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Biomedical subjects

G Zbinden

Publications and source records attributed to G Zbinden.

At least 73 records · Page 4Linked to original sources

[Early pancreatic lesions induced by N-nitroso-bis(2-hydroxypropyl) amine in the golden Syrian hamster].

Early lesions of the exocrine pancreas of the Syrian Golden Hamster induced by lifetime weekly oral or subcutaneous administration of N-nitroso-bis (2 hydroxy propyl) amine (250 mg/kg) were studied by light and electron microscopy and autoradiography. There were no pathological differences according to the way of administration. The histogenesis of induced pancreatic neoplasms may be summed up as follows: hyperplasia of ductular cells with new islet cell formation that lead to the development of peri or intra insular cystic ductules which become cystedenomas and carcinomas.

Animals

Newer diagnostic procedures in chronic toxicity studies in rats.

A large number of diagnostic procedures which are either adapted from clinical laboratory tests or are based on pharmacological and biochemical concepts are available for introduction into routine animal toxicology. In order to illustrate the variety of possible experimental approaches several examples are given, ranging from simple determinations of bleeding time and fibrinolysis to cardiovascular function studies including serial electrocardiography, measurement of the cardiac output and the catecholamine-arrhythmia threshold. Moreover, the use of serial fine needle aspiration biopsy for early diagnosis of various liver lesions is described. It is stressed that these diagnostic procedures should not be included indiscriminately into the classical toxicological programs, but should be used judiciously to test a clearly stated scientific hypothesis.

Animals

Heart rate- and ECG-recording in the rat by biotelemetry.

A method for 24 h recording of the heart rate (HR) in unrestrained, freely moving rats is described. Commercially available biotelemetry transmitters were used in combination with normal ranged FM-receivers. The data presented show a pronounced diurnal rhythm in the HR of the rat. When the rats are exposed to noise a large increase in the HR could be demonstrated. The system described is also suitable for analysis of the time parameters of the electro-cardiogram (ECG).

Animals

Current trends in safety testing and toxicological research.

The paper reviews current concepts of toxicological evaluation of new drugs and other chemicals. Instead of completing a predetermined check-list toxicologists now consider the potential adverse effects of the substances under actual conditions of use. They then design experimental models which have a high probability to predict the toxic effects. Moreover, the enhanced susceptibilities of special risk populations is more and more taken into consideration.

Animals

Granuloma pouch assay. IV. Induction of sister-chromatid exchanges in vivo.

SCEs were induced, in vivo, in cells of a rapidly proliferating subcutaneous granulation tissue, initiated by the formation of a subcutaneous air pouch, on the backs of adult male rats (Granuloma Pouch Assay). 2 days after pouch formation the test compounds were applied, and 24 h later the granulation tissue was excised and dissociated into single cells. Isolated cells were cultured in vitro in media containing BrdU, and SCEs were determined within 24-48 h. The spontaneous frequency was 14.4 +/- 1.1 per metaphase. Mitomycin C (MMC) and cyclophosphamide (CP) induced a significant and dose-dependent increase in SCE frequencies. Results obtained after i.v., i.p. and intra-pouch application routes are compared.

Animals

Experimental methods in behavioral teratology.

The possibility that the exposure of the embryo to certain chemical substances can lead to behavioral disturbances is known from human epidemiological studies, e.g., in chronic poisoning with mercury and ethanol. Therefore, efforts are made to develop toxicological techniques with which new behavioral teratogens can be recognized. The review describes the most important experimental methods which are presently explored, and which are based on a rich body of knowledge accumulated by experimental psychologists. Most of the tests were developed with small animals, mostly with rats. They range from a rather straightforward determination of various reflexes to complex behavioral situations involving mechanical devices, operant conditioning techniques and procedures evaluating social behavior. In applying these methods in routine toxicology, it is important to remember, that many behavioral effects determined in newborn and adult animals are subtle. Moreover, they are influenced by a large variety of environmental factors affecting the health and the behavior of the mothers and of the offspring in the early and later phases of development. Therefore, the experiments must be conducted under highly standardized conditions and must be controlled rigorously. It is concluded that the best experimental strategy for the evaluation of potential behavioral teratogens is not yet established. Therefore, it would be premature to decide on a fixed protocol to be included in routine animal safety experiments for drugs and other chemical substances.

