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Biomedical subjects

W Bartsch

Publications and source records attributed to W Bartsch.

At least 19 recordsLinked to original sources
PubMed2001

Cross-fostering inhalation toxicity study with HCFC-123 in lactating Sprague-Dawley rats.

A study was performed in Sprague-Dawley rats (Crl:CD BR) to differentiate between effects of hydrofluorocarbon 123 (HCFC-123) on the lactating dam or on the fetus using fostering and cross-fostering of the offspring. Pregnant and/or lactating dams without the pups present were exposed to the test substance (1000 ppm) or clean air by whole-body inhalation for 6 h/day from day 6 to 19 post conceptionem (p.c.) and from day 5 to 21 post partum (p.p.). Pups were cross-fostered to new dams within the first 2 days after birth. Treatment of the mothers with HCFC-123 led to decreases in serum glucose, cholesterol, and triglycerides and increases in absolute and relative maternal liver weights. Decreased litter and individual pup weight and decreased serum triglycerides were observed in the pups of treated foster mothers. Treatment of the mothers with HCFC-123 did not influence milk production based on the body weight difference of the dam before suckling and 60 min after beginning of suckling using 12-pup "standard litters" of untreated dams. Total fat, glucose, and protein contents in the milk were also not influenced by the treatment. Trifluoroacetic acid (TFA), a main metabolite of HCFC-123, was observed in urine samples of standard litters that had been nursed by treated dams. In conclusion, the effects on offspring due to HCFC-123 treatment consisted of decreased pup weight and decreased serum triglycerides at weaning. All effects were due to treatment of the lactating dams, as no prenatally induced effects were found. Since milk production and nutritional constituents of the milk were not influenced, but significant amounts of the main metabolite were found in pup urine, an effect of HCFC-123 or its metabolite on the pups via maternal milk is considered to be a possible cause for their decreased weight gain.

Administration, Inhalation↗
PubMed1999

Detection and quantification of complexed and free soluble human vascular endothelial growth factor receptor-1 (sVEGFR-1) by ELISA.

Vascular endothelial growth factor (VEGF) is an important factor for endothelial cell proliferation and a key regulator of blood vessel development in embryos and angiogenesis in adult tissues. Its biological activity is mediated by two receptor tyrosine kinases, VEGFR-1 (Flt-1) and VEGFR-2 (KDR). In contrast to VEGFR-2, a naturally occurring soluble form of the VEGFR-1 (sVEGFR-1) is produced by endothelial cells by differential splicing of the flt-1 gene, and it is a secreted gene product. In order to develop a specific enzyme-linked immunosorbent assay (ELISA) for the measurement of sVEGFR-1, we established five anti-human receptor antibodies and characterized them in detail. These antibodies recognize different epitopes located within the seven Ig-like domains of the extracellular receptor protein but have no neutralizing activity in ligand binding assays. Together with a polyclonal antiserum, a specific human sVEGFR-1 ELISA was developed using the mAb #190.11. The ELISA can detect human sVEGFR-1 with a minimum detection limit of 1 ng/ml. The ELISA does not show any cross-reactivity with other related soluble receptors. Using this assay, human sVEGFR-1 was measured in the supernatant of different VEGFR-1 expressing cell types. No sVEGFR-1 protein was detectable after heparin Sepharose treatment or size-exclusion filtration (< 30 kDa). The ELISA assay for sVEGFR-1 was also used to measure the amount of the soluble receptor in amniotic fluid samples of patients undergoing amniocentesis during the course of normal pregnancies. The concentration of the samples was in the range of 5-35 ng/ml. This ELISA could be useful powerful tool for investigations concerning the physiological function of the soluble receptor under normal and pathophysiological conditions.Furthermore, it may facilitate studies of the mechanisms of receptor production.

Animals↗
PubMed1996

Absence of effect of caffeine on the thyroid in the Syrian golden hamster: results of a 90-day study.

