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Biomedical subjects

P C Barrow

Publications and source records attributed to P C Barrow.

7 recordsLinked to original sources
PubMed1997

Reproductive toxicity, mutagenicity and antigenicity of pamiteplase (genetical recombination).

Pamiteplase (genetical recombination), YM866, is a novel recombinant modified human tissue-type plasminogen activator developed by Yamanouchi Pharmaceutical Co. Ltd., Tokyo, Japan. An intended route of administration in the clinical use of this drug is intravenous administration. We conducted an intravenous fertility and general reproduction studies of this drug in male and female rats and teratology study of this drug in rabbits at the dose levels of 0 (vehicle control), 0.1, 0.3 or 1 mg/kg/day. In the rat, no treatment-related abnormalities were observed up to the maximum dose in parental animals and their offspring. In the teratology study in rabbits, prolonged coagulation time at the injection site was observed at 0.3 mg/kg or more. One death and one abortion occurred at 1 mg/kg on days 22 and 23 of pregnancy, respectively. No toxic effects on the litters were observed up to the maximum dose. Results of evaluation of the mutagenicity of YM866 and its ability to induce chromosome aberrations using the L5178Y TK+/- mouse lymphoma assay, human lymphocyte chromosome aberration assay and the micronucleus assay in mice were negative. Evaluation of the immunogenicity of YM866 by repeated intravenous injection in chimpanzees elicited no confirmed antibody titers.

Abnormalities, Drug-Induced↗
PubMed1996

Continuous deep intravenous infusion in rabbit embryotoxicity studies.

1. This investigation was undertaken to evaluate the suitability of an intravenous infusion technique in the pregnant rabbit. 2. 18 New Zealand White rabbits were anaesthetised on day 1 of gestation and an indwelling catheter was implanted into the superior vena cava by introduction into the jugular vein. The catheter was attached by a tether system to a remote infusion pump. 3. The pregnant rabbits were infused with physiological saline at a rate of 4 ml kg-1 day-1 until day 19 of gestation. A caesarean examination was performed on day 29 of gestation. The results obtained were compared with historical control data from 150 mated rabbits. 4. Anaesthesia and catheter implantation caused a slight transient reduction in maternal food consumption and weight gain. Pregnancy rate, pre-implantation loss and early resorption incidence were not affected. 5. Late resorption incidence and post-implantation loss were higher in the infused group by comparison with the historical controls but the individual data did not suggest an effect of treatment. Foetal weight was not adversely influenced. Three of the infused dams each contained one malformed foetus: a possible influence of infusion in the aetiology of these abnormalities cannot be excluded nor confirmed within the limitations of this experiment.

Animals↗
PubMed1995

Intravenous reproductive and developmental toxicity studies of cimadronate (YM175), a novel bisphosphonate, in rats and rabbits.

Cimadronate (YM175) is a novel bisphosphonate with potent inhibitory activity on bone resorption under development for the treatment of tumor-induced hypercalcemia, metastatic bone disease and osteoporosis. We conducted intravenous reproductive toxicity and teratology studies (Segment I, II and III) of this compound in rats and teratology study in rabbits. The test compound was dissolved in physiological saline, which was also given as the vehicle control. Rats were administered at a dosage of 0.06, 0.16 and 0.62 mg/kg/day in the male Segment I study. Dose levels in the other studies in rats including the female Segment I were 0.16, 0.31 and 0.62 mg/kg/day. In the Segment I study, no treatment-related abnormalities were observed in reproductive parameters or fetuses. In the Segment II study, slightly retarded fetal ossification was noted at 0.31 mg/kg/day or more, but the incidence of malformation did not increase. In the Segment III study, death of the dams and abnormal tooth growth of offspring were observed at 0.16 mg/kg/day or more. Further Segment III study showed that the no toxic effect level was 0.003 mg/kg/day. In the rabbit teratology study, dose levels were 0.01, 0.025 or 0.05 mg/kg/day. No toxic effects on pregnant females or their litters were observed at up to 0.05 mg/kg/day.

Abnormalities, Drug-Induced↗
PubMed1971

Differences in distribution of esterase between cell fractions of rat liver homogenates prepared in various media. Relevance to the lysosomal location of the enzyme in the intact cell.

The distribution of esterase in subcellular fractions of rat liver homogenates was compared with that of the lysosomal enzyme acid phosphatase and the microsomal enzyme glucose 6-phosphatase. Most of the esterase from sucrose homogenate sediments with glucose 6-phosphatase and about 8% is recovered in the supernatant. However, up to 53% of the esterase can be washed from microtome sections of unfixed liver, in which less cellular damage would be expected than that caused by homogenization. About 40% of both esterase and acid phosphatase are recovered in the soluble fraction after homogenization in aqueous glycerol or in a two-phase system (Arcton 113-0.25m-sucrose), although glucose 6-phosphatase is still recovered in the microsomal fraction of such homogenates. The esterase of the microsomal fraction prepared from a sucrose homogenate is much more readily released by treatment with 0.26% deoxycholate than are other constituents of this fraction. The release of esterase from the microsomal fraction by the detergent and its concomitant release with acid phosphatase after homogenization in glycerol or the two-phase system suggests that a greater proportion of esterase may be present in lysosomes of the intact cell than is indicated by the results of standard fractionation procedures.

Acid Phosphatase↗
PubMedDate not supplied

The reproductive and developmental toxicity profile of beta-cyclodextrin in rodents.

A 3-generation study with two mating phases per generation and a teratology phase was performed in the rat to assess the reproductive and developmental toxicity of beta-cyclodextrin (beta-CD) in the diet. Transient neonatal growth retardation occurred with 5% beta-CD: a similar, but equivocal, effect was also observed with 2.5%. No permanent defects or other indications of developmental toxicity were found. There was no significant maternal toxicity. The dietary level of 1.25% was found to be a NOAEL for developmental toxicity. Further investigations showed the growth retardation to be specific to dietary administration during lactation: it was not produced by parenteral (i.p.) administration and was not influenced by treatment of the dams or litters during gestation. Slight maternal nutritional deficiency, caused by physico-chemical interactions of beta-CD with nutrients in the gut is proposed as the mechanism of action. No difference in milk composition was found.

Animals↗
PubMedDate not supplied

Preclinical testing for teratogenicity and developmental toxicity: methods and limitations.

With regard to the risk of reproductive or developmental toxicity, the regulatory decisions to allow clinical trials in humans or the marketing of a new drug are based almost entirely on animal data. This is not the case for other types of toxicity for which the preclinical data are supported by data from clinical trials. Whilst animal studies have been remarkably successful in the detection of reproductive toxicology over the last 40 years, they are not infallible. The efficacy of animal experimentation is largely dependent on the selection of appropriate animal models. Progress in the study of teratogenic mechanisms, comparative physiology, developmental biology and pharmacokinetics will hopefully continue to bring about more economical and effective uses of animals. Nevertheless, owing to the limitations of animal models, the monitoring of human births unfortunately remains an essential defence in the detection and early prevention of chemical-induced birth defects.

Abnormalities, Drug-Induced↗