Animals

Granuloma pouch assay. II. Induction of 6-thioguanine resistance by MNNG and benzo[a]pyrene in vivo.

Growth of granulation tissue was initiated with croton oil on the inside of a subcutaneous air pouch, on the back of adult male rats. Two days later, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and benzo[a]pyrene (BP) were applied directly into the pouch in doses ranging from 0.05 to 1.8 mg and from 0.03 to 0.5 mg, resp. The granulation tissue was excised after 48 h. Isolated single cells were checked for their 6-thioguanine resistance in vitro. The influence of cell density during expression time in vitro, of 6-thioguanine concentration and cell density in selective media on the recovery of mutant cells was investigated. The spontaneous mutation frequency was 0.53 x 10(-5). There was a dose-dependent increase in mutation frequencies with both compounds. The frequency was 5 times as high with MNNG as with BP.

Animals

Inhibition of 5-hydroxytryptophan nephrotoxicity by alpha-difluoromethyl-dopa, an inhibitor or L-amino acid decarboxylase.

Oral and intraperitoneal treatment of rats with L-5-hydroxytryptophan (5-HTP) caused dose-dependent kidney damage characterized by increase in kidney weight, functional disturbances and focal tubular necrosis. Alpha-Difluoromethyl-DOPA (DFMD), a drug that inhibits the conversion of 5-HTP to L-5-hydroxytryptamine (5-HT) abolished the nephrotoxicity of 5-HTP.

5-Hydroxytryptophan

Assessment of emetine cardiotoxicity in a subacute toxicity experiment in rats.

We explored the usefulness of cardiovascular function studies for the detection and characterization of emetine cardiotoxicity in a subacute toxicity experiment. Rats received 1 mg/kg, s.c., emetine five times weekly for up to 7 weeks. In unanesthetized animals, statistically significant changes of the electrocardiogram (EKG) appeared in the following sequence: prolongation of QRS interval (5th day), flattening of T wave (beginning of 4th week), and prolongation of PR interval (end of 4th week). Terminal cardiovascular studies were conducted under urethane anesthesia. EKG changes were comparable to those recorded in conscious rats, but no decrease in T wave voltage occurred. Blood pressure and heart rate remained unchanged. Cardiac output was decreased after 5 and 7 weeks of treatment, when heart weights were also significantly reduced. The response of cardiac output and mean arterial blood pressure to intravenously injected norepinephrine and epinephrine remained unchanged. Catecholamine-induced arrhythmias occurred less frequently in emetine-treated animals than in controls. No significant structural lesions of the heart muscle were detected by light microscopy. The cardiotoxic effects observed in rats were similar to those reported in humans receiving the usual therapeutic dose of approximately 1 mg/kg/day. We conclude that cardiovascular function studies can make an important contribution to the predictive value of animal toxicity experiments.

Anesthesia

Electrocardiographic changes in rats during chronic treatment with antidepressant and neuroleptic drugs.

Five antidepressants, 3 phenothiazines and 5 butyrophenone neuroleptics were administered to rats orally at maximally tolerated doses for 22 weeks. The electrocardiogram (ECG) was recorded weekly. In animals treated with antidepressants quinidine-like changes of the atrioventricular and intraventricular conduction developed. There were also elevation of T-wave and right rotation of the electrical axis. Dibenzepine had the least effect on the ECG. In the group of phenothiazines chlorpromazine induced tachycardia and thioridazine widening of the QRS complex. Prothipendyl had no effect. ECG-changes induced by some of the butyrophenone derivatives were tachycardia and widening of the QRS-complex. In rats treated with protriptyline the ECG changes were correlated with drug concentrations in serum and myocardial tissue. The studies provided a quantitative assessment of the cardiac effects of clinically proven psychotropic drugs. They will be useful as a baseline for the preclinical evaluation of new derivatives.

