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Biomedical subjects

J E Fitzgerald

Publications and source records attributed to J E Fitzgerald.

At least 37 records · Page 2Linked to original sources
PubMed1986

Teratology studies of ametantrone acetate in rats and rabbits.

Ametantrone acetate is an antineoplastic drug chemically described as 1,4-bis [[2-[(2-hydroxyethyl)-amino] ethyl]amino] -9,10-anthracenedione diacetate salt. The drug has activity against leukemia and solid tumors in animal models. The purpose of this study was to investigate the teratogenic potential in pregnant rats and rabbits when administered during the critical period of organogenesis. Daily doses of 1.5, 3.0, and 6.0 mk/kg were administered IP to pregnant rats on days 6 through 15 of gestation, and 0.2, 0.4, and 0.8 mg/kg to rabbits on days 6 through 18. Dose-related weight loss occurred in both species during treatment as well as in the entire gestation period. Maternal and fetal parameters were evaluated upon uterotomies in rats on gestation day 20 and rabbits on day 28. In both species, there was dose-related blue discoloration of abdominal viscerae and of skin at injection sites. In rats, fetal malformations and developmental variations were comparable between treated and control fetuses. However, the incidence of fetal malformations was increased in rabbits given 0.4 and 0.8 mg/kg but not at 0.2 mg/kg. Based on these data, ametantrone was considered teratogenic at dose levels of 0.4 mg/kg and above in rabbits.

Abnormalities, Drug-Induced↗
PubMed1986

Teratology study in rats with amsacrine, an antineoplastic agent.

Amsacrine, an acridinylamino derivative used in the treatment of refractory leukemias, was evaluated for its teratogenic potential in pregnant rats. The compound was given by intraperitoneal (ip) administration on Days 6 to 9 of gestation to groups of 20 female CD rats at levels of 0.5, 1.0, and 2.0 mg/kg. Appropriate vehicle and untreated controls were included. Dams given 2.0 mg/kg lost weight during and after the treatment period. Food consumption was comparable to controls at all dose levels except for the high dose group in the post-treatment period. Decreased litter size, increased postimplantation loss, and reduced fetal weights occurred with doses of 2.0 mg/kg. Significantly reduced fetal body weight and increased incidence of stunting were the only adverse findings at 0.5 and 1.0 mg/kg, respectively. Two fetuses at 2.0 mg/kg, one at 1.0 mg/kg, one at 0.5 mg/kg, and two vehicle control fetuses had gross abnormalities. Fetotoxicity, manifested by inhibition of osteogenesis and minor skeletal abnormalities, occurred with doses of 0.5 mg/kg or more. The results indicate that amsacrine was embryolethal to rats at doses of 2.0 mg/kg and embryotoxic at lower dose levels. Teratogenicity was not evident at doses which did not affect fetal survival.

Abnormalities, Drug-Induced↗
PubMed1986

Studies on reproduction in rats with pirmenol, an antiarrhythmic agent.

Fertility and perinatal-postnatal studies were performed in CD rats given pirmenol, an antiarrhythmic agent, at dosages of 0, 25, 50, and 100 mg/kg. The drug was administered orally as diet admixtures in all studies. In the male fertility study, mature male rats were treated for 61 days prior to mating with virgin, untreated female rats. In the female fertility study, mature virgin female rats were treated for 15 days prior to mating with untreated partners with treatment continuing throughout mating, pregnancy, parturition, and weaning of the litters. In both studies, one-half of the dams in each group were killed on Day 21 of pregnancy and the remaining dams were allowed to deliver and wean their offspring and postnatal development was monitored. At weaning, two males and two females were arbitrarily selected from each litter, allowed to mature on unmedicated diet, and then mated within treatment groups to produce the F2 generation. In the perinatal-postnatal study, pregnant females were treated continuously from Day 15 of pregnancy until weaning of the litters on Day 21 postbirth. No adverse effects on fertility, general reproductive parameters, or offspring survival and development were evident at doses employed in these studies.

Animals↗
PubMed1986

Preclinical toxicology studies with the lipid-regulating agent gemcadiol.

Gemcadiol is a medium-length diol moiety with lipid-regulating properties in animals and man. The compound was not toxic when single doses were administered to rodents with the lethal dose greater than 7000 mg/kg in rats and mice. Rats treated for 13 or 52 weeks with 30 to 300 mg/kg had reversible food intake suppression and weight gain inhibition, decreased blood cholesterol, slight anemia, and generally dose-related but reversible decreases in glucose, and increases in alkaline phosphatase and blood urea nitrogen. Liver weights were increased, and there was accompanying hypertrophy and increased cytoplasmic eosinophilia of hepatocytes with associated peroxisome proliferation. Rats treated for 52 weeks also had mild renal tubular dilatation. Dogs given 25 to 300 mg/kg of gemcadiol for up to 52 weeks tolerated the compound better than rats. Effects related to compound administration were elevated serum alanine aminotransferase activity in female animals only, and microscopic cytoplasmic vacuolation and hyaline body formation in both sexes. Monkeys given 25 to 300 mg/kg gemcadiol for 13 weeks had slightly decreased serum cholesterol and slightly increased serum creatine phosphokinase. Teratology studies in rats or rabbits indicated no teratogenic response. Gemcadiol affects principally the liver, and the hepatic alterations seen in rats and dogs may reflect compensatory manifestations of altered metabolism related to the lipid-regulating activity of the compound.