Caffeine in drinking water was offered ad lib. to male and female Syrian golden hamsters (Mesocricetus auratus W) for 90 days. Animals were randomly assigned to three dose groups (91.3, 274 and 822 mg/litre) and one control group (filtered tap water), each consisting of 20 male and 20 female animals. In relation to body weight, mean caffeine consumption was higher in females (low dose: 14.7; medium dose: 50.8; high dose: 104.8 mg/kg body weight/day) than males (low dose: 9.0; medium dose: 24.6; high dose: 65.2 mg/kg body weight/day). Caffeine in plasma was measured after 3 days, 3 wk and 3 months of treatment. As expected from calculation of the caffeine intake, mean values were higher in females (low dose: 0.6; medium dose: 3.6; high dose: 7.2 mg/litre) than in males (low dose: 0.4; medium dose: 0.7; high dose: 2.9 mg/litre). After 3 days of treatment, a transient, non-dose-related increase in mean (SEM) tri-iodothyronine (n=10) was found in the medium and high-dose (751+/-23 and 742+/-25 ng/litre, respectively) groups of males compared with that in the controls (610+/-39 ng/litre)(P<0.05). The values measured at later time points (days 24 and 91) were similar in all groups. No treatment-related changes were found in thyroxine (days 3, 24 and 91) and other clinicochemical analytes (day 91), absolute and relative adrenal weight (day 91), gross pathology and thyroid histopathology (day 91). In conclusion, no signs of thyroid toxicity of caffeine were observed in the Syrian golden hamster.

Administration, Oral↗
PubMed1994

Elevated surfactant protein A in bronchoalveolar lavage fluids from sarcoidosis and hypersensitivity pneumonitis patients.

Interstitial lung diseases often are accompanied by histopathologic evidence of alveolar type 2 cell alterations. In the alveolar milieu, the surfactant-specific protein A (SP-A) is a secretory product of alveolar type 2 cells. Therefore, we measured SP-A levels in bronchoalveolar lavage (BAL) fluids from patients with untreated sarcoidosis (n = 35) and hypersensitivity pneumonitis (HP [n = 10]) and compared the results with those from 21 healthy control subjects. In sarcoidosis patients, SP-A was markedly higher than in control subjects with a mean of 8.0 micrograms/ml of recovered BAL fluid +/- 0.7 SEM (p < 0.0001 compared with control subjects). In HP, SP-A values were comparable with those in sarcoidosis with a mean of 9.0 micrograms/ml +/- 1.7 SEM. Mean SP-A in the control group was 4.0 micrograms/ml +/- 0.3 SEM. These results suggest that SP-A secretion is stimulated in sarcoidosis and HP. Further studies seem justified to investigate the role of the surfactant system in interstitial lung diseases as well as the potential clinical usefulness of SP-A measurements in BAL.

Adolescent↗
PubMed1994

Pharmacokinetics of the organic nitrates trans-N-(4-nitroxycyclohexyl)-urea in dogs and trans-N-(4-nitroxycyclohexyl)-acetamide in dogs and in man.

The pharmacokinetic behavior of the organic nitrates BM 12.1247 (trans-N-(4-nitroxycyclohexyl)-urea) and BM 12.1307 (trans-N-(4-nitroxycyclohexyl)-acetamide, CAS 137291-91-3) were examined in beagle dogs after oral and intravenous administration. To this end, a reliable and specific assay using capillary gaschromatography with electron capture detection (GC-ECD) was developed. BM 12.1247 showed its maximum plasma level after 2.2 h by oral application; the bioavailability was nearly 100%. The elimination half-life of 8.8 h p.o. Corresponded to the half-life after i.v. administration, concerning BM 12.1307, the elimination half-lives were still longer, they reached 11-13 h and bioavailability reached 68-70%; these results were confirmed by crossover tests. In a first application of healthy volunteers it was possible to show that the organic nitrate BM 12.1307 is eliminated much more slowly in man than in dog, the half-life of the compound in man being longer than the half-life in dog by a factor of 2.3.

Acetamides↗
PubMed1993

Anabolic steroids--action on cellular level.

Although the nature of actions of anabolic steroids is principally that of androgens, it still remains difficult to relate the effects observed to specific cellular processes and to describe them clearly as related to specific mechanisms of action. The dissociation between "anabolic" and "androgenic" actions of a steroid can in part be explained by organ specific patterns of steroid-metabolizing enzymes, which lead to the formation of more or less active compounds in different organs. Some actions of anabolic steroids, particularly that in skeletal muscle are obviously also mediated by interaction of the parent compound or a metabolite with receptors of other steroid classes than androgens, e.g. that of glucocorticoids and/or estrogens.

Anabolic Agents↗
PubMed1992

The surfactant system of the adult lung: physiology and clinical perspectives.