Animals

Biological assessment of chemical DNA damage in germ cells of male rabbits.

DNA damage represents a key step in mutagenesis and carcinogenesis. Excision repair has been described to be the major pathway restoring damaged DNA. Assaying DNA repair may thus illuminate the mechanism of mutagenesis and carcinogenesis and serve as an indicator of the mutagenic and carcinogenic potential of environmental chemicals and drugs. The paper demonstrates a practical application of these concepts. DNA damage induced by chemical substances in male germ cells of rabbits was assessed by the demonstration of DNA repair synthesis in meiotic and post-meiotic maturation stages. Incorporation of tritium-labeled thymidine was monitored in spermatozoa obtained by serial ejaculation. The test was validated with several standard mutagens and carcinogens, and its usefulness was demonstrated with a study on 3 suspected genotoxic drugs, i.e. hycanthone, isoniazid, and metronidazole.

Animals

Unscheduled DNA synthesis in male rabbit germ cells induced by methylmethane sulfonate, cyclophosphamide and adriamycin.

Male rabbit germ cells were labelled by intratesticular injection of [3H]-thymidine (3H-T). In sperms of control animals, radioactivity was first demonstrated between the 40th and 43rd day after labelling, corresponding to preleptotene spermatocytes. In rabbits treated with 22.5 mg/kg methylmethane sulfonate (MMS), significant radioactivity was shown in sperms collected from day 19 ownwards. These cells derived from spermatocyes and early spermatids at the time of labelling. 3H-T incorporation into these cell populations represents unscheduled DNA synthesis (UDS), a repair process initiated after chemical damage of germ cell DNA. After i.v. injection of 20 mg/kg cyclophosphamide, an alkylating agent that must be activated, labelled sperms were found 28--37 days after treatment. This shows that UDS took place in spermatocytes during the pachytene and zygotene stages. Adriamycin (1.0 and 3.0 mg/kg) induced UDS during pachytene and zygotene stages of spermatogenesis. Sperm counts decreased during spermatogonial stages by a factor of about ten in cyclophosphamide and adriamycin treated rabbits. It was not changed after MMS-treatment.

Animals

Application of fine-needle aspiration biopsy for the diagnosis of dysplastic and neoplastic liver cell changes induced by N-nitrosomorpholine in rats.

Male rats were treated with the hepatocarcinogen, N-nitrosomorpholine (NNM, 10 mg ad 100 ml drinking water) for 19 weeks. Repeated fine-needle aspiration biopsies of the liver were performed percutaneously. Cytomorphologic and cytochemical criteria were used for the characterization of dysplastic and carcinoma cells. The alterations seen in the smears were correlated with histopathologic findings in the punctured liver lobes. Cells showing type I dysplasia were recognized in smears obtained from day 7 on. They corresponded to the swollen, glycogen-free cells developing in zone 3 of the Rappaport acinus during the early treatment phases. In later stages type I dysplastic cells were observed in smears. This coincided with the development of neoplastic nodules seen in histopathologic preparations. Carcinoma cells were recognized first after 15 weeks. Marked gamma-glutamyl transpeptidase (gamma-GT) activity could be demonstrated cytochemically in biopsy smears and biochemically in biopsy homogenates during the early phases of NNM-treatment. Simultaneously, a rise in gamma-GT activity was also observed in the serum.

Animals

The no-effect level, an old bone of contention in toxicology.

This discussion of the NEL presents some thoughts how toxicologists could be encouraged to use more sophisticated modern techniques for the study of various environmental chemicals. It is proposed to use the concept of the NEL only for data obtained by conventional techniques in routine toxicity experiments. Information on the mechanisms of the biologic effects of chemicals should, whenever possible, be used preferentially for the assessment of human risk and should therefore also be considered for the establishment of the ADI.

Dose-Response Relationship, Drug