Biomedical subjects

P Vanparys

Publications and source records attributed to P Vanparys.

13 recordsLinked to original sources

PubMed1992

Discrimination of aneuploidogens from clastogens by C-banding, DNA and area measurements of micronuclei from mouse bone marrow.

Micronuclei (MN) obtained from mouse bone marrow cells, in vivo exposed to 3 typical clastogens (procarbazine, azathioprine, ethyl methanesulfonate) and 3 typical aneuploidogens (vinblastine, tubulazole, colchicine), were examined for C-band, area and DNA content. C-banding allows a clear discrimination between clastogens and aneuploidogens: the clastogens do not exceed 50% C-band-positive MN and the aneuploidogens all 3 produce 65-75% C-band-positive MN. Concerning the DNA content the percentages of MN containing more DNA than an average chromosome (chr) are lower than 12% for the clastogens and 38-60% for the aneuploidogens. As far as the area of the MN is concerned the percentages of MN which have a larger area than chr are lower than 23% for the clastogens and range from 47% to 71% for the aneuploidogens. Additionally 3 other mutagens were studied. Hydroquinone induces 43% C-band-positive MN with DNA content far below the content of chr; considering the area measurements, however, hydroquinone behaves as an aneuploidogen (65% of the MN are larger than chr). Mitomycin C lies between the clastogens and the aneuploidogens for all 3 criteria but 5-azacytidine is comparable to the model aneuploidogens.

Aneuploidy↗

PubMed1992

Sampling times in micronucleus testing.

A series of micronucleus inducers were evaluated in the mouse bone marrow micronucleus test to determine if a 72-h sampling time enhances the sensitivity for detecting genotoxic agents. Male and female Swiss albino mice were dosed once with 7,12- dimethylbenz[a]anthracene, 6-mercaptopurine, benzo[a]pyrene, benzene, cyclophosphamide, 2-acetylaminofluorene, tubulazole, or mitomycin C. According to the EEC and OECD guidelines, the mice were killed at 24, 48 and 72 h after dosing. All test compounds induced an increase in the number of micronucleated polychromatic erythrocytes at 24 and/or 48 h. From the results obtained, it was evident that the 72-h sampling time does not enhance the sensitivity of the micronucleus test. The present data show that for screening purposes two sampling times at 24 and 48 h are sufficient to detect clastogens as well as aneugens. Although quantitative differences were found in sensitivity to micronucleus inducers between male and female mice, no qualitative differences were observed between the two sexes.

Animals↗

PubMed1991

Micronuclei as an index of cytogenetic damage: past, present, and future.

The workshop was designed to present what is known about the production of micronuclei, what protocols are now accepted or proposed internationally, what new results have been obtained, and what new methods and protocols are likely to be forthcoming. This report is designed to convey the flavour of the workshop and to provide the essence of the new information. After the workshop an effort was made to determine what single protocol would satisfy the requirements set for the micronucleus test by as many regulatory agencies as possible. The result, reported here, includes the requirements of six regulatory authorities in Canada, the European Economic Community, the Organization for Economic Co-operation and Development, Japan, and the United States.

Animals↗

PubMed1991

Toxicity and mutagenicity of the molluscicidal plant Ambrosia maritima L.

The acute and subchronic toxicity of the molluscicidal plant, Ambrosia maritima L., has been tested on rats. No toxic signs could be detected neither after oral administration of 5 g/kg of dried leaves of the plant as a powder or as a methanolic extract, nor after the incorporation of 50,000 ppm powdered leaves in the feed during 4 weeks. Using an aqueous extract of the plant material of A. maritima or using ambrosin, one of the active molluscicidal components of the plant, no mutagenic activity could be detected in the S. typhimurium strains TA97, TA 98, TA1538, TA100 and TA1535.

Administration, Oral↗

PubMed1990

The micronucleus assay as a test for the detection of aneugenic activity.

The aim of this work was to determine the usefulness of the micronucleus assay for the detection of aneugenic potential. Chemicals affecting microtubule assembly, i.e., colchicine, vinblastine sulfate and tubulazole, and chemicals affecting targets other than microtubuli, i.e., mitomycin C, cyclophosphamide and miconazole, and the clastogens azathioprine and procarbazine were administered once orally or intraperitoneally to male and female mice. Bone marrow preparations were made at 24, 48 and 72 h after dosing. All the clastogens and aneugens, except miconazole, yielded positive results in the micronucleus test. Measurements of the area of the micronuclei and their distribution clearly showed that the chemicals affecting microtubule assembly produced larger micronuclei than did the clastogens. The pattern of area distribution of the micronuclei found with cyclophosphamide and mitomycin C was between those found for the tubulin inhibitors and the clastogens. These findings indicate that the micronucleus test not only detects chemicals affecting microtubule assembly, but also can discriminate them from clastogens by measurements of the area of the micronuclei.