Pulmonary surfactant is synthesized and secreted by alveolar type II cells and constitutes an important component of the alveolar lining fluid. It comprises a unique mixture of phospholipids and surfactant-specific proteins. More than 30 years after its first biochemical characterization, knowledge of the composition and functions of the surfactant complex has grown considerably. Its classically known role is to decrease surface tension in alveolar air spaces to a degree that facilitates adequate ventilation of the peripheral lung. More recently, other important surfactant functions have come into view. Probably most notable among these, surfactant has been demonstrated to enhance local pulmonary defense mechanisms and to modulate immune responses in the alveolar milieu. These findings have prompted interest in the role and the possible alterations of the surfactant system in a variety of lung diseases and in environmental impacts on the lung. However, only a limited number of studies investigating surfactant changes in human lung disease have hitherto been published. Preliminary results suggest that surfactant analyses, e.g., from bronchoalveolar lavage fluids, may reveal quantitative and qualitative abnormalities of the surfactant system in human lung disorders. It is hypothesized that in the future, surfactant studies may become one of our clinical tools to evaluate the activity and severity of peripheral lung diseases. In certain disorders they may also gain diagnostic significance. Further clinical studies will be necessary to investigate the potential therapeutic benefits of surfactant substitution and the usefulness of pharmacologic manipulation of the secretory activity of alveolar type II cells in pulmonary medicine.

Adult↗
PubMed1992

Pharmacological profile of beta-adrenoceptor blockers with vasodilating properties, especially carvedilol--rationale for clinical use.

The rationale for the combined use of beta-adrenoceptor antagonists and vasodilators is to improve the efficacy of the antihypertensive therapy and to reduce the incidence of side effects. If suitable coagents are selected and used at appropriate doses, the disadvantages of each separate component (compromised blood flow to individual organs, increase in total peripheral resistance, unfavorable lipid profile for beta-blockers; stimulation of counter-regulatory mechanisms, retention of water and electrolytes for vasodilators) can be balanced. In addition, the favorable effects of each (reduction in cardiovascular morbidity and mortality for beta-blockers, and favorable hemodynamic profile for vasodilators) may be used to advantage. Such a treatment rationale can be accomplished by a free combination or by using a dual-acting drug. From the practical point of view, the latter may be preferable. The basic requirement for such a drug is that the two effects are evoked in the same dose range. Carvedilol is a dual-acting drug designed to produce beta-blockade and vasodilation in the same dose range. The vasodilation is mediated predominantly by specific alpha 1-adrenoceptor blockade; at markedly higher concentrations additional vasodilating actions can be observed. These effects resemble those of Ca(2+)-antagonistic properties. However, they do not contribute to the acute blood-pressure-lowering activity, but may be responsible for the increased blood flow to some organs. At beta-blocking doses, carvedilol reduces the total peripheral resistance, and blood flow to the kidneys is preserved. Cardioprotection has been demonstrated in a variety of experimental investigations.

Adrenergic beta-Antagonists↗
PubMed1992

Vasodilatory action of carvedilol.

Carvedilol is a dual-acting drug designed to produce two complementary effects: beta-blockade and vasodilation. These effects are induced in the same dose range, a prerequisite for utilizing both properties in an appropriate manner. The vasodilation is mediated predominantly by specific alpha 1-adrenoceptor blockade. At markedly higher concentrations, additional vasodilating actions besides alpha 1-blockade can be observed. These effects resemble those of Ca(2+)-antagonistic properties. However, they do not contribute to the acute blood pressure-lowering activity of carvedilol but may be responsible for the increased blood flow to specific organs. At beta-blocking doses, carvedilol reduces the regional and systemic vascular resistance in various experimental models, healthy volunteers, and in patients with cardiovascular diseases such as hypertension, coronary artery disease, and heart failure. The profile of carvedilol thus insures beneficial treatment of hemodynamic disorders characterized by increased sympathetic tone and increased vascular resistance.

Adrenergic beta-Antagonists↗
PubMed1992

Pharmacokinetics of the organic nitrates trans-2-amino-2-methyl-N-(4- nitroxycyclohexylmethyl)-propionamide in dogs, and of 4-(2-nitroxyethyl)-piperidine in dogs and in monkeys.

The plasma concentrations of the organic nitrates (nitric acid esters) trans-2-amino-2-methyl-N-(4-nitroxycyclohexylmethyl)-propionamide (BM 12.1200) and of 4-(2-nitroxyethyl)-piperidine (BM 12.1173, CAS 129999-77-5) were determined in dog plasma by capillary gas chromatography with electron capture detection (GC-ECD). Intra- and interassay variation coefficients of the gas chromatographic analysis lay between 2.9 and 8.8%; recoveries amounted to 50-62%. Both nitric acid esters were absorbed quickly and attained maximum plasma levels within 1 h. The total bioavailability of BM 12.1200 is > 55%, and that of BM 12.1173 is 63%; their elimination half-lives are, respectively, 4.2 h and 1.3-1.4 h. Thus, BM 12.1173 and the reference substance IS-5-MN (isosorbide-5-mononitrate) show corresponding elimination half-lives. These results regarding the pharmacokinetic parameters of BM 12.1173 were confirmed by cross-over application of BM 12.1173 and IS-5-MN to Macaca Arctoides. In comparison to all species which have been treated with IS-5-MN thus far, the shortest elimination half-life (t1/2 = 0.6 h) is found in monkeys.

