic acid hydrazide or 4-maleimidophenylacetic acid hydrazide was bound to the 13-keto position through a benzoyl hydrazone or phenylacetyl hydrazone bond. The acid-sensitive transferrin conjugates prepared with the carboxylic hydrazone doxorubicin derivatives exhibited an inhibitory efficacy in the MDA-MB-468 breast cancer cell line and U937 leukemia cell line comparable to that of the free drug (employing the BrdU (5-bromo-2'-deoxyuridine) incorporation assay and tritiated thymidine incorporation assay, respectively, IC50 approximately 0.1-1 mM), whereas conjugates with the amide derivatives showed no activity. Furthermore, antiproliferative activity of the most active transferrin conjugate (i.e. the conjugate containing a benzoyl hydrazone link) was demonstrated in the LXFL 529 lung carcinoma cell line employing a sulforhodamine B assay. In contrast to in vitro studies in tumor cells, cell culture experiments performed with human endothelial cells (HUVEC) showed that the acid-sensitive transferrin conjugates of doxorubicin were significantly less active than free doxorubicin (IC50 values approximately 10-40 higher by the BrdU incorporation assay), indicating selectivity of the doxorubicin-transferrin conjugates for tumor cells. Fluorescence microscopy studies in the MDA-MB-468 breast cancer cell showed that free doxorubicin accumulates in the cell nucleus, whereas doxorubicin of the transferrin conjugates is found localized primarily in the cytoplasm. The differences in the intracellular distribution between transferrin-doxorubicin conjugates and doxorubicin were confirmed by laser scanning confocal microscopy in LXFL 529 cells after a 24 h incubation that revealed an uptake and mode of action other than intercalation with DNA. The relationship between stability, cellular uptake, and cytotoxicity of the conjugates is discussed.

Chromatography, High Pressure Liquid↗
PubMed1998

Preparation, characterization and in vitro efficacy of albumin conjugates of doxorubicin.

One strategy for improving the antitumor selectivity and toxicity profile of antitumor agents is to design drug carrier systems with suitable transport proteins. Thus, four maleimide derivatives of doxorubicin were bound to thiolated human serum albumin which differed in the stability of the chemical link between drug and spacer. In the maleimide derivatives, 3-maleimidobenzoic or 4-maleimidophenylacetic acid was bound to the 3'-amino position of doxorubicin through a benzoyl or phenylacetyl amide bond and 3-maleimidobenzoic acid hydrazide or 4-maleimidophenylacetic acid hydrazide was bound to the 13-keto position through a benzoyl hydrazone or phenylacetyl hydrazone bond. The acid-sensitive albumin conjugates prepared with the carboxylic hydrazone doxorubicin derivatives exhibited an inhibitory efficacy in the MDA-MB-468 breast cancer cell line and U937 leukemia cell line comparable with that of the free drug (using the BrdU-(5-bromo-2'-deoxyuridine)-incorporation assay and tritiated thymidine incorporation assay respectively, IC50 approximately 0.1-1 microM) whereas conjugates with the amide derivatives showed no or only marginal activity. These results demonstrate that antiproliferative activity depends on the nature of the chemical bond between doxorubicin and carrier protein. Acid-sensitive albumin conjugates are suitable candidates for further in vitro and in vivo assessment.

Antibiotics, Antineoplastic↗
PubMed1997

Large increase in cardiac output in a patient with ARDS and acute right heart failure during inhalation of nitric oxide.

BACKGROUND: Inhaled nitric oxide (NO), a selective pulmonary vasodilator, reduces pulmonary artery pressure in patients with acute respiratory distress syndrome (ARDS). In spite of the reduction of right ventricular afterload, the effect of NO on cardiac output remains unclear. METHODS: A patient with ARDS and echocardiographically determined severe acute right heart failure was treated with increasing concentrations of inhaled nitric oxide (NO). Haemodynamic and gas exchange variables were determined for each concentration of NO. NO treatment was continued for 3 days. RESULTS: During initial right heart failure, administration of NO resulted in a large increase (32%) in cardiac output in a dose-dependent manner. When right ventricular function had improved, inhalation of NO did not increase cardiac output. CONCLUSION: Our observations suggest that inhalation of NO is likely to increase cardiac output in ARDS when severe acute right heart failure is present.

