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Biomedical subjects

M Brandl

Publications and source records attributed to M Brandl.

At least 37 records · Page 2Linked to original sources
PubMed1999

[Development and application of dynamic MR imaging in the evaluation of perfusion changes in rectal carcinoma during radiotherapy in clinical routine. Preliminary results].

PURPOSE: This study was aimed at measuring microcirculatory parameters and contrast medium accumulation within the rectal carcinoma during fractionated radiotherapy in the clinical setting. MATERIAL AND METHODS: Perfusion data were observed in patients with rectal carcinoma (n = 8) who underwent a pre-operative combined chemo/radiotherapy. To acquire perfusion data, an ultrafast T1 mapping sequence was carried out on a 1.5-Tesla whole body imager to obtain T1 maps at intervals of 14 or 120 seconds. The overall measurement time was 40 minutes. The transaxial slice thickness (5 mm) was chosen in such a way that both arterial vessels and the tumor could be clearly identified. The gadolinium-DTPA (Gd-DTPA) concentration time curve was evaluated for arterial blood and tumor after intravenous constant rate infusion. The method allows a spatial resolution of 2 x 2 x 5 mm and a temporal resolution of 14 seconds. Patients underwent MR imaging before and at constant intervals during fractionated radiotherapy. RESULTS: Spatial and temporal resolution of dynamic T1 mapping was sufficient to reveal varying CM accumulation levels within the tumor and to identify the great arteries in the pelvis. In 6 patients Gd-DTPA concentration-time-curves were evaluated within the tumor during radiation. Pi index of Gd-DTPA versus radiation dose showed a significant increase in the first or second week of treatment, then either returned slowly to pretreatment level or a renewed increase was observed. The average Pi-value at the beginning was 0.16 (+/- 0.049), reaching highest level of 0.23 (+/- 0.058). In all groups the rise from the Pi-value to the Pi-maximum was statistically significant. The relative increase in perfusion ranged between 20 to 83%. CONCLUSION: The results show, that the ultrafast MR-technique described above provide a suitable tool for monitoring tumor microcirculation during therapeutic interventions and offers the potential for an individualized optimization of therapeutic procedures.

Aged↗
PubMed1999

Bispecific antibody fragments with CD20 X CD28 specificity allow effective autologous and allogeneic T-cell activation against malignant cells in peripheral blood and bone marrow cultures from patients with B-cell lineage leukemia and lymphoma.

Bispecific antibodies directed against tumor-associated target antigens and to surface receptors mediating T-cell activation, such as the TCR/CD3 complex and the costimulatory receptor CD28, are capable of mediating T-cell activation resulting in tumor cell killing. In this study, we used the B-cell-associated antigens CD19 and CD20 as target structures on human leukemic cells. We found that a combination of bispecific antibody fragments (bsFab2) with target x CD3 and target x CD28 specificity induces vigorous autologous T-cell activation and killing of malignant cells in peripheral blood and bone marrow cultures from patients with chronic lymphocytic leukemia and follicular lymphoma. The bsFab2 targeting CD20 were considerably more effective than those binding to CD19. The colony-forming capacity of treated bone marrow was impaired due to large amounts of tumor necrosis factor alpha produced during bsFab2-induced T-cell activation. Neutralizing tumor necrosis factor alpha antibodies were found to reverse this negative effect without affecting T-cell activation and tumor cell killing. CD20 x CD28 bsFab2, when used alone rather than in combination, markedly improved the recognition of leukemic cells by allogeneic T cells. Therefore, these reagents may be capable of enhancing the immunogenicity of leukemic cells in general and, in particular, of increasing the antileukemic activity of allogeneic donor buffy coat cells in relapsed bone marrow transplanted patients.

Antibodies, Monoclonal↗
PubMed1999

Degradation products of mycophenolate mofetil in aqueous solution.