Administration, Oral↗
PubMed1990

Pharmacological characteristics of the stereoisomers of carvedilol.

The racemic compound carvedilol possesses two complementary pharmacological effects, vasodilation and beta-blockade. The R- and S-enantiomers of carvedilol and the racemate were investigated with respect to the beta-blocking, vasodilating, and hypotensive actions. In agreement with results obtained with other beta-blockers, only the S-enantiomer of carvedilol exerts beta-blocking effects. In contrast, no substantial difference between the enantiomers could be seen with respect to alpha-blockade. The greater hypotensive activity of S-carvedilol may be attributed to beta-blockade, which inhibits counter-regulatory mechanisms provoked by vasodilation. From these results it is concluded that there is a rationale for using carvedilol as the racemate. Using the S-enantiomer would lead to relatively strong beta-blockade with only a weak vasodilating effect. The R-enantiomer alone would act only as a hypotensive agent without beta-blockade.

Adrenergic alpha-Antagonists↗
PubMed1989

Steroid sulfate sulfatase in human benign prostatic hyperplasia: characterization and quantification of the enzyme in epithelium and stroma.

Characteristics and activities of estrone sulfate (E1S) and dehydroepiandrosterone sulfate (DHAS) sulfatases were studied in epithelium and stroma of benign hyperplastic tissues from human prostates. Tissues were obtained by suprapubic prostatectomy, and epithelium and stroma were separated mechanically by standard techniques. The assay procedure comprised homogenization in Tris-buffer, incubation of the homogenate with [3H]E1S or [3H]DHAS, separation of free steroids from nonhydrolyzed steroid sulfates by extraction with ether, and their final quantification by LSC. The main results were: (1) The pH-optimum of the sulfatase was found at pH 7.0. (2) The highest specific sulfatase activity was found in the epithelium and was associated with its nuclear fraction. (3) Michaelis-Menten constants Km (microM) were 8.7 +/- 1.4 (7) and 4.3 +/- 0.8 (5), maximum velocity rates Vmax (nmol/h x mgDNA) were 47.4 +/- 8.8 (7) and 8.4 +/- 1.5 (5) for E1S and DHAS, respectively (means +/- SEM (n]. (4) The enzymatic cleavage of E1-sulfate was competitively inhibited by DHA-sulfate and vice versa with inhibition constants Ki (microM) of 4.0 +/- 0.5 (2) for E1S and 2.7 +/- 0.4 (2) for DHAS. On the basis of these findings, possible roles of steroid sulfate-sulfatases in forming precursors of active androgens and estrogens from the high amounts of E1S and DHAS in blood are discussed.

Aged↗
PubMed1988

Inhibition of human placental aromatase in a perfusion model. Comparison with kinetic, cell-free experiments.

In vitro perfusion of human placenta was evaluated for characterization of aromatase inhibitors. The results were compared with those in kinetic experiments in cell-free system. Inhibition constants (Ki) were determined by measuring the release of tritiated water during coincubation of human placenta microsomes with varying amounts of [1 beta,2 beta 3H]androstenedione and inhibitor in the presence of NADPH-generating system. Irreversible inactivation constants (Kinact) were determined in a similar manner following preincubation of the microsomes with different amounts of inhibitor for varying times. Lineweaver-Burk plots indicated a competitive type of inhibition with Ki values of 37 nM for 4-hydroxy-androstenedione, 3,700 nM for testolactone, 15 nM for 1-methyl-androsta-1,4-diene-3,17-dione, and 7.5 nM for 19-azido-androstenedione. Additionally, irreversible enzyme inactivation by all four substances could be demonstrated with Kinact values of 3.64 x 10(-3), 0.57 x 10(-3), 0.34 x 10(-3), and 0.69 x 10(-3)sec-1, respectively. Perfusion of a single cotyledon of human term placenta was performed by infusing medium through catheters placed in a fetal artery and in the maternal intervillous space. Perfused medium was collected from a cannulated fetal vein and from the maternal basal plate. The medium was supplemented with [3H]androstenedione (4.2 nM) and inhibitor. The perfusates were analyzed for their [3H]estrone and estradiol content following phenolic partition and Sephadex-LH 20 chromatography. The main results were, (1) the recovery of labelled steroids increased rapidly after perfusion started and reached a plateau within 60 min, when 55 and 30% (mean values) of the infused radioactivity were recovered in the fetal and maternal perfusates, respectively, (2) similar amounts of estrone and estradiol were found in both effluates, whereas androgens (mainly androstenedione and lower amounts of 5 alpha-androstane-3,17-dione) were found nearly exclusively in the fetal perfusate, (3) formation of estrogens (estrone + estradiol) reached a plateau within 20 min of perfusion. (4) The percentage of estrogens formed was not changed by increasing androstenedione concentration in the perfusion medium unless this concentration exceeded 3.5 microM indicating limited capacity of aromatase. (5) The four aromatase inhibitors reduced estrogen formation by 50% at concentrations about 100-fold of their Ki determined in the cell-free system, (6) irreversible aromatase inhibition could not be demonstrated in the perfusion model. It was concluded that the human placenta perfusion model can be successfully used to evaluate aromatase inhibitors.