Aneuploidy↗

PubMed1990

Safety aspects of oral antifungal agents.

Four main targets have to be considered when evaluating the safety of new systemically acting, oral antifungals: the liver, the endocrine system, serum cholesterol and the developing embryo. The major endocrine targets for high levels of the antifungal azoles are the adrenal cortex and the gonads. Endocrine studies demonstrate that itraconazole has little potential for interfering with steroid hormones in man. Available data also indicate that itraconazole has low predictable hepatotoxicity potential in man. In rats, serum cholesterol levels are raised during treatment with itraconazole, especially after chronic exposure. This is, however, a species-specific phenomenon which leads to secondary events at toxic doses, especially in long-term toxicity studies. In man, including patients with existing hypercholesterolaemia, serum cholesterol levels are not raised. Ketoconazole has been shown to be teratogenic at high, toxic doses in pregnant rats. The same observation has been made for itraconazole, and it may also be true for fluconazole. However, all three azoles show no teratogenicity in the rabbit. Studies with itraconazole in adrenalectomised rats and in rats given exogenous arachidonic acid indicate that adrenal effects occurring at toxic dose levels are important mediators of teratogenicity. Since itraconazole does not affect adrenal function at levels used to treat infections in man, the teratogenic risk is estimated to be low. Itraconazole is therefore a promising new drug, especially with regard to the assessment of its safety in the liver and endocrine system. Moreover, it is more potent and has a broader antifungal spectrum than other azole antifungals, and its development is considered to be an important step forward in chemotherapy.

Abnormalities, Drug-Induced↗

PubMed1989

The mouse bone marrow micronucleus assay can be used to distinguish aneugens from clastogens.

The occurrence of aneuploidy can be measured in several assays. However, none of them have been sufficiently validated. The bone marrow micronucleus test may be considered as a method for aneuploidy detection. In this work, micronuclei were induced by two aneugens, vincristine sulfate (0.1 mg/kg) and nocodazole (80 mg/kg), and two clastogens ethylmethanesulfonate (EMS) (300 mg/kg) and cyclophosphamide (60 mg/kg). Three criteria have been examined in order to distinguish micronuclei induced by aneugens and clastogens: the area of the micronuclei, the percentage of micronuclei with C-band-positive material and the DNA content of the micronuclei. C-band-positive micronuclei were found in 47% of the micronuclei for vincristine sulfate, 58% for nocodazole, 17% for EMS and 20% for cyclophosphamide. Areas of micronuclei showed a significant difference when induced by aneugens or by clastogens. Finally, the DNA content of micronuclei also showed a totally different distribution pattern when comparing the aneugen vincristine sulfate with the clastogen EMS. The three methods analysed could thus all make a difference between micronuclei induced by aneugens and those induced by clastogens.

Aneuploidy↗

PubMed1989

Toxicological profile and safety evaluation of antifungal azole derivatives.

For the development of new systemically acting, oral antifungal azoles, it is of key importance to compare them with ketoconazole, the first available drug in this therapeutic class. Ketoconazole is a major breakthrough although hepatic side-effects as well as interactions with mammalian steroids might rarely occur during prolonged treatment. The prediction of these side-effects is difficult but the potential to interact with mammalian cytochrome P-450 enzymes is considered to be important. Therefore, for the selection of itraconazole a multidisciplinary approach was applied to study this potential. The present paper deals with the toxicological profile of itraconazole and its safety evaluation. In addition, a further comparison with ketoconazole and also with fluconazole is provided, in so far sufficient information is available. For the liver as a potential target organ, the available data indicate that itraconazole is not a predictable hepatotoxic drug in man. The major endocrine targets for overdosing with antifungal azoles are the adrenal cortex and the gonads. Endocrine studies show that itraconazole is not bearing a potential to interfere with steroid hormones in patients, which is a major improvement when compared to ketoconazole. In rats, elevation of serum cholesterol is observed especially after chronic exposure to itraconazole. This species-specific phenomenon leads at toxic dose levels to secondary events, especially in the long-term toxicity studies. In man, including those with existing hypercholesterolemia, serum cholesterol is not adversely affected by itraconazole. In pregnant rats, ketoconazole was shown to be teratogenic at high, toxic doses. The same observation has been made for itraconazole and this also might be true for fluconazole.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗

PubMed1987

Mutagenic and leukemogenic activity of haloperidol: a negative study.

