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R Marsboom

Publications and source records attributed to R Marsboom.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1984

Effect of a high dosage of ketoconazole all or not combined with ovariectomy on N-nitroso-N-methylurea-induced mammary cancer in the rat.

Rats bearing mammary carcinomas induced by N-nitroso-N-methylurea (NMU) were subjected to either no treatment (C), to ovariectomy (O), to continuous ketoconazole dosing at 400 ppm into the diet (K) or to both ovariectomy and ketoconazole dosing (O + K). In both C and K groups survival over the experimental period of 15 weeks was low (12.5% and 15.8%, respectively). In the O group and the O + K group survival markedly improved (52.6%, P less than 0.05 and 68.4%, P less than 0.01, respectively) and partial or complete tumor regression was noted respectively in 2 and 8 rats out of 19. Whereas C and K dosed groups showed an equally high tumor multiplicity and fast tumor growth, both parameters were markedly reduced in the O group and more markedly reduced in the O + K group which showed an overall decrease of the number of tumors. These findings indicate a synergistic effect of ketoconazole dosing and ovariectomy.

Animals↗
PubMed1983

Safety studies evaluating the effect of mebendazole on liver function in dogs.

The effect of repeated and exaggerated mebendazole administration was evaluated in dogs with and without experimentally induced altered liver function. Irish Setters and Toy Poodles were dosed at 1, 3, and 5 times the therapeutic dose (22 mg/kg) of mebendazole for 17 days, without any effect on the liver. Mixed breed dogs that received increasing doses of mebendazole at 11 to 110 times the therapeutic dose for 2 months did not show adverse effects and remained in good health throughout the experiment. There was not substantial evidence that carbon tetrachloride-induced liver changes were exacerbated by subsequent repeated treatments with mebendazole at 15 times the therapeutic dose. Additionally, in dogs whose liver function was compromised experimentally by glutathione depletion and microsomal enzyme induction, administration of mebendazole at this same dosage for 30 days did not result in any hepatotoxic effect. When mebendazole was given at 15 times the therapeutic dose prior to an hypoxic episode in dogs pretreated with a barbiturate and high protein diet, there was no evidence of any adverse effect on liver function. These metabolic manipulations, in conjunction with mebendazole administration, failed to reveal any mechanism of hepatic dysfunction associated with mebendazole treatment. Unrecognized factors appear to be involved with the rare cases of hepatic dysfunction that have been reported after mebendazole administration. Only careful documentation of field cases and further laboratory research can identify these factors.

Animals↗
PubMed1982

Mutagenicity tests with astemizole in vitro and in vivo.

Possible induction of chromosomal aberrations and/or sister chromatid exchanges by astemizole was studied in vitro on human lymphocytes. In vivo chromosomal damage was assessed by a micronucleus test on rats and a dominant lethal test on both male and female mice. All these tests yielded negative results for astemizole so that is can be concluded that astemizole has no potential to induce chromosomal aberrations.

Animals↗
PubMed1981

The biological and toxicological properties of imazalil.

1-[2-(2,4-Dichlorophenyl)-2-(2-propenyloxy)-ethyl]-1H-imidazole (imazalil) base and different salts were tested in vitro on various pathogenic fungi and bacteria; in vivo on guinea-pigs, rats and turkeys experimentally infected with dermatophytes and Candida albicans. In vitro the dermatophytes were the most sensitive. The plant-pathogenic fungi were more sensitive to the base than to the salts. The antibacterial activity was low. The in vivo antifungal activity was high for the dermatophytes and rather low for Candida. The acute, subacute and chronic toxicity studies in rats and dogs showed that imazalil wa a well tolerated substance. Ocular and dermal irritation were not seen at therapeutic doses. Fertility and reproductive capacity were not affected and embryotoxicity and teratogenicity were not seen. No mutagenic or cancerogenic potential was found.

Administration, Oral↗
PubMed1980

[Estimation of the teratogenic effects of therapeutic drugs].

Therapeutics may induce embryological abnormalities in the laboratory animal, Now, it is known from experience that the currently applied experimental procedures allow to detect potential teratogenic risks in animals. There is only a slight possibility that a new therapeutic would be highly teratogenic as very special conditions are fundamental for the exteriorisation of the teratogenic effect, such as the sensibility and the developmental stage of the embryo, its genetic constitution and the physiology and pathology of the mother. The wellknown difficulties associated with the extrapolation of experimental results require that more species are used and that historical control data for each species and strains are kept allowing a global assessment of the results which better weighs the potential risk against the therapeutic activity of each new therapeutic.

Abnormalities, Drug-Induced↗
PubMed1980

A comparison between manual and semiautomatic white cell differentiation.

Manual and semiautomatic white cell differentiations have been found to produce comparable results. Semiautomatic counting can be accomplished with a smaller number of cells than required in manual counting without significant loss of accuracy. Cell types have been compared one by one to detect systematic deviations between the counting procedures. Complete differentials have been compared by means of a multivariate method called canonical correlation. The result of the canonical correlation is displayed graphically. Highly significant correlations have been found between 100-cell manual and 100-, 50-cell semiautomatic differentials.

Animals↗
PubMed1978

Domperidone, a novel and safe gastrokinetic anti-nauseant for the treatment of dyspepsia and vomiting.

The new potent anti-nauseant 5-chloro-1-(1p[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-propyl]-4-piperidinyl)-1.3-dihydro-2H-benzimidazol-2-one (domperidone), which in contrast to available anti-emetics does not provoke extrapyramidal or adrenolytic adverse effects, also enhances gastric emptying motility. Controlled clinical trials have confirmed its prokinetic effects on the stomach and its lack of side-effects, even at high doses. This anti-nauseant appears to be a safe and effective treatment for patients, both adults and children, with dyspepsia or vomiting.

Animals↗
PubMed1978

Antiarrhythmic, electrophysiologic and hemodynamic effects of lorcainide.

Lorcainide hydrochloride or N-(4-chlorophenyl)-N-[1-(1-methyl-ethyl)-4-piperidinyl]benzeneacetamide mono-hydrochloride (R 15889) is a new anti-arrhythmic drug. Studies in dogs show that lorcainide is effective against post-infarction and ouabain-induced ventricular arrhythmias, and abolishes acetylcholine and aconitine-induced atrial fibrillation; it elevates the threshold of electrically induced ventricular fibrillation. In isolated dog and cow Purkinje fibers, in dog ventricular and in guinea-pig auricular muscle preparations, lorcainide decreases the rate of rise of the transmembrane action potential, the conduction velocity and spontaneous activity. It prolongs the refractory period of isolated Purkpinje and ventricular muscle preparations, and the functional refractory period of the AV node in the guinea-pig heart. It has no effect on Ca mediated electrical activity. Isometric force measurements in isolated cat papillary muscles and hemodynamic studies in anaesthetized and unanaesthetized dogs indicate that lorcainide moderately decreases myocardial contractility. Side effects observed at large doses are of central origin and include salivation, tremor and vomiting. Intravenous injection induces transient peripheral vasodilatation. Lorcainide is an antiarrhythmic of the local anaesthetic type. It is characterized by a good oral absorption, a long duration of action and a large safety factor.

Acetamides↗