Acute Disease↗
PubMed1996

Acute health effects of exposure to high levels of air pollution in eastern Europe.

Acute effects of winter-type air pollution characterized by high levels of SO2, moderate levels of particles, and low acidity were studied. A panel of 155 asthmatic children and 102 adults with a history of asthma from the former German Democratic Republic cities of Erfurt and Welmar and from the Czech Republic city of Sokolov participated from September 1990 through June 1992. The panelists recorded daily symptoms, medication intake, and peak expiratory flow (PEF). Statistical analysis was based on linear regression of population-averaged time series controlling for trend, meteorology, and autocorrelation. A temporospatial time series approach was also applied to the data to eliminate possible confounding by some known or unknown variables that occurred simultaneously in two of the study areas. Weak same-day effects and a stronger cumulative effect of air pollution on children was observed both for PEF and for symptoms. PEF decreased -0.90% (-1.35 to -0.46%), and a symptom score increased 14.7% (0.8-28.6%) in association with an average increase of 128 micrograms/m3 SO2 over the previous 5 days. Effects on adults were smaller and less consistent. Morbidity of children was best predicted by SO2 and sulfate concentrations. The authors conclude that prolonged, high exposure to winter-type pollution was associated with small adverse health effects in asthmatics.

Adolescent↗
PubMed1995

Inhaled nitric oxide reduces pulmonary transvascular albumin flux in patients with acute lung injury.

BACKGROUND: In acute lung injury, when pulmonary microvascular permeability is enhanced, transvascular fluid filtration mainly depends on pulmonary capillary pressure. Inhaled nitric oxide has been shown to decrease pulmonary capillary pressure. Therefore, the effect of inhaled nitric oxide at a concentration of 40 ppm on pulmonary transvascular albumin flux was studied in nine patients with acute lung injury. METHODS: Transvascular albumin flux was measured by a double radioisotope method using 99mTc-labeled albumin and 51Cr-labeled autologous red blood cells. Radioactivity of both isotopes was externally measured over the right lung by a gamma scanner and simultaneously in arterial blood. The normalized ratio of 99mTc/51Cr lung to 99mTc/51Cr blood (normalized index) was calculated. The normalized slope index which is the slope of the regression line of the normalized index versus time represents the accumulation rate of albumin in the interstitial space of the lungs. Normalized slope index and pulmonary capillary pressure were determined before, during, and after inhalation of 40 ppm nitric oxide. Pulmonary capillary pressure was estimated using the visual analysis of the pressure decay curve after pulmonary artery occlusion. RESULTS: Normalized slope index decreased from 0.0077 +/- 0.0054 min-1 (SD) off nitric oxide to -0.0055 +/- 0.0049 min-1 (P < 0.01) during nitric oxide and increased to 0.0041 +/- 0.0135 min-1 after nitric oxide. Pulmonary capillary pressure declined from 24 +/- 4 mmHg off nitric oxide to 21 +/- 4 mmHg during nitric oxide (P < 0.01), whereas pulmonary artery wedge pressure and cardiac output did not change. CONCLUSIONS: It is concluded that 40 ppm inhaled nitric oxide decreases pulmonary transvascular albumin flux in patients with acute lung injury. This effect may be the result of the decrease in pulmonary capillary pressure.

Acute Disease↗
PubMed1994

Indirect myocardial revascularization--an experimental study in the dog.

It has been shown in previous studies that grafting a free skeletal muscle flap onto the heart of the dog produces myocardial revascularization. In order to evaluate the functional aspect of these neovessels, an Ameroid constrictor was implanted into the LADs (left anterior descending coronary artery) of five dogs. At the same time, the free muscle flap was grafted onto the anterior wall of the heart. The arterial anastomosis was achieved with the internal mammary artery. Venous flow was drained into the right atrium. About 12 months later, the regional myocardial blood flow was evaluated adopting the radioactive microsphere technique. This was carried out with the LAD occluded by the Ameroid constrictor and the circumflex artery (CX) open (control conditions). Then the CX was occluded in order to exclude collateral blood flow. Afterwards another occlusion of the CX was performed ("preconditioning") to produce maximal opening of the anatomical collaterals. It was found that regional myocardial blood flow was unchanged in the antero-lateral parts of the hearts despite complete occlusion of the coronaries supplying this area. In the parts supplied by the CX, though, flow was minimal. "Preconditioning" positively influenced the perfusion of this region only in the epicardial parts. Histologically large sinusoid-like blood conductors connected the graft and the heart. Thus, grafting a free skeletal muscle flap onto the heart in the dog produces functional myocardial revascularization in the dog.