Abnormalities, Drug-Induced↗
PubMed1986

Structure-activity relationships in the induction of mammary gland neoplasia in male rats with substituted aminopyrazoles.

In toxicity studies with a potential antipsychotic agent, N-(4-[2-fluorobenzoyl]-1,3-dimethyl-1H-pyrazol-5-yl)-2-([3- (2-methyl-1-piperidinyl)propyl]amino)-acetamide(Z)-2-butenedioate (1:2) (FP-1), mammary gland neoplasia in male rats was induced within 13 weeks. Tumor induction by the parent compound (FP-1) and structural analogs was also explored. Rats were given 50 mg/kg/day of FP-1 or the diethyl glycine analog, FP-2. Other experimental groups received the FP nucleus, a benzoylpyrazolylacetamide, or the FP side chains alone or administered concurrently with the nucleus. Most animals survived the 13 weeks without significant clinical effects. Clinically detectable, gross subcutaneous mammary nodules developed only in rats given FP-1 or the FP nucleus coadministered with the FP-1 side chain. Additional mammary gland neoplasms were found at necropsy or on histopathologic examination of mammary glands from rats receiving FP-1, FP-2, and the FP nucleus. The neoplastic effect was not influenced by the structure of the side chains. Since these substituted aminopyrazoles are novel chemicals, the mechanism for this neoplastic effect is not yet clearly established; however, the proliferating effect resides in the nucleus of this series of compounds and is likely related to alteration of DNA in target mammary tissue.

Animals↗
PubMed1985

Cardiotoxicity study of amsacrine in rats.

The cardiac functional and tissue changes produced by the antineoplastic agent, amsacrine, were evaluated in CD male rats. Amsacrine was administered intraperitoneally to groups of 12 male rats in single weekly doses of 12, 6, and 3 mg/m2 for 13 weeks. The drug elicited target organ toxicity in the bone marrow, lymphoid tissue, and gonads. There were blood biochemical alterations with transient elevations of total serum creatine phosphokinase, creatine phosphokinase-MB fraction, aspartate aminotransferase, and lactate dehydrogenase levels at 12 mg/m2, suggesting myocardial damage; however, there was no associated pathologic evidence of cardiotoxicity. This study indicates that amsacrine has negligible cardiotoxicity in rats when administered weekly for 13 weeks even at the lethal dose levels.

Aminoacridines↗
PubMed1985

Studies on reproduction in rats with meclofenamate sodium, a nonsteroidal anti-inflammatory agent.

Reproduction and teratology studies were performed in rats given meclofenamate sodium, a nonsteroidal anti-inflammatory agent. Dosages of 0, 3, 6, and 9 mg/kg were administered orally as dietary admixtures in the Fertility and Perinatal-Postnatal studies. In the Teratology study, dosages of 10, 12, 15, and 20 mg/kg were administered by intragastric intubation. In the Male-Fertility study no adverse effects on fertility or litter and offspring parameters were observed in two generations. In the Female-Fertility and Perinatal-Postnatal studies, maternal toxicity (death associated with intestinal ulceration and adhesions) was particularly evident during lactation. Prolonged gestation periods, decreased weanling weights, and increased weanling mortality were evident at dosages of 6 and 9 mg/kg. Increased postimplantation loss occurred at 6 and 9 mg/kg in the Term Sacrifice subgroup of the Female-Fertility study. Fertility rates were unaffected and all other litter and offspring parameters of the F1 and F2 generations appeared normal. In the Teratology study no adverse effects on embryonic or fetal development were evident at maternally toxic dosages up to 20 mg/kg.

Abnormalities, Drug-Induced↗
PubMed1985

Spermatocytic seminoma in the rat.

During the necropsy of a 2-yr-old untreated control rat from a carcinogenicity study, a tan brown nodular mass was observed within the tunica albuginea of one testis. Both testes were processed for light and transmission electron microscopy. Histologically, the testicular mass was composed of round to polyhedral cells with distinct cell boundaries, amphophilic cytoplasm, fine nuclear chromatin, and a delicate fibrovascular supporting stroma. Ultrastructurally, the tumor cells displayed features associated with spermatocytic differentiation. Based on the light microscopic and the ultrastructural features, the tumor was considered a spermatocytic seminoma of the testis, a rare tumor in the rat.

Aging↗
PubMed1984

Isoforms of an endogenous lectin in rabbit bone marrow.

A lectin which may mediate inter-erythroblast associations during red blood cell development in rabbit bone marrow has previously been purified and characterised. We have now detected different forms of this lectin in purified preparations and crude tissue extracts, by isoelectric focusing in agarose gels followed by rocket immunoelectrophoresis and by indirect antibody staining of focused proteins blotted onto nitrocellulose paper. These minor antigens are probably isoforms of the bone marrow lectin previously characterised.

