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Biomedical subjects

G Zbinden

Publications and source records attributed to G Zbinden.

At least 55 records · Page 3Linked to original sources
PubMed1986

Neurobehavioral screening in rats: validation study.

The usefulness of a neurobehavioral check-list for the detection and characterization of neurotoxic effects of chemical compounds was evaluated in rats. The animals were given single doses of the test compounds, and higher or lower doses of the substances were administered in subsequent weeks, depending on the outcome of the experiments. The testing procedure proved to be useful for detecting the neurobehavioral hazards of psychotherapeutics and other drugs with known neurobehavioral side-effects. However, the investigational technique was less satisfactory for evaluating alcohols and various neurotoxic agents. With these compounds, even repeated dosing did not improve the predictability of the testing scheme. Swimming performance was also investigated and was found to be impaired only in rats treated with neuroleptic drugs. Based on this validation study, the advantages and pitfalls of the neurobehavioral check-list approach are discussed.

Alcohols↗
PubMed1985

Characterization of proteolytic systems in human and rat urine.

Activities of proteolytic enzymes were detected in rat and human urine by using [125 l] iodo-insulin B chain as a substrate. The pH optimum of human urine activity was in the acidic range (pH 2.0) whereas the rat urine had two pH optima, one at the acidic range similar to human urine and another at pH 7.5. The activities were linear with time and amount of enzyme. Study with various proteinase inhibitors revealed that the acidic pH activities of human and rat urine were apparently of carboxyl endopeptidases since they were totally inhibited by pepstatin 10-8M. The neutral pH proteolysis of rat urine was inhibited by chelating agents and therefore it was considered as a metalloendopeptidase activity. These findings show the difference between the content of urinary proteolytic enzymes in humans and in rats by using a sensitive and simple radioactive assay.

Animals↗
PubMed1985

Thrombogenic effects of xenobiotics.

The mechanisms by which xenobiotics may cause or promote thrombosis include vascular damage, induction of a hypercoagulable state and disturbances of blood flow. This paper discusses the methods available to detect various types of thrombogenic substances. Pathomorphological techniques are best suited to demonstrate thrombosis caused by localized vascular damage or generalized endothelial lesions. For the assessment of disseminated microcirculatory thrombosis, the consumption of platelets and clotting factors and the appearance of specific platelet proteins and fibrinogen and fibrin split products can be determined in the blood. Hypercoagulability which is defined as a perturbation of the hemostatic equilibrium resulting in a shift in the direction of thrombosis, is of particular importance in toxicology. Many in vitro, ex vivo and in vivo methods have been proposed to detect and to measure the ability of xenobiotics to induce a prethrombotic state. Their usefulness is demonstrated with several examples.

Adrenocorticotropic Hormone↗
PubMed1985

Early biochemical and morphological changes of the rat adrenal medulla induced by xylitol.

Long-term administration of high doses of xylitol and other polyols in rats has been associated with an increase in adrenal medullary hyperplasia and neoplasia. In order to exclude age-related factors and to differentiate between unspecific stress reactions and direct effects of the compound administered, a model was developed for quantifying early adrenomedullary responses. Male SD rats were fed xylitol (10% or 20% in the diet) for 2 and 8 weeks, and early biochemical changes were correlated with a stereological analysis of the adrenal medulla. At first, the in vivo rate of catecholamine (CA) biosynthesis was slightly decreased (at 2 weeks). This was followed by an increase in dopamine-beta-hydroxylase (DBH) activity (at 8 weeks). By that time, the total chromaffin cell volume had increased and the number of chromaffin cells per reference volume had decreased in a dose-dependent way. The total number of chromaffin cells per adrenal gland showed a distinct tendency towards an increase. Adrenal epinephrine and norepinephrine contents were not altered, and both tyrosine hydroxylase and phenylethanolamine-N-methyltransferase activities remained unchanged. These data suggest that continued xylitol administration evoked an inhibitory effect on CA synthesis that, together with stimulation of the adrenal medulla brought about by the compound, resulted in compensatory medullary hypertrophy and hyperplasia.