The thermal and peroxide-catalyzed degradation products of mycophenolate mofetil (1) were studied in aqueous solution at pH 2.0, 3.5, 6.0, and 8.2. The major thermal degradation product observed was mycophenolic acid (2). At pH 6.0 and 8.2, 2 was the only product observed in the absence of peroxide, while at pH 2.0 and 3.5, the lactone analogue of mycophenolic acid (5), a hydroxylactone due to oxygenation of the double bond (6), and an unidentified product were formed. Compound 6 degraded to 4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-car baldehyde (9) on prolonged storage and was present in the sample stressed at pH 2. Mycophenolic acid (2), the N-oxide of mycophenolate mofetil (3), the hydroxylactone of mycophenolic acid (6), and the erythro form of 4-methoxy-5-methyl- 2-(2-methyl-5-oxo-tetrahydro-furan-2-yl)-3,6-dihydro-2H-1, 7-dioxa-as-indacen-8-one (8) were observed in the presence of hydrogen peroxide at pH 3.5, 6.0, and 8.2. In addition, at pH 8.2, 4-hydroxy-4-(4-methoxy-5-methyl-8-oxo-2,3,6, 8-tetrahydro-1,7-dioxa-as-indacen-2-yl)-pentanoic acid (7) was seen. Peroxide-stressed samples at pH 2.0 gave no major degradation peaks, but a small amount of the hydroxylactone of mycophenolic acid (6) was formed.

Chromatography, High Pressure Liquid↗
PubMed1998

Erosion and controlled release properties of semisolid vesicular phospholipid dispersions.

Phosphatidylcholine, when dispersed in aqueous medium in high concentrations (300 mg/g and above) by high pressure homogenisation, forms semisolid pastes of vesicular morphology. The multivesicular matrix can accommodate hydrophilic compounds in the aqueous compartments. The disintegration and release of hydrophilic marker of these dispersions were studied in vitro by using a flow-through cell. Slow release of the marker over periods of hours up to days took place via two different mechanisms: (1) erosion of the matrix with release of marker-filled liposomes and marker which had been trapped in between the liposomes and (2) diffusion of marker through the membranes. Whereas for lipid concentrations up to 300 mg/g almost spontaneous disintegration occurred, more concentrated pastes (350-400 mg/g) showed zero-order erosion kinetics for 4-6 h. Erosion was rate limiting for overall release. For 450 and 500 mg/g lipid dispersions, the release of free marker followed square root of time kinetics for 13 or 21 h, respectively, which is typical for matrix-controlled diffusion. Underlying the diffusion was a slow zero-order erosion of the matrix. The results are important for the future development of vesicular phospholipid gels as sustained release therapeutic system, e.g. as implantable depot.

Drug Carriers↗
PubMed1998

Evidence for differences in the mechanisms by which antibodies against CD44 promote adhesion of erythroid and granulopoietic progenitors to marrow stromal cells.

Adhesive interactions between haemopoietic progenitor cells and stromal elements involve a number of different molecules, some of which may be progenitor- lineage- and stage-specific. CD44 is one such molecule, although little is known about the mechanism(s) by which it is involved. In this study, several anti-CD44 monoclonal antibodies (mAb) increased the adherence of clonogenic cells, without affecting the total number of types of progenitors recoverable from the adhesion cultures. All of these mAb recognized epitopes on the globular head of CD44. In contrast, two mAb that recognized other regions of CD44 reduced progenitor adhesion to stroma. The mechanism by which one of the anti-CD44 mAb (L178) enhanced progenitor adhesion did not involve CD44-crosslinking, and was independent of VLA-4-, VLA-5- or LFA-1-mediated interactions, Ca or Mg cations, or accessory cells. In addition, CD44 expression on both progenitors and stromal cells contributed to L178-enhanced progenitor adhesion. Baseline adherence of erythroid progenitors to stroma required tyrosine kinase activity, whereas that of granulopoietic progenitors did not. However, the increase in adhesion did require tyrosine kinase activation. Additional experiments suggested that enhanced adhesion of CFU-GM to stroma may also be adenylate cyclase-dependent. Taken together, the present studies indicate both similarities and differences in the mechanisms of CD44-mediated adhesion of erythroid and granulopoietic progenitors to stromal cells.

Adenylyl Cyclases↗
PubMed1997

Biodistribution and computed tomography blood-pool imaging properties of polyethylene glycol-coated iopromide-carrying liposomes.

