Search PubMed⌕ Search

Biomedical subjects

U Winkler

Publications and source records attributed to U Winkler.

At least 19 recordsLinked to original sources
PubMed1992

[New perspectives in oncology: is selective destruction of tumor cells with immunotoxins in Hodgkin's disease an additional therapeutic alternative?].

In the present paper, the authors describe the production and testing of immunotoxins for clinical application in Hodgkin's disease. The immunotoxins were constructed by chemical coupling of deglycolysated ricin-A to monoclonal antibodies against antigens on Hodgkin's and Reed-Sternberg cells (CD25, CD30, IRac). The cytotoxic effect of the immunotoxins was investigated in vitro against Hodgkin's and Reed-Sternberg cells (H-RS) and in vivo against solid Hodgkin's tumors in nude mice and disseminated Hodgkin's tumors in SCID mice. Cross-reactivity with normal tissue and the staining behaviour observed in sections of Hodgkin's tissue of various subtypes proved important parameters for the assessment of clinical applicability. Of more than 30 evaluated MoAb's, eight immunotoxins were produced, of which six showed both, cytotoxic effects of considerable potency against Hodgkin's tumor cells and low cross-reactivity with vital human organs. The most effective immunotoxin, RFT5 gamma 1.dgA, (CD25) inhibits the growth of H-RS cells at concentrations of 7 pMol and destroys about 60% of solid Hodgkin's tumors of 0.5 cm in diameter in nude mice. This immunotoxin binds to virtually all tumor cells in more than 90% of patients with Hodgkin's disease. Sufficient quantities of RFT5 gamma 1.dgA were produced for the treatment of patients with refractory Hodgkin's disease. These patients are currently being treated in a phase I clinical trial.

Animals↗
PubMed1992

Sulfonyl fluoride serine protease inhibitors inactivate RNK-16 lymphocyte granule proteases and reduce lysis by granule extracts and perforin.

Cytolytic granules purified from natural killer lymphocytes (NK) contain a pore-forming protein (perforin) and a number of serine proteases. When these proteases are inhibited by serine protease-specific isocoumarin reagents the serine proteases are inactivated and the cytolytic activity of the granules is decreased. Paradoxically, it has been found that the general serine protease inhibitor phenylmethylsulfonyl fluoride (PMSF) frequently cannot block killing even though it inhibits many of the serine proteases. At the same time it has been reported that "purified" perforin alone can lyze cells. To address these inconsistencies we first compared the ability of PMSF and four new sulfonyl fluoride serine protease inhibitors to inhibit proteases and cell lysis. We determined the effects on lysis and the second order inhibition rate constants for five granule protease activities: ly-tryptase, ly-chymase, Met-ase (methionine cleaving), Ser-ase (serine cleaving) and Asp-ase (aspartic acid cleaving). One compound, 2-(Z-NH(CH2)2CONH)C6SO2F, was a potent inhibitor of Met-ase activity (k(obsd)/[I] = 162 M-1 s-1), ly-chymase activity (k(obsd)/[I] = 147 M-1 s-1), and granule-mediated as well as perforin-mediated lysis. PMSF was a poor inhibitor of granule proteases (k(obsd)/[I]'s less than 7 M-1 s-1 for four activities and no inhibition of Ser-ase); the lack of reactivity is consistent with the failure of PMSF to block granule lytic activity. We also prepared enriched perforin by anion exchange chromatography and showed that a ly-chymase and a Met-ase associated with perforin. By inhibiting these proteases we also inhibited lytic activity.

Animals↗
PubMed1992

[Neutral and zwitterionic detergents: dependence of biological effectiveness on critical micellar concentration].

The biological activity of various zwitterionic and nonionic detergents was studied as a function of the corresponding critical micellar concentration (CMC-values). The criteria chosen to measure biological activities were inhibition of bioluminescence, lysis and cell-killing of Vibrio fischeri, hemolysis, and inhibition of Daphnia magna. When Zwittergent-detergents were studied in three different bioassays their biological activity increased with decreasing CMC-values. However, the biological activity of various TWEEN-detergents and alkylglucopyranosides depended on CMC-values in a very different way. We therefore conclude that CMC-values, length of alkylgroups and charge are parameters not yet sufficient to predict the potential toxicity of detergents.

Animals↗
PubMed1992

The reactivity of peripheral vessels of normo- and hypertensives.