Androstenedione↗
PubMed1988

Hemodynamic profile of BM 14.478: a new positive inotropic and vasodilating agent.

BM 14.478 (7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H pyrrolo [2,3-f]benz-imidazol-6-one) was investigated in anesthetized rats and cats and conscious dogs. Left ventricular dp/dt was increased after intravenous injection of 0.01-0.1 mg/kg in rats (7,200 +/- 300 to 10,700 +/- 500 mm Hg/s), 0.001-0.3 mg/kg in cats (2,800 +/- 200 to 4,500 +/- 100 mm Hg/s) and 0.01 +/- 3.0 mg/kg in dogs (2,400 +/- 100 to 4,400 +/- 500 mm Hg/s). The inotropic potency was about 5- to 18-fold higher than that of milrinone. Effects persisted for more than 6.5 h in dogs after administration of 1 mg/kg p.o., which was definitely longer than that of milrinone. Hypotension and a moderate tachycardia were observed in the same dose range. In conscious dogs the compound increased cardiac output by 39 +/- 10%, and stroke volume by 17 +/- 7% and lowered total peripheral resistance by 45 +/- 5% and right atrial pressure by 3.0 +/- 0.3 mm Hg. BM 14.478 induced no tolerance after repeated administration in dogs when administered in a dose of 1 mg/kg p.o. b.i.d. for 10 days.

Animals↗
PubMed1987

17 beta-Hydroxysteroid dehydrogenase in the human prostate: properties and distribution between epithelium and stroma in benign hyperplastic tissue.

In order to delineate differences in the mechanism of androgen action in epithelium (E) and stroma (S) of the human prostate, we studied the 17 beta-hydroxysteroid dehydrogenase (17 beta-HSDH) in these tissues of benign prostatic hyperplasia (BPH). Tissue was obtained by suprapubic prostatectomy. E and S were separated; samples were homogenized in buffer and incubated with [3H] steroids (4-androstenedione (Ae), estrone (E1), or dehydroepiandrosterone (DHEA] and NADH (4.2 mmol/l) as cosubstrate for 60 min at 37 degrees C. Separation and quantification of the metabolites were performed by TLC and LSC, respectively. The main results were: (1) Following incubation with DHEA and E1, only the metabolites 5-androstene-3 beta,17 beta-diol and estradiol, respectively, were found. Following incubation with Ae, testosterone, 5 alpha-dihydrotestosterone and 5 alpha-androstane-3 alpha-(beta),17 beta-diol were detected as metabolites (the sum of these metabolites were used for calculations). (2) The Michaelis constants were identical in E and S (mean +/- SEM (n), mumol/l, Ae 6.92 +/- 1.01, E1 7.84 +/- 0.69, DHEA 3.73 +/- 0.38). (3) The maximum velocity rate for the three substrates in E was 5-10-fold that in S (P at least less than 0.01), the value in the whole tissue homogenate (WT) being intermediate (pmol/mg protein h), for Ae: E 383 +/- 56, S 40 +/- 3, WT 75 +/- 13; for E1: E 362 +/- 71, S 33 +/- 4, WT 63 +/- 8; for DHEA: E 132 +/- 21, S 26 +/- 4, WT 36 +/- 4. On the basis of these results the role of 17 beta-HSDH in forming active androgens and estrogens from less potent precursors is discussed in the stromal and epithelial compartment of the human prostate.

17-Hydroxysteroid Dehydrogenases↗