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J Schuppler

Publications and source records attributed to J Schuppler.

11 recordsLinked to original sources
PubMed1990

Toxicological studies on a benzofurane derivative. I. A comparative study with phenobarbital on rat liver.

The benzofurane derivative benzbromarone (BBR) previously has led to liver tumor formation after long-term treatment of rats, but no indications of genotoxicity were detected. The present studies were designed to elucidate the mechanism(s) possibly involved in liver tumor formation by BBR. Female Wistar rats were used. Phenobarbital (PB) served as a positive control. (1) Short-term treatment (7 days) with daily doses of 2 to 100 mg/kg BBR led to adaptive responses in the liver, i.e., growth (increases in DNA, RNA, and protein) and induction of monooxygenases. These changes were also observed after feeding BBR for 8, 33, 77, and 102 weeks at doses of 2, 10, and 50 mg/kg/day but tended to weaken with time. Similar effects were obtained with PB fed at 2, 10, or 50 mg/kg/day. However, unlike PB, BBR did not enhance the expression of cytochrome P450-PB as demonstrated by immunostaining of histological liver sections. (2) BBR feeding for 102 weeks, but not for 77 weeks, produced some neoplastic liver nodules and at 50 mg/kg produced one hepatocellular carcinoma (HCC). Thus, BBR was tumorigenic in the present study, but was clearly weaker than PB which had induced liver nodules and HCCs at 77 weeks and even more markedly at 102 weeks. (3) To check for tumor-initiating activity 100 mg/kg BBR was given 14 hr after a two-thirds hepatectomy followed by promotion with PB (50 mg/kg) for 15 weeks. No phenotypically altered liver foci were detected. (4) To test for tumor-promoting activity rats received a single dose of N-nitrosomorpholine (250 mg/kg), and subsequently BBR or PB at doses of 2, 10, and 50 mg/kg/day. While PB markedly enhanced the development of neoplastic nodules and HCCs, BBR had only a weak enhancing effect on the induction of HCC, which was not dose related. gamma-glutamyl transpeptidase-positive foci dramatically increased in PB-treated animals, in contrast they showed no response after 2 and 10 mg/kg BBR and even decreased after 50 mg/kg BBR. (5) With PB changes in liver growth, monooxygenase activity, foci expansion, and tumor promotion all correlating with tumorigenesis in a quantitative manner, apparent no-observed-effect-levels are somewhat below 2 mg/kg (or 10 mg/kg for liver enlargement). (6) These studies suggest that BBR belongs to a group of nongenotoxic, growth-stimulating drugs with tumorigenic potential in rat liver. Its effects on the liver are different from those of PB, but seemed to resemble those of peroxisome proliferators, a hypothesis studied in the subsequent papers.

Animals↗
PubMed1977

Effect of cyproterone acetate on prolactin secretion in the female Rhesus monkey.

Adult female rhesus monkeys were given cyproterone acetate orally in doses of 0.04, 0.4, 4 and 40 mg per kg per day for 12 weeks. Its effects were assessed on serum prolactin (PRL) concentration, the morphology of the PRL cells, and the development of the mammary glands. Serum PRL was relatively unchanged in the control animals from the fourth through the twelfth weeks of the study. In contrast, PRL was significantly elevated in each group of drug-treated animals during the same time periods. There was no development of the mammary glands nor was there any evidence of milk secretion in the control animals; however, in the monkeys given cyproterone acetate the mammary glands had extensive lobuloalveolar growth and milk-like secretion that could be expressed as early as the fourth or fifth week of the study. By immunocytochemistry and differential light microscopic staining techniques, the PRL cells in the pituitary glands of the experimental animals were found to be more numerous and much larger than those present in the controls. They displayed a well developed Golgi complex and had an abundance of cytoplasmic RNA. These data suggest that PRL secretion is markedly enhanced by cyproterone acetate.

Animals↗
PubMed1976

[Toxicological examination of pure diflucortolone valerate and its formulations as ointment, fatty ointment and cream in animal experiments (author's transl)].

On the basis of absolute DL50 values 6alpha,9-difluor-11beta-hydroxy-16alpha-methyl-21-valeryloxy-1,4-pregnadiene-3,20-dione (diflucortolone valerate, Nerisona) is virtually non-toxic after single oral administration (mouse greater than 4 g/kg, rat ca. 3.1 g/kg, dog greater than 1 g/kg). Given s.c. (LD50 mouse ca. 180 mg/kg, rat ca. 13 mg/kg) and i.p. (LD50 mouse ca. 450 mg/kg, rat ca. 98 mg/kg) it is highly active and therefore produces also toxic effects. The formulations Nerisona ointment, fatty ointment and cream have proven practically non-toxic in rats after single oral gavage (LD50 greater than 33 g/kg). The daily s.c. administration over 6 weeks revealed systemic glucocorticoid effects in rats at 0.0004 mg/kg and in dogs at 0.04 mg/kg. Similar effects were seen in dogs after daily dermal treatment for 13-14 weeks with Nerisona ointment at 100 mg/kg body weight. On the skin of rabbits and dogs there were no differences in the reaction at the application site between Nerisona ointment, fatty ointment and cream and the corresponding ointment, or cream bases by daily dermal administration for 28 days. However, the 13-14 week dermal study in dogs with Nerisona ointment revealed atrophy of the epidermis at the application site in several cases. The daily dermal application of Nerisona ointment during organogenetic phases of pregnancy caused embryotoxic effects in rats at 500 mg/kg and in rabbits at 50 mg/kg. All of these findings are discusses as well-known glucocorticosteroid effects.

Administration, Oral↗
PubMed1975

Comparative kinetics of 45Ca and 89Sr in chronic uremic syndrome in the rat.

In rats a chronic uremic syndrome was induced by 5/6 resection and subsequent irradiation of the kidneys. After 5 weeks 45Ca and 89Sr were injected simultaneously, and the different metabolic handling of the two elements was determined applying an open two-compartment model of Calcium kinetics. The uremic animals were compared with two groups of rats which were pairfed, and fed ad libitum, respectively. Besides an elevenfold faster urinary excretion when calculated with Sr, and which was reduced to about one half in the uremic rats, a significant discrimination by bone in favour of Ca was found, with a rather stable factor of 1.2 in the three groups. This is considered to evidence that urinary excretion and bon uptake of Sr are independent processes.

Animals↗
PubMed1975

Congenital dyserythropoietic anemia with ultrastructural features of type I and II.

The autopsy and electron microscopic findings in a pair of brothers with congenital dyserythropoietic anemia (CDA) are presented. In both patients autopsy revealed severe secondary hemochromatosis, including cirrhosis of the liver and fatal heart involvement. According to current ultrastructural criteria, a mixture of CDA type I (interchromatin bridges, wide euchromatin-cytoplasmic connections) and of type II (marginal cisternae, nuclear protrusions, multinuclearity, karyorrhexis) was found in erythroblasts of one patient. In the second patient electron microscopy of bone marrow stored in formalin for several years allowed the diagnosis of CDA with marginal cisternae in retrospect. These findings illustrate the usefulness of electron microscopy for the diagnosis of CDA in unsolved cases of chronic ineffective erythropoiesis, even from formalin fixed material. For subtyping CDA into type I and II, however, other than morphological parameters should be used for definition. In the clinical management splenectomy and a drastic phlebotomy programme have been found favourable.

Adult↗