Adrenal Medulla↗
PubMed1985

Ethical considerations in toxicology.

Since most of the research necessary for the safety evaluation of chemicals requires the killing of laboratory animals, toxicologists are faced with an ethical conflict between their professional duties and the interests of the animals. In the past, the protection of consumers against chemical injury was considered to be of the greatest importance, and society approved of all efforts to detect even the slightest hazards from man-made and environmental chemicals. In recent years, toxicologists have become aware of their ethical responsibilities not only for the safety of the human population but also for the welfare of the animals. They have begun to review the classical toxicological procedures critically and now require that the maximum amount of relevant information is obtained from the smallest number of laboratory animals. Toxicologists have also become aware of the alternative methods that permit the investigation of toxicological responses in unicellular organisms and cell cultures. The problem of testing chemicals for irritant properties on skin and mucous membranes is an excellent example of how concern for animals has generated a range of original and imaginative research leading not only to a reduction in the use of animals but also to a more efficient and scientific approach to an important health problem.

Animals↗
PubMed1985

Interpretation of cell toxicity data for the estimation of potential irritation.

Three cytotoxicity assays were evaluated using 57 chemicals of various classes (inorganic and organic metal salts, solvents, detergents, reagents, drugs) which have widely different mechanisms of cytotoxicity. Baby hamster kidney fibroblasts (BHK-21/C13) and early (Keller) and late (MRC-5) passage human fibroblasts were used to measure cell detachment, cloning efficiency, and growth inhibition under subconfluent culture conditions. For the majority of chemicals, for which comparisons were made, the ranking order was roughly the same in all three tests and with all three cell types. However, for some chemicals specific growth effects could either be detected or excluded because the relationship between the data from the detachment assay and that from one of the growth assays was characteristically altered. The ranking order resulting from our in vitro data correlated better with threshold limit values for human workroom air (TLV/TWA) than with LD50 values (rat, oral). Correlations with data from Draize skin and eye irritation tests were not determined since the available in vivo values were derived using various different scoring systems. However, when our in vitro data were used to divide the chemicals into three crude classes, (i) non-irritant, (ii) mild to moderate irritant, or (iii) strong irritant or corrosive, and the results were compared with the known irritation potential for skin and mucous membranes derived from human exposure data, the in vitro data were more than 80% predictive of the in vivo classifications.

Animals↗
PubMed1985

Aristolochic acid induces 6-thioguanine-resistant mutants in an extrahepatic tissue in rats after oral application.

The mutagenic activity of the natural plant product aristolochic acid (AA) was tested in the Granuloma Pouch Assay, which detects gene mutations induced in a subcutaneous granuloma tissue of rats. After direct exposure of the target tissue, AA induced high frequencies of mutants at a relatively low cytostatic/cytotoxic level. AA was more potent that N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) at equimolar doses. After oral application of AA, a dose-dependent mutagenic activity was seen. In contrast a very weak and inconsistent mutagenic effect was seen after systemic application of MNNG. These observations suggest that after oral application AA is not detoxified efficiently and can exert its mutagenic activity in extrahepatic tissues whereas MNNG is detoxified to a large extent at the site of administration.

Administration, Oral↗
PubMed1984

The effect of methyl-2-tetradecylglycidate (McNeil 3716) on heart mitochondrial metabolism in rats.

Methyl-2- tetradecylglycidate (MTG), one of a new class of hypoglycemic agents, given to healthy rats, prompted uncoupling of oxidative phosphorylation in heart mitochondria (measured ex vivo) without a concomitant effect on mitochondrial electron transfer reactions. At the same time heart creatinephosphate -kinase was inhibited and subsequently the semipermeability of the inner mitochondrial membrane was impaired as demonstrated by an influx of creatine. The triglyceride and total phospholipid content of heart tissue and its mitochondria showed a transient elevation. The hearts were enlarged, flabby and discoloured and had dilated ventricles. These effects could be the account of an adverse effect of MTG on the heart energy metabolism.