The mutagenic and leukemogenic potential of haloperidol, a neuroleptic of the butyrophenone class, has been studied in an in vitro Ames Salmonella/microsome test and in an 18-month carcinogenicity study in mice. Three variants of the Salmonella mutation assay were included: the spot test, the standard plate incorporation test and the preincubation test. There was no evidence that haloperidol had any mutagenic activity in any of the Salmonella mutation tests with any of the Salmonella typhimurium tester strains in the presence or absence of Aroclor 1254-induced rat- or mouse-liver S9-mix. In the 18-month study, haloperidol was injected intraperitoneally as a solution (HaldolR) at a dosage of 5 mg/kg daily for 5, 10 and 20 consecutive days in 5-week-old mice. Leucocyte counts at several time points and histopathological tumor evaluation 18 months later did not reveal any leukemogenic or other carcinogenic effect. On the basis of these data, it may be concluded that haloperidol is not mutagenic in Salmonella nor leukemogenic in mice.

Animals↗

PubMed1987

Mutagenicity evaluation of azaperone in the Salmonella/microsome test.

Azaperone was evaluated for its mutagenic potential by the Salmonella/microsome test. No mutagenic activity towards six S. typhimurium strains could be evidenced with azaperone at doses up to 2,000 micrograms/plate, either without or with metabolic activation at usual test conditions. Higher concentrations of liver post-mitochondrial fraction from Aroclor 1254 (ARO)-pretreated rats did not reveal any increase in the number of revertants towards S. typhimurium strains TA1537, TA1538 and TA98. Moreover, a plate-incorporation test with liver post-mitochondrial fractions from mice pretreated with phenobarbital (PB) and a liquid preincubation test with liver post-mitochondrial fractions from rats pretreated with ARO also failed to reveal any mutagenic action of azaperone towards S. typhimurium strain TA98. Thus, none of the tests used provided any indication of azaperone having a mutagenic action.

Azaperone↗

PubMed1985

Genetic toxicology in the pharmaceutical industry.

The main objective of the pharmaceutical industry is health protection. Drugs not intended for use in life-threatening diseases should be free from toxic effects, but every natural or man-made chemical has potential toxicity depending on the exposure dose. The pharmaceutical industry considers genetic toxicology as a part of overall safety evaluation. No single genetic toxicity test is satisfactory; a battery of test is necessary to cover the whole spectrum of genetic events. Numerous tier approaches have been proposed for mutagenicity testing but from the toxicological viewpoint a phylogenic testing model seems more appropriate than a sequential step model. Evaluation of the mutagenic potential of drugs should rely on in vivo animal models, although for screening purposes and to promote understanding of the mutagenic action, in vitro tests using different systems can be used. Rejection solely on the basis of in vitro tests can lead to the unnecessary loss of a valuable drug. More inexpensive and relatively short tests on non-mammalian and mammalian cells are needed for studying structure-mutagenic activity relationships. For extrapolating to man and in the framework of clinical studies, it might be worthwhile to focus more time on developing inexpensive and simple tests using models directly relevant to man (e.g. human body fluids).

Animals↗

PubMed1985

In vivo mutagenicity evaluation of domperidone in Drosophila germ cells and rat bone marrow cells.

Possible induction of chromosome aberrations and gene mutations by domperidone was studied in vivo respectively by a micronucleus test on female rats and a sex-linked recessive lethal test on Drosophila. In accordance with previous results all these studies revealed negative findings for domperidone so that it can be concluded that domperidone has no potential to induce chromosome aberrations and/or gene mutations.

Animals↗

PubMed1985

Toxicological properties of closantel.

The acute, subacute and chronic toxicity studies in laboratory animals showed that closantel is a well tolerated substance. At multiples of the clinical dose, overdosing might result in central nervous system effects and death. Repeated oral dosing was without effects up to 40 mg/kg in rats and dogs except for focal swelling of the epididymis in male rats at 40 mg/kg due to formation of spermatic granulomas. In sheep repeated dosing at 10 and 40 mg/kg orally and at 5 and 20 mg/kg intramuscularly every four weeks during 40 weeks demonstrated an acceptable safety margin in this target species. Reproduction studies including a three-generation study in rats showed that fertility was not affected except slightly in male rats at 40 mg/kg whereas an embryotoxic or teratogenic potential in rats and rabbits was absent. Peri- and postnatal parameters in rats were not affected. In target animals, reproduction was extensively studied in bulls, rams and ewes showing no risk of closantel for reproduction parameters. A mutagenic potential was found to be absent in a Salmonella Ames test, a sex-linked recessive lethal test in Drosophila melanogaster and a dominant lethal test in male and female mice. In 400 mice and 400 rats closantel was shown not to be carcinogenic. Tolerance studies in sheep and cattle demonstrated that oral and parenteral clinical doses were very well tolerated and devoid of serious side-effects.

Administration, Oral↗