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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
PubMed1983

Toxicological screening models: drug-induced oxidative hemolysis.

In an attempt to obtain a simple screening system for the assessment of toxic-hemolytic effects of chemical substances, a battery of hematological tests was used. Phenacetin served as reference substance. The drug caused reversible formation of methemoglobin and Heinz bodies and an increase in peripheral reticulocytes after 2 and 4 weeks of treatment. Furthermore, an increase in the mean corpuscular volume of red blood cells (RBC) and the volume of RBC ghosts in hypotonic solutions, and a decrease of the mean corpuscular fragility was observed. The latter changes are considered to be a consequence of regenerative RBC compensation rather than due to structural membrane alteration caused by the drug. The results suggest that only a combination of several hematological tests can provide comprehensive information about the hemolytic potential of chemical substances, and that for screening purposes small numbers of animals are often sufficient.

Animals↗
PubMed1983

Inhibition of cardiotoxic, nephrotoxic and neurotoxic effects of doxorubicin by ICRF-159.

Cardiotoxicity of doxorubicin, 2 mg/kg i.p. twice weekly in rats, was assessed by serial electrocardiography and electron microscopy. The toxic effects were markedly inhibited by ICRF-159, 50 mg/kg p.o. given 1 h before doxorubicin. The development of nephropathy characterized by proteinuria, hyperlipidemia and glomerular and tubular changes was significantly retarded, and the degenerative changes of peripheral nerves were markedly reduced. On the other hand, ICRF-159 enhanced the depressant effects of doxorubicin on bone marrow function. Doxorubicin reduced body weight gain, caused ascites, decrease in heart and thymus weight, and increase in liver and kidney weight. These changes were also inhibited or attenuated by ICRF-159 pretreatment.

Animals↗
PubMed1983

[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↗
PubMed1982

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↗
PubMed1982

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↗
PubMed1982

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↗
PubMed1982

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↗
PubMed1982

Cell detachment and cloning efficiency as parameters for cytotoxicity.

Cell detachment and cloning efficiency of Baby Hamster Kidney cells (BHK-21 C13) were used as parameters to quantify cytotoxicity in vitro of 3 endogenous chemicals (glutathione, L-methionine, L-cysteine HCl) and 4 organotin compounds (tributyltinoxide, tributyltinchloride, tetrabutyltin, tetraphenyltin). IC50 values (inhibitory concentration at which the cloning efficiency was reduced to 50%) were estimated to be larger than 10(-3) M for all 3 endogenous substances, which served as a calibration of the cell culture system for non-toxic chemicals. For the 2 tributyltin salts the IC50 values were estimated to be near 10(-6) M and for the 2 tetraalkyltin compounds near 10(-5) M. The estimated CD50 values (concentration at which 50% of the cells detach) were at least twice as large as the corresponding IC50 values for all 7 chemicals tested. For the toxic tributyltin salts the cell detachment assay was 30-60 times less sensitive than the cloning efficiency assay. However, both assays rank all compounds tested in the same sequence of toxicity as that known from in vivo studies.

Animals↗
PubMed1982

Epoxide hydrolase activity in small biopsy samples of preneoplastic and neoplastic rat liver.

Epoxide hydrolase (EH) activity was measured in serial fine-needle aspiration biopsy (FNAB) samples of male rats chronically treated with the hepatocarcinogen, N-nitrosomorpholine (NNM, 10 mg/100 ml drinking water). The development of neoplasia was confirmed histopathologically at the end of the experiment. The enzyme activity was significantly increased after 2 days of NNM administration and reached a 3 to 4-fold increase after 2 weeks that remained stable throughout the experiment. Although EH is not related to the metabolism of NNM, the induction of enzyme as readily recognized with the FNAB method might be a useful marker in the attempt to characterize hepatocarcinogenic substances in rats.

Animals↗
PubMed1982

Comparison of cardiotoxicity of two anthracenediones and doxorubicin in rats.

Two new anthracenediones with antineoplastic activities resembling those of the anthracycline antibiotics were studied in a rat cardiotoxicity model system. NCS-196473 was approx. 10-fold less toxic than doxorubicin and caused only minor electrocardiogram (ECG) changes. Its dihydroxyanalog NSC-279836 was somewhat more toxic than doxorubicin, caused marked leukopenia and induced ECG changes and moderate elevation of serum GOT, LDH and creatine phosphokinase (CK). Both anthracenediones induced marked alterations of mitochondrial structure in the heart but no dilatation of the sarcoplasmic reticulum and distortion of the contractile elements. It is concluded that the cardiotoxic effects of the anthracenediones are of a less specific nature than those caused by doxorubicin.

Animals↗
PubMed1981

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↗
PubMed1981

Distribution of nuclear size and DNA content in serial liver biopsies of rats treated with N-nitrosomorpholine, phenobarbital and butylated hydroxytoluene.

Nuclear size distribution and DNA content distribution were determined in liver biopsies of rats using an electronic particle counter and an impulse cytophotometer, respectively. Nuclear size distribution and DNA content distribution were found to be highly correlated regardless whether peak areas or peak heights of the histograms were compared. Treatment with the hepatocarcinogen NNM caused a dose-dependent increase in octoploid nuclei and a shift of the 2 n : 4 n ratio in favor of the diploid nuclei. Treatment with Pb and BHT had minor effects on nuclear size and DNA content distribution. The paper demonstrates the usefulness of the fine-needle aspiration biopsy procedure for the evaluation of liver changes induced by chemical substances.

Animals↗
PubMed1980

Mutagenicity testing of pharmaceuticals: present status. Introduction.

An international conference was held in Paris from March 12 to 14, 1980, to discuss the proposed guidelines on testing of medicinal products for their mutagenic potential, issued in April 1979 by the Committee on Proprietary Medicinal Products in Brussels. This introductory paper describes the goals of the conference and an appraisal of the discussions held at this meeting.

Drug Evaluation, Preclinical↗
PubMed1980

Unscheduled DNA synthesis in the testis, a secondary test for the evaluation of chemical mutagens.

DNA damage induced by methylmethane sulfonate, cyclophosphamide, doxorubicin and procarbazine in male germ cells was assessed in rabbits by the demonstration of unscheduled DNA synthesis (UDS), in meiotic and postmeiotic phases of maturation. Immediately after treatment by the intravenous route tritiated thymidine was injected into both testicles. Subsequently, rabbits were ejaculated serially, sperm heads were isolated and assayed for radioactivity by liquid scintillation counting. Dose-dependent UDS was demonstrated in late spermatocytes and early spermatids. High doses of hycanthone also induced UDS, but isoniazid and metronidazole had no effect. The rabbit testis UDS test takes into account metabolic and pharmacokinetic aspects of the test substances and provides information about their penetration through the blood-testicular barrier. It is therefore useful for secondary evaluation of potential mutagens. UDS induced by procarbazine was abolished by simultaneous treatment with Ara-C. Thus, the test also recognizes substances that inhibit DNA repair synthesis.

Animals↗