Animals↗
PubMed1984

Morphometric and biochemical analysis of adrenal medullary hyperplasia induced by nicotine in rats.

The administration of nicotine (1 and 4 mg/kg/day, subcutaneously for up to 6 weeks) to male Sprague-Dawley rats first induced a time-and dose-dependent increase in catecholamine (CA) synthesis. This was followed by an increase in endogenous CA levels and in total volume and number of chromaffin cells, as measured by stereological methods on serially sectioned adrenal glands. Thus, continued stimulation of the sympathoadrenal system generated an increase in biosynthetic enzyme activity, and subsequently adrenal medullary hypertrophy and hyperplasia developed as an adaptive reaction. The proposed model is useful for quantifying both biochemically and morphometrically early adrenal changes long before irreversible pathologic alterations are manifested.

Adrenal Glands↗
PubMed1984

Behavioral effects of cyclazocine on rats assessed in the open field and residential maze.

Changes in behavior of rats caused by different doses of cyclazocine (0.1, 0.4, 0.75, 1.5, and 3.0 mg/kg) were detected by two different methods: the open field and the residential maze. In the residential maze the locomotion was recorded automatically, whereas in the open field the measurements were made by direct observation. In the maze low doses of cyclazocine (less than 1.5 mg/kg) caused a marked change in the time course of locomotion and local activity at the beginning of the 23-h sessions. The duration of this effect was dose-dependent, between 2 and 4 h. The highest dose (3 mg/kg) induced a strong stimulation of locomotor activity which lasted about 1 h, and stereotyped patterns, i.e., long periods of unidirectional runs through circular alleys. In the open field rearing and grooming behavior proved to be the most sensitive parameters. The frequency of both was reduced at a dose of 0.4 mg/kg. Locomotion showed the highest values at 1.5 mg/kg and decreased with the highest dose (3 mg/kg) to control levels. The study demonstrated that the principal changes induced by cyclazocine were of a qualitative nature, characterized by monotonous locomotor activity. The computerized residential maze procedure proved to be well suited to detect and quantify this behavioral change.

Animals↗
PubMed1984

Toxicological assessment of the hemostatic system, regulatory requirements, and industry practice.

Disturbances of the hemostatic system which may be caused by chemicals include hemorrhagic diathesis, caused by inhibition of blood clotting, impairment of platelet function, and hyperactivity of fibrinolysis. Activation of the plasmatic clotting system, platelet aggregation, and inhibition of fibrinolysis may lead to thromboembolic complications. Although much is known about the functions of the hemostatic system a rational and cost-effective approach for its assessment in industrial toxicology is lacking. In this review the physiology of hemostasis and the available laboratory tests are discussed, current regulatory requirements are described, and industry practice is analyzed based on experience accumulated over the last 23 years. Proposals for a more flexible and scientific approach to testing of hemostatic mechanisms in toxicology are made.

Animals↗
PubMed1984

Toxicological screening.

Well-defined dose- and time-related toxic effects of chemicals can often be detected using simple tests with small numbers of animals. The strategies for the establishment of toxicological screening tests are discussed. The most important steps are the definition of the targets, the selection of the methods, and the setting of the test criteria. Screening tests must then be validated with standard reference chemicals, and the test criteria must be adjusted so that the standards can be detected regularly. Maximal flexibility is allowed in the design of the tests. For evaluation, the results obtained in treated animals can be compared with those of controls, using conventional concepts of biostatistics. It is also possible to base the evaluation on preset test criteria. Toxicological screening tests do not replace conventional safety studies, but they help in selecting the most promising candidates in a series of related chemicals and in establishing priorities for further testing. As an example, a screening for the hemolytic effects of chemicals is presented.

Drug Evaluation, Preclinical↗
PubMed1984

Toxicological studies with a novel synthetic anthracycline, the bis-hydrazone bridged analog of 4-demethoxydaunorubicin (SC-33428).