The effect of calcium antagonist nifedipine (N) was studied in the changes of blood pressure, total peripheral resistance, activity of the transport membrane ATPase of erythrocyte ghosts, the plasma level of digitalis-like factor and the plasma renin activity. The studies were performed in 10 healthy volunteers and in 19 hypertensive patients after the intake of a single dose of 20 mg N. The changes were studied in the hypertensives after the intake of the drug in daily doses of 3 times 10 mg over 4 weeks, too. The systolic and diastolic blood pressure and peripheral resistance of the forearm decreased in hypertensives after a single dose of nifedipine as well as after the treatment with 30 mg daily over 4 weeks (170.8/109.5 vs 145.3/98.3 mmHg). As compared with the membrane ATPase activity of normotensives, that of the hypertensives was distinctly depressed (0.403 vs 0.321 mumol P(i).mg-1.h-1; p less than 0.01), while after N treatment, the enzyme activity increased to values of those of the normotensives 0.403 mumol P(i).mg-1.h-1). The mean peripheral resistance was not significantly depressed after the long-term treatment with N (2,085 vs 1,535 dyn.s-1.cm-5), while in several hypertensives (9 of 19) a distinct reduction was measured. Analogous results were found in case of the mean renin activity and the activity of several hypertensives after the N treatment. The N effect on the membrane ATPase system is discussed in connection with the hypothesis of Blaustein [1977] (Na(+)- with consecutive Ca(2+)-overload of the cell) and a possible influence of the drug on the electrolyte transport via membrane.

Adenosine Triphosphatases↗
PubMed1992

Treatment of endometriosis with leuprorelin acetate depot: a German multicentre study.

During the past decade, the development of various gonadotrophin-releasing hormone (Gn-RH) agonists, which induce reversible hypo-oestrogenism has opened a new area in the medical management of endometriosis. In an open, multicentre phase III study, the efficacy, tolerance and safety of the Gn-RH agonist leuprorelin acetate were tested. The preliminary results of 104 women treated in seven German centres are presented. Pelvic endometriosis was diagnosed by laparoscopy and classified according to the American Fertility Society scoring system: 33% of patients had minimal, 22% mild, 28% moderate and 8% severe endometriosis and in 9% no pathological results were obtained. The patients' mean age was 30 +/- 6 years and 66 had infertility problems. Treatment was started within the first 3 days of the menstrual cycle and consisted of a subcutaneous injection of leuprorelin acetate 3.75 mg, repeated once monthly over 24 weeks. A follow-up period of 12 months after the last injection has been completed in 70 patients, including a second laparoscopy. At all visits, symptoms were evaluated, physical examinations performed, and blood samples collected for haematological screening, serum chemistry determinations and measurement of the gonadotrophins oestradiol and progesterone and leuprorelin acetate. The median score at laparoscopy fell from 12 before operation to 8 after operation and 2 after treatment with leuprorelin acetate. Of the total number of patients, 89% had improvements in their endometriosis, 8% a deterioration and 3% no change. Patients reported improvement in the following: dysmenorrhoea 93%, dyspareunia 62% and pelvic pain 70%. However, all women complained of at least one of the following symptoms: hot flushes 86%, sleep disturbance 62%, sweating 61%, headache 41%, nausea 32% and depression 20%. Fifty-five percent of patients reported additional side effects such as vaginal dryness, fatigue and lower abdominal pain. After the third injection, amenorrhoea persisted in 94% of the women. Four weeks after the first leuprorelin acetate injection median concentrations of oestradiol fell from 45 pg/ml to 11 pg/ml, follicle-stimulating hormone from 7 U/L to 3 U/L and luteinising hormone from 5 U/L to 1 U/L and remained almost unchanged over the observation period. During the 6 months' treatment, laboratory parameters showed no significant deviations from normal; only total cholesterol, high-density lipoprotein cholesterol and alkaline phosphatase increased. Treatment results were judged as good and satisfactory in 82% and 11% of cases, respectively. On the basis of this study, it can be concluded that leuprorelin acetate treatment is safe, well tolerated and effective in the medical management of endometriosis and endometriosis-related complaints.

Adult↗
PubMed1992

Influence on hormone levels, lipid metabolism and reversibility of endocrinological changes after leuprorelin acetate depot therapy.

The effect of leuprorelin acetate depot on the endocrine system and on lipid metabolism was evaluated in a multicentre, noncomparative study. During the first month of treatment, suppression of serum oestradiol levels to below 20 pg/ml was achieved and luteinising hormone and follicle-stimulating hormone levels were reduced to less than 50% of pretreatment values. A negative influence on lipid metabolism was not recorded. The high-density lipoprotein/low-density lipoprotein ratio did not change during therapy. Resumption of menstruation occurred within a mean period of 3 months after the last leuprorelin acetate depot injection.