RATIONALE AND OBJECTIVES: Surface-modified contrast-carrying liposomes potentially are useful as computed tomography (CT) blood-pool agents. The biodistribution and CT-imaging behavior of conventional as well as polyethylene glycol (PEG)-coated iopromide-carrying liposomes were tested. Two different types of PEG-ylated lipids were used to demonstrate possible differences. METHODS: Iopromide-containing liposomes were prepared by a continuous high-pressure extrusion method and subsequently PEG-ylated by simple mixing with either DSPE-PEG2000 or CHHS-PEG2000. The resulting liposomes were investigated in rats (biodistribution) and rabbits (imaging). RESULTS: Surface modification with CHHS-PEG consistently resulted in less effective stabilization of liposomes in the blood than with DSPE-PEG. In the biodistribution study, no significant differences in blood concentration could be found 1 hour after injection between the different formulations at a dose of 250 mg total iodine/kg body weight (approximately 500 mg lipid/kg). At this dose, the unmodified as well as the DSPE-PEG liposomes displayed prolonged blood circulation with CT density differences above 70 Hounsfield units (aorta) for up to 20 minutes (n = 1). CONCLUSIONS: DSPE-PEG-coated and unmodified liposomes proved to be useful for CT blood-pool imaging displaying favorable imaging properties. Future studies will have to demonstrate whether PEG-ylation offers diagnostic or toxicologic advantages over conventional vesicles in this indication.

Animals↗
PubMed1995

Racemization of ketorolac in aqueous solution.

The racemization of ketorolac was studied in aqueous buffered solution at 25 and 80 degrees C and analyzed in detail with respect to the catalytic species in solution. The reaction has a U shaped pH rate profile at 80 degrees C with the pH of maximum stability occurring in the region of pH 3.0-7.5. A T90 value of 8 months was observed for a 1.5% (R)-ketorolac tromethamine solution at pH 7.4 and 25 degrees C. Additionally, the data shows that alternative salt forms are necessary in order to prepare a stable single isomer formulation. Alternative buffers, in particular phosphate buffer, provide formulations exhibiting a T90 greater than 2 years.

Catalysis↗
PubMed1995

Approaches for improving the stability of ketorolac in powder blends.

Methods for improving the stability of ketorolac powder blends under elevated humidity and temperature conditions were investigated. The approaches that were examined for potentially increasing the stability of ketorolac were varying the ketorolac salt form, altering the excipient ratios, and adding antioxidants or pH modifiers to the formulation. The ketorolac powder blends were stored for 3 months at 75% relative humidity (RH) and 40, 50, and 60 degrees C. The results showed that the salt form of ketorolac had a large impact on stability after 3 months of storage at 50 degrees C/75% RH. The calcium salt powder blend and the free acid powder blend exhibited only 0.2% and 0.5% drug loss, respectively, whereas the tromethamine salt powder blend showed a 10.2% drug loss. Varying the ratios of lactose, microcrystalline cellulose, and croscarmellose sodium in the powder blends of ketorolac tromethamine showed that croscarmellose sodium and microcrystalline cellulose destabilized ketorolac. Addition of propyl gallate (1% w:w) to ketorolac tromethamine powder blends increased the stability of the ketorolac significantly. Addition of pH modifiers caused a modest improvement in the stability of ketorolac.

Analgesics, Non-Narcotic↗
PubMed1995

Quantitative NMR microscopy of multicellular tumor spheroids and confrontation cultures.

In cancer research, tumor spheroids are a well established system to study tumor metabolism resembling the situation in vivo more closely cell monolayers. Spherical aggregates of malignant melanoma cells (MV3) and their invasion into rat brain aggregates have been investigated by quantitative NMR microscopy. Relaxation times (T1, T2) and diffusion parameter images were acquired with an in-plane resolution of 14 x 14 microns2. The authors were able to demonstrate that the morphology of the spheroids can be visualized on these NMR maps. The contrast was mainly manifested in relaxation maps, where average relaxation times T1 = 1.94 +/- 0.17 s and T2 = 42.8 +/- 6.3 ms were obtained for proliferating cells, and T1 = 2.49 +/- 0.31 s and T2 = 104.3 +/- 29.4 ms for the necrobiotic center. The mean diffusion coefficients were 0.59 +/- 0.12 micron2/ms and 0.85 +/- 0.14 micron2/ms, respectively. The authors could follow the dynamic process of tumor cell invasion in the investigated co-culture system. Knowledge about tumor cell migration and tumor cell invasion is essential for the understanding of cancer and its therapy. Quantitative NMR microscopy can study this dynamic process noninvasively and therefore may help to assess the influence of therapy on the micromilieu of these spheroids.