The toxicological effects of SC-33428, a bis-hydrazone bridged analog of 4-demethoxydaunorubicin were evaluated in rats. The bone marrow depressant effects were more pronounced than those caused by equal doses of doxorubicin, but the cardiotoxic and the nephrotoxic effects were clearly less marked. The concentrations of SC-33428 in serum, heart and kidneys after single and repeated i.p. injections were considerably lower than those reached with doxorubicin. Since the drug is at least as active as doxorubicin in various tumor models, it is likely that it will distinguish itself in the clinic by a broader margin of safety.

Animals↗
PubMed1983

The mutagenic activity of 5-bromo-2'-deoxyuridine (BrdU) in vivo in rats.

BrdU tablets were implanted subcutaneously in rats, and BrdU concentrations were determined in the serum. Within 5 hr peak concentrations of 10 micrograms BrdU/ml blood were reached. The influence of BrdU in vivo on cell cycling, DNA synthesis, spontaneous sister chromatid exchange (SCE) frequencies, and gene-mutation frequencies (6-TGr) was determined in freshly isolated cells from a subcutaneous granulation tissue. The most significant effect of BrdU in vivo was a doubling of the spontaneous 6-TGr frequency. In reconstruction experiments in vitro the mutagenic activity of BrdU applied in concentrations found in vivo was 2.5-6-fold higher. With the use of agar-coated tablets, BrdU concentrations in the blood were reduced by half, and no peak concentration was found. The differential staining of chromatids was still sufficient. Since the mutagenic effect of BrdU in vitro was found to be strongly concentration dependent, the use of agar-coated tablets is recommended in experiments in which the compound is used to demonstrate SCE in vivo.

Animals↗
PubMed1983

Neurobehavioral tests in single- and repeated-dose toxicity studies in small rodents.

The discovery of neurobehavioral hazards is an important goal of the majority of the toxicological studies. Quite often it is possible to detect signs of neurobehavioral toxicity through non-instrumental observations and from the response of the animals to simple manipulations. Psychopharmacologists have long used these techniques to identify new drugs with potential usefulness as psychotropic agents. Their approach may also be applicable for the detection of neurotoxic chemicals. Based on a review of the literature and personal experience a neurobehavioral check-list is proposed which can easily be incorporated into the animal care and treatment routine used in single- and repeated-dose toxicity studies with small rodents. The instrumental tests which measure motor activity, neuromuscular functions, muscle strength, emotionality and social behavior are also discussed. The usefulness of these procedures in toxicology is not yet established. Their introduction into the testing routine creates considerable logistic difficulties and might not be compatible with good laboratory practices. Therefore, it is suggested to explore the procedures developed by psychopharmalogists and behavioral scientists and to validate them with a variety of neurobehavioral toxins. Tests which produce relevant and reproducible data may then be added to the toxicological protocols, preferably within the framework of safety pharmacology.

Animals↗
PubMed1983

G0-G1 transition of rat hepatocytes detected by changes in nuclear chromatin condensation after in vivo treatment with phenobarbital.

The transition of hepatocytes from G0 to late G1-phase was studied in phenobarbital (PB) treated rats using visual and cytofluorometric evaluations of nuclear fluorescence patterns after quinacrine dihydrochloride (QDH) staining. In controls, about 90% of the nuclei showed bright nuclear fluorescence indicating G0-phase. After 10 days there was a reduction in fluorescence intensity which became more marked with continued PB treatment, indicating a shift from a resting G0 state to a later G1 phase of the cell cycle. The relevance of these findings for the understanding of tumor promoting properties of PB is discussed.

Animals↗
PubMed1983

Single dose carcinogenicity of procarbazine in rats.

Rats carrying a 2-day-old subcutaneous air pouch were treated with single doses of procarbazine. Local fibrosarcomas developed in the pouch after oral, intraperitoneal and local administration of 300 mg/kg, but no tumours were induced if the drug was injected into unstimulated subcutaneous tissue. Tumours only appeared in those animals in which growth of the granuloma tissue was stimulated with a dose of croton oil. The high dose of procarbazine (300 mg/kg) also induced an increase in total tumour incidence at other sites.

Adenoma↗