Bone Density↗
PubMed1992

Plasmatic haemostasis in gonadotrophin-releasing hormone analogue therapy: effects of leuprorelin acetate depot on coagulatory and fibrinolytic activities.

The plasmatic parameters of coagulatory and fibrinolytic activity were studied in 15 patients with biopsy-proven endometriosis treated with leuprorelin acetate for 6 months. Bleeding time remained constant, indicating the absence of increased bleeding tendencies. The activity of the main inhibitor of the fibrinolytic response, plasminogen activator inhibitor, was reduced by 25%, suggesting an improvement in fibrinolytic reactivity. Plasma levels of fibrin degradation fragments were reduced by 35%, suggesting a marked reduction in the rate of fibrin generation and degradation. A simultaneous reduction in thrombin-antithrombin III complexes and prothrombin fragment 1 + 2 (-10%) indicated that this effect was induced by reduced procoagulant activity, ie, thrombin generation. These data indicate that in gonadotrophin-releasing hormone (Gn-RH) analogue therapy the basal rate of coagulatory processes is reduced. The frequency and extent of fibrin-generating and degrading processes are reduced, suggesting a beneficial effect of Gn-RH analogues on the risk of thromboembolic disease.

Antithrombin III↗
PubMed1992

Experience with leuprorelin acetate depot in the treatment of fibroids: a German multicentre study.

Between October 1988 and October 1990 in a noncomparative multicentre study, 114 patients were treated for uterine fibroids with the gonadotrophin-releasing hormone (Gn-RH) agonist, leuprorelin acetate depot. The mean age of the women was 33 years and 55.3% of them had a history of infertility. After confirmation of the diagnosis by ultrasound and/or operation, treatment began between day 1 and 3 of the cycle with leuprorelin acetate depot 3.75 mg subcutaneously. Therapy was carried out for a total of 6 months with one injection every 4 weeks. Treatment was paralleled by measurements of endocrine and metabolic parameters, estimation of myoma and uterine size by ultrasound and self-reporting of the patients of drug-related complaints. Four of the 114 women did not complete the whole treatment, two of them because of general side effects, one because of carcinophobia and unsatisfactory regression of the myoma and the last one for unspecified reasons. During treatment, a mean reduction of the uterine volume of about 67% was observed, in conjunction with shrinkage of the myoma in 92.1% of cases (mean decrease of 56% of the fibroids) with a large interindividual difference. Maximal diminution of uterine and fibroid size had been nearly completely reached within the first 12 weeks of therapy. After 4 weeks of the Gn-RH agonist depot most of the patients had achieved postmenopausal status, which continued throughout the remaining 20 weeks of treatment. In accordance with this finding, the majority of general side effects was due to the hypo-oestrogenic endocrine status. Liver and lipid metabolism was almost unaffected, although increasing calcium and alkaline phosphatase serum levels as well as an increased urinary calcium/creatinine ratio demonstrated an increased metabolic turnover of the bone. Haemoglobin concentrations, however, increased in those cases with fibroid-related anaemia. Thus the slow-release form of leuprorelin acetate is an adjunct to myomectomy especially in those women in whom family planning is not yet completed.

Adult↗
PubMed1991

Cell proliferation and vascularization in human breast carcinomas.

Cell proliferation and vascularization were studied in 10 human breast carcinomas by an immunoenzyme technique. The monoclonal antibody (MAb) Ki-67 was used as a marker for proliferating cells and a polyclonal antibody directed against human von-Willebrand factor to identify blood vessels. The proportion of Ki-67-labelled cells varied from 1% to 20%, the number of small blood vessels from 4.4/mm2 to 57.6/mm2. Within single histological sections of individual tumours the percentage of proliferating cells was not related to the number of small blood vessels. However, after evaluation of 5 sections of each tumour, the average values showed that tumours with a high grade of vascularization had a higher percentage of Ki-67-positive cells than poorly vascularized samples. The influence of vascular density on cell proliferation was investigated in a selected area of one of the tumours (in 2-dimensions) and with regard to the over- and underlying sections (in 3-dimensions). After 2-dimensional evaluation, distances from proliferating cells to the closest blood vessel between 10 and 390 microns were observed, and after 3-dimensional evaluation none of the proliferating cells measured was located more than 130 microns away from the closest vessel.