Anastomosis, Surgical↗
PubMed1993

Free skeletal muscle transplantation to an infarction area: an experimental study in the dog.

In plastic surgery, free skeletal muscle flaps are used for treatment of non-healing injuries like chronic osteitis or radiation ulcers. We wanted to evaluate if the neoangiogenesis induced by these flaps can also constitute a method for revascularization in ischemic heart disease. In diffuse small vessel coronary heart disease, patients are not suitable for bypass surgery because it is impossible to create a microanastomosis with the coronary artery. As an alternative, a free striated muscle flap, transplanted onto the heart, can constitute a source of neovessels. With the induction of extra-intracardial collaterals that develop within 4 weeks after transplantation of the flap, a new surgical approach may be offered to those patients. Our experimental work was performed with 20 dogs. In these, a myocardial infarction of the anterior wall was selectively produced using the Judkins-technique (Radiology 89: 815-824, 1967) for injection of Sephadex-microspheres. Four weeks later a free pectoralis muscle flap was transplanted onto the anterior wall of the heart. Arterial blood supply was achieved with an anastomosis with the internal mammary artery. The venous flow was directed into the right atrium. Four to eight weeks after surgery, the patency of the anastomosis was studied by angiography, showing patency in almost all surviving animals. Histological examination of the hearts revealed a prominent vascular network penetrating into the underlying myocardium. Corrosion cast preparations, as well as a postmortem angiography, showed even further penetration of the neovessels into the uninjured parts of the myocardium. Thus, myocardial revascularization may be achieved by transplantation of a skeletal muscle onto the heart.

Anastomosis, Surgical↗
PubMed1993

[Inhaled nitric monoxide. Application and continuous measurement of concentration].

Inhaled nitric oxide (NO) is a selective pulmonary vasodilator that may be useful in the treatment of patients with severe pulmonary hypertension. We describe a delivery system of inhaled NO that allows safe application and continuous measurement of the inspired NO concentration during mechanical ventilation. From a gas cylinder containing NO in N2 (600 ppm NO), an adjustable amount of gas is introduced into the inspiratory side of the tubing system via a pressure reduction valve, a magnetic valve, and a special injection nozzle. The NO concentration is diluted to the desired value by the tidal volume. The magnetic valve is connected to the ventilator and opens at the beginning of each inspiration and closes after a predetermined time. The gas volume is proportional to the pressure at the magnetic valve and the opening time. To monitor the inspiratory NO concentration, a specimen of gas is taken from an angle-connector and passed over an electrochemical sensor. The second nozzle of the sensor is connected to a water seal, which is adjusted to the positive end-expiratory pressure level of the ventilator to insure that the gas flow over the sensor is limited to inspiration.

Administration, Inhalation↗
PubMed1992

Prolongation of hospital stay and extra costs due to ventilator-associated pneumonia in an intensive care unit.

A prospective cohort study was performed to determine the prolongation of stay and the extra costs incurred due to the occurrence of ventilator-associated pneumonia in intensive care unit patients. Over a 16-month period a sample of 270 consecutive adult patients from a large university anesthesiological intensive care unit requiring ventilation therapy for more than 24 hours was analyzed. A matching procedure using multiple control patients without pneumonia per infected patient (= case) was employed. Of 78 cases 21 (26.9%) died and were excluded from the matching procedure as well as 23 (29.5%) for whom suitable controls could not be found. The maximum number of controls per case was five. The mean added stay was calculated to be 10.13 days and the extra costs attributable to the prolongation of stay were 14,253 German Marks (US$8,800) per patient, demonstrating considerable added stay and costs due to ventilator-associated pneumonia acquired during intensive care. However, it should be taken into account that the calculations for excess stay and costs are based on a subset of rather ill patients and thus cannot generally apply to all ventilated patients and that cases were excluded which could not be matched.

Adult↗