Animals↗
PubMed1995

Acute toxicity and depression of phagocytosis in vivo by liposomes: influence of lysophosphatidylcholine.

Small unilamellar phospholipid vesicles (liposomes), intended as drug carriers, have recently been demonstrated to reversibly depress phagocytic activity in rats when injected in a single high dose (2g of lipid per kg body weight) as revealed by the carbon clearance test. Depression of the phagocytic function was found to vary widely depending on the lipid used [M. Brandl et al., Pharm. Pharmacol. Lett., 4 (1) 1-4, 1994]. This study has now been extended in two directions: Firstly, liposomes made of the same type of lipid but different batches of raw material were compared in terms of their influence on phagocytosis as well as for their contents of impurities. The test revealed great variability of RES suppression between different batches of hydrogenated soy PC, whereas the reproducibility of the carbon clearance test was satisfactory with liposomes made of a single batch of raw material. Thin layer chromatographic analyses of the used phosphatidylcholines (PCs) and limulus tests on lipopolysaccharides revealed lysophosphatidylcholine (lysoPC) as the only impurity which showed parallels with the observed differences in phagocytosis. Secondly by "spiking" phosphatidylcholine with increasing amounts of lysoPC the latter could be proven to enhance RES depression by liposomes in a dose-dependent manner. At the same time a strong and dose-limiting increase in acute toxicity of PC vesicles was observed with increasing contents of lysoPC. However, in cholesterol-containing vesicles lysoPC-spiking did not significantly alter their behaviour, for lysoPC contents of up to 10%. Only PC/cholesterol-vesicles containing lysoPC contents as high as 15% provoked enhanced RES depression and toxicity compared to lysoPC-free vesicles. LysoPC and cholesterol in liposomes are known to play a destabilizing and stabilizing role respectively within liposomal bilayers which might influence recognition and uptake of vesicles by macrophages and thus modulation of phagocytosis.

Animals↗
PubMed1994

Entrapment of haemoglobin into liposomes by the dehydration-rehydration method: vesicle characterization and in vivo behaviour.

Haemoglobin (Hb) was isolated from human erythrocytes under conditions which maintained NADH-cytochrome-b5 reductase activity and suppressed oxidation of Hb during storage at 4 degrees C (methaemoglobin values < 3% after 29 days). Hb was entrapped into liposomes composed of hydrogenated egg phosphatidylcholine and equimolar cholesterol according to the dehydration/rehydration procedure of Kirby and Gregoriadis ((1984) Biotechnology 2, 979). However, encapsulation of Hb in its intact form was poor (< 5%) as a result of its oxidation and denaturation during freeze-drying. The addition of cryoprotectants and the use of both, higher initial concentrations of Hb and very small void vesicles resulted in Hb-rich dehydration/rehydration vesicles (phospholipid/Hb molar ratio of about 200:1) of the preferred size of 110 nm (mean). Highly homogeneous and small void vesicles as starting material were prepared using the one-step method of Brandl et al. ((1990) Drug Dev. Ind. Pharm. 16, 2167). The cryoprotectants were chosen with respect to their sufficient protection of Hb without affecting its loading into vesicles during freeze-drying and rehydration. 51Cr-labelling of Hb was used for the in vivo monitoring of the fate of Hb-containing vesicles rather than 125I-labelling since the latter induced strong interactions of Hb with liposomes. Upon intravenous administration into rats, liposomal 51Cr-Hb showed greater blood levels and prolonged circulation times in the blood compared to free Hb. The present approach provides high yield entrapment of labile molecules into vesicles of small size known to exhibit long circulation time.

Animals↗
PubMed1991

[Role of the anesthetist in the recovery stage].