Antibodies↗
PubMed1991

The function of lymphocyte proteases. Inhibition and restoration of granule-mediated lysis with isocoumarin serine protease inhibitors.

To kill other cells, lymphocytes can exocytose granules that contain serine proteases and pore-forming proteins (perforins). We report that mechanism-based isocoumarin inhibitors inhibited the proteases and inactivated lysis. When inhibited proteases were restored, lysis was also restored, indicating that the proteases were essential for lysis. We found three new lymphocyte protease activities, "Asp-ase,""Met-ase," and "Ser-ase," which in addition to ly-tryptase and ly-chymase, comprise five different protease activities in rat RNK-16 granules. The general serine protease inhibitor 3,4-dichloroisocoumarin (DCI) inhibited all five protease activities. Essentially all protease molecules were inactivated by DCI before lysis was reduced, as determined from DCI's second order inhibition rate constants for the proteases, the DCI concentrations, and the times of pretreatment needed to block lysis. The pH favoring DCI inhibition of lysis was the pH optimum for protease activity. Isocoumarin reagents acylate, and may sometimes secondarily alkylate, serine protease active sites. Granule proteases, inhibited by DCI acylation, were deacylated with hydroxylamine, restoring both the protease and lytic activities. Hydroxylamine does not restore alkylated proteases and did not restore the lytic activities after inhibition with 4-chloro-7-guanidino-3-(2-phenylethoxy)-isocoumarin, a more alkylating mechanism-based inhibitor designed to react with tryptases. It is improbable that isocoumarin reagents directly inactivated pore-forming proteins because 1) these reagents require protease activation, 2) their nonspecific effects are alkylating, and 3) alkylated proteins are not restored by hydroxylamine. We conclude that serine proteases participate in lysis when lysis is mediated by the complete assembly of granule proteins.

Animals↗
PubMed1991

High frequency oscillatory ventilation near resonant frequency of the respiratory system in rabbits with normal and surfactant depleted lungs.

It has been suggested that high frequency oscillatory ventilation (HFV) might improve gas exchange and reduce the risk of pressure-related side-effects compared to conventional mechanical ventilation (CMV). Whereas most studies have used arbitrarily set frequencies for HFV, we evaluated the effects of HFV near resonant frequency (fr). Anaesthetised and tracheotomized adult rabbits (n = 10; 3.8-5.1 kg body weight) were ventilated by alternating periods of CMV and HFV near fr. Negative ventilator resistance was used for complete resistive unloading of the respiratory system before each HFV period. This enabled a continuous swinging at resonance thus allowing measurement of fr and selection of exactly that frequency for the HFV run. Intra-animal CMV-HFV comparisons (n = 4) were performed on each animal: with healthy lungs at a mean airway pressure (MAP) of 0.5 kPa and after saline lung lavage at MAPs of less than 1.5 kPa; 1.5-1.8 kPa; greater than 1.8 kPa. Surfactant removal caused total respiratory system compliance (Ctot) to decrease from 44 +/- 5 to 22 +/- 3 ml/kPa. Corresponding fr was 244 +/- 48 and 360 +/- 30 min-1, respectively. HFV produced effective pulmonary gas exchange but did not improve arterial oxygenation in comparison with CMV at matched MAPs both before and after surfactant depletion. Volume amplitudes of oscillation necessary to achieve normocapnia were slightly above the natural plus equipment (2 ml) dead space. Maximum intra-alveolar pressure (Pmax) was calculated for the HFV runs from MAP, Ctot, and the volume amplitude of oscillation. Pmax during CMV was nearly twice that during HFV at equivalent PaCO2 and equivalent MAPs throughout the experiments.

Animals↗
PubMed1991

Studies on lipid peroxidation in pancreatic tissue. In vitro formation of thiobarbituric-acid-reactive substances (TBRS).

In pathogenic studies on acute pancreatitis the importance of a temporary ischemia on induction of autodigestion was demonstrated. Because of the involvement of oxygen-derived free radicals in the ischemia/reperfusion injury of other tissues we have investigated the influence of artificial oxidants, as FeCl3 and H2O2, on pancreatic tissue and isolated pancreatic acinar cells. Lipid peroxidation was determined as thiobarbituric-acid-reactive substances (TBRS). In these experiments the TBRS concentration was elevated within the first min of incubation with FeCl3. The exposure of pancreas homogenates and intact acinar cells to H2O2 had no remarkable effect on formation of TBRS. Under this condition the survival of cells was strongly reduced, while cells exposed to FeCl3 revealed a remarkably slower rate of cytolysis. The missing correlation between cell lysis and elevation of TBRS suggests that lipid peroxidation might not be essential process in pancreatic acinar cell damage.

Animals↗
PubMed1991

[Nasal mucosa in tropical climate].

Morphological and functional results of the factors influencing the nasal mucous membranes of 150 persons living in a tropical zone are presented. In particular, an increased rate of hyperplastic mucosa was found in comparison with a group of 850 subjects from central Germany. The macroscopic results correlated with exfoliative cytological examination. On the other hand, the rates of moderate and severe hyposmia (9.3%) as well as moderate and extreme nasal obstruction (34%) were lower.

Adult↗
PubMed1991

[Temperature-controlled bipolar electrocoagulation].

The safety of electrocoagulation for laparoscopic surgery has been greatly improved by the introduction of the bipolar coagulation technique. But complications caused by coagulation, especially by the overheated forceps, are still reported. In order to reduce those complications, a temperature controlled bicoagulation system was developed. This system allows coagulation with lower temperatures which can be kept constant during the coagulation process. In experiments with human fallopian tubes obtained by adnexectomy and rabbit uterine horns it is shown that those lower temperatures are sufficient for homogeneous coagulation. On line monitoring of the temperature during coagulation provides the surgeon with the possibility of directly controlling the actual temperature at the tip of the forceps. The temperature curves can easily be stored in order to be able to demonstrate the particular coagulation process even after years.

Animals↗
PubMed1990

A method of calculating total respiratory system compliance from resonant frequency: validity in a rabbit model.

Ten anesthetized, tracheotomized, adult rabbits were used to test the validity of a method for calculation of total respiratory system compliance from resonant frequency (Cr). Reference values were obtained during constant flow inflation of the relaxed respiratory system by dividing the volume gain by the related difference in pressure at the airway opening (inflation method compliance, Ci). The animals were connected to a new type of servo-controlled infant ventilator. Besides volume-controlled mechanical ventilation at constant inspiratory flow rate and intermittent mandatory ventilation, there is a negative ventilator resistance mode integrated in this device for resistive unloading (Schulze A, Schaller P, Gehrhardt B, Mädler H-J, Gmyrek D: Pediatr Res 28:79-82, 1990). To measure resonant frequency (fr), the respiratory system was totally unloaded for a short period by a negative ventilator resistance exceeding the combined resistances of the endotracheal tube and airways. This evoked a continuous oscillation at fr. By analogy with electrical circuit theory, Cr was calculated according to C = 1/(4 pi 2.I.fr2) where C is compliance and I is inertance. The inertance of the endotracheal tube is given and that of the bronchial tree was ignored assuming a much greater total cross-sectional area and therefore much lower inertance when compared with the endotracheal tube. Three pairs of Ci - Cr values were obtained from each animal: 1) during intact respiratory muscle activity; 2) after pancuronium relaxation, and 3) after surfactant depletion by saline washout.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

[Rhinolaryngological functional diagnosis in exposure to irritants].

2,601 workers with exposure to irritant noxae received a standard occupational rhinolaryngeal check up supplemented with higher specialized methods. The measurements of mucociliary clearance, the screening--olfacto-/gustometry, the cytological investigations of the nasal mucous membranes with the smear technique, and the sonography of paranasal sinuses, too, were qualified for occupational practice. The significance of leading symptoms and the unity of upper and lower respiratory tract are to emphasize.

Environmental Exposure↗
PubMed1990

[Chamomile blooms--a heterogenous drug (manufacture of mixed teas with Matricariae flos)].

Sieve analyses have proved that the camomile commercial drug is an extremely heterogeneous material which contains ultracoarse particles greater than 4 mm (aprox. 70%) in addition to fine particles less than 0.71 mm (approx. 15%). The ultra-coarse particles are not usable in tea mixtures. For camomile, it is proposed a homogeneous infusion drug (less than 2 mm). The comminution should be performed in the pharmacy. Where species are mixed with camomile, the particle sizes should not exceed 2 mm. The homogeneity of these mixtures is determined by weight comparison of a series of tea-spoon weights. For the comminution of the drugs the authors suggest the use of a "Retsch" cutting mill or a similar appliance which ensures that only few fine particles to be produced. For the removal of suspended fine particles in the infusum of camomile the use of Cilia filter bags is suitable.

Drug Compounding↗