Surveillance of the patient in the particularly critical phase immediately following operation and anaesthetic must be considered a purely anaesthesiological task. Today, it is no longer considered sufficient merely to keep the patient under observation until his protective reflexes have returnded; rather, appropriate postoperative therapeutic measures must be initiated already during the recovery phase to enable the patient to be returned to the nursing ward with his or her vital functions optimal and stabilised. The tasks of the anaesthetist in the recovery phase are as follows: safeguarding of the transportation phase of the patient from the operating room to the recovery unit; hand-over of the patient to the recovery staff; monitoring for possible complications in the recovery phase, collection of suitable diagnostic parameters to determine the current state of the patient; initiation of optimised treatment as dictated by the state of the patient; documentation of all findings as well as all therapeutic measures instituted, and deciding on the further transfer of the patient.

Anesthesia Recovery Period↗
PubMed1990

High-performance liquid chromatographic (HPLC) and HPLC-mass spectrometric (MS) analysis of the degradation of the luteinizing hormone-releasing hormone (LH-RH) antagonist RS-26306 in aqueous solution.

The kinetics of the degradation of an LH-RH antagonist, RS-26306,1, in aqueous solution from pH 1 to pH 11 were studied by reverse-phase HPLC. The pH-rate profiles at 50, 60, and 80 degrees C were U-shaped with the rate law of kobs = kHaH + kw + kOHaOH. The predicted 25 degrees C shelf life at the pH of maximum stability, pH approximately 5, is greater than 10 years. The products from the degradation were analyzed by HPLC-MS using thermospray ionization. Below pH 3, the primary product, 2, forms from the acid-catalyzed deamidation of the C-terminal amide. Above pH 7, epimerization of the individual amino acids is the principal reaction. Between pH 4 and pH 6, intramolecular serine-catalyzed peptide hydrolysis becomes important, yielding a tripeptide, 3, and a heptapeptide, 4. At the pH of maximum stability all three pathways for degradation are observed.

Chemical Phenomena↗
PubMed1990

Plasma level changes of fentanyl and midazolam after release of a prolonged thigh tourniquet.

In 14 elderly orthopedic patients undergoing total knee joint replacement, the influence of complete arterial occlusion of the limb on the course of plasma levels of fentanyl and midazolam was examined. The patients were premedicated with midazolam intramuscularly (0.05 mg/kg) and were then given neurolept anesthesia in dosages of 0.1 mg/kg midazolam and 0.01 mg/kg fentanyl intravenously prior to the placement of the tourniquet. Up to 4 h after the tourniquet was released, plasma levels of fentanyl and midazolam as well as pH value, PaCO2 and plasma lactate levels were measured. In 12 patients there was an increase in fentanyl and in 10 patients an increase in midazolam plasma levels after tourniquet release. The maximum increase varied between 1 min and 2 h after release. The plasma levels of midazolam after removal of the tourniquet varied greatly between individuals. Especially patients older than 70 years showed excessively high concentrations of midazolam. These results would indicate that there can be a clinically significant increase of fentanyl and midazolam levels due to initial reperfusion of the lower extremity following prolonged ischemia. Therefore a correspondingly extended period of postoperative surveillance is advisable.

Aged↗
PubMed1989

Nitrogen absorption in pancreatectomized patients: protein versus protein hydrolysate as substrate.

To investigate nitrogen absorption in the absence of the pancreas, six patients with total pancreatectomy, all in stable nutritional and metabolic condition, underwent two periods of enteral nutrition identical in all respects except for the nitrogen source. Nitrogen source was either lactalbumin or its hydrolysate. The quantity and quality of calories infused simulated the patient's usual diet, which was a high-protein diet (2.0 +/- 0.4 gm/kg body weight). Pancreatic enzyme replacement therapy was discontinued during each period of enteral nutrition. All patients had greater nitrogen absorption during the enteral nutrition with lactalbumin hydrolysate than that with lactalbumin (91% +/- 2% vs 61% +/- 6% of nitrogen intake, p less than 0.02). Despite this difference in absorption, nitrogen balances during the two periods of enteral nutrition were not significantly different. This appeared to be caused by a urea production rate that was greater during the enteral nutrition with lactalbumin hydrolysate than the rate during that with lactalbumin (26 +/- 1 gm/24 hr vs 16 +/- 3 gm/24 hr, p less than 0.05). Plasma concentrations of amino acids and proteins did not differ significantly during the two treatments. In conclusion, the data suggest that (1) the intestine plays a significant role in protein digestion and that (2) enteral feeding with a protein hydrolysate could eliminate the need for a high-protein diet in patients with pancreatic insufficiency.

Absorption↗