Animals↗
PubMed1984

Teratology study with the synthetic prostaglandin ONO-802 given intravaginally to rabbits.

ONO-802, a synthetic E1 prostaglandin, was administered intravaginally via pessaries to Dutch belted rabbits at doses of 250, 62.5, and 12.5 micrograms/kg on days 6 through 18 of gestation. Rabbits in a vehicle control group were treated with pessaries that did not contain ONO-802 during the same period. Another group of animals remained untreated throughout gestation. Necropsies were performed on rabbits found dead and on those killed on gestation day 30. Body weight, food and water consumption, and clinical signs were monitored during the experiment. Major organs were weighed when the dams were necropsied on gestation day 30, and litter and fetal data were collected. Abortion and maternal deaths occurred in drug-treated groups. Body weight gains and food and water consumption were adversely affected by treatment particularly at the 250 and 12.5 micrograms/kg dose levels. Wastage (postimplantation loss) was significantly increased among treated groups (all dose levels), while other litter and fetal parameters were unaffected. ONO-802 was not teratogenic at maternal and embryotoxic dose levels.

Abortifacient Agents↗
PubMed1984

Two-phase teratology study with the synthetic prostaglandin ONO-802 given intravaginally to rats.

The synthetic prostaglandin ONO-802 was administered intravaginally to Sprague Dawley rats at doses of 1.0, 0.5, and 0.125 mg/kg on days 6 through 15 of gestation. A vehicle control group was treated with pessaries that did not contain the drug while another group remained untreated. Body weight, food, water consumption, and clinical signs were monitored during the experiment. In Phase One, 20 pregnant animals from each group were sacrificed at term, major organs were weighted, and litter and fetal data were collected. In Phase Two ten dams per group were allowed to deliver their litters, and the offspring were evaluated for survival, growth, developmental signs, and physiological function. Selected F1 offspring were retained to assess learning and emotional behavior or reproductive capacity. Administration of either 0.5 or 1.0 mg/kg of ONO-802 resulted in a slight reduction in food consumption and body weight gain. Water consumption was increased both during and after the dosing period for the mid and high dose dams. Significantly increased weights for the heart, lungs, liver, adrenals, and ovaries and decreased weights for the thymus gland were noted at term sacrifice of the 1.0 mg/kg dams, whereas the 0.5 mg/kg group had increased weights of the adrenals and ovaries only. Litter parameters were unaffected by treatment. Weights of the female fetuses of the 1.0 and 0.5 mg/kg groups were significantly reduced when compared to controls. There were no significant drug-related abnormalities among the F1 offspring and no evidence that treatment of the F0 dams affected the development, behavior, or reproductive performance of the F1 offspring. Thus, ONO-802 was not teratogenic when given to rats by the intravaginal route.

Abortifacient Agents↗
PubMed1984

Lack of in vivo and in vitro genotoxicity with the nonsteroid, antiinflammatory agent sodium meclofenamate.

Sodium meclofenamate (Meclomen), CI-583, is an anthranilic acid salt developed as a nonsteroidal, antiinflammatory agent. A multitest battery of short-term tests was employed to characterize the genotoxic and mutagenic potential of the compound by measuring point mutations in bacteria, induction of sister-chromatid exchange, chromosome aberrations, and gene mutations in mammalian cells in vitro. In vitro assays included metabolic activation. The in vivo assay was for chromosome aberrations in bone marrow cells from rats. At toxicity-limited doses for each assay, no activity was detected in the bacterial or mammalian cell mutation assays, and sister-chromatid exchange frequencies were not increased over control rates. When sodium meclofenamate was evaluated in vitro, chromosome aberrations were induced under metabolic activation in CHO cells. Chromosome aberrations and clastogenic activity were not demonstrated after oral administration of Meclomen to male rats. It was concluded that sodium meclofenamate does not possess overt mutagenic potential under these conditions. The activity seen in vitro with CHO cells after metabolic activation did not correlate with the results from the other tests and was attributed to the formation of reactive metabolites not present or formed in in vivo systems.

Animals↗
PubMed1984

Carcinogenicity studies in rodents and ripazepam, a minor tranquilizing agent.

The carcinogenesis potential of ripazepam , a benzodiazepine derivative, was studied in mice and rats for 78 and 104 weeks, respectively. Groups of 50 male and 50 female CD1 mice and CD rats each were given doses of 15 and 150 mg/kg of ripazepam in the diet. Survival rates were adequate for statistical analysis. Significant suppression of body weight gains occurred in rats but not in mice given 150 mg/kg/day. The compound failed to increase tumor rates or alter the average latency of neoplasm in the rat, the number of male animals with tumors was increased at 150 mg/kg and this was related to a significant increase in the number of animals with hepatocellular tumors. Hepatocellular tumors were increased also in female mice but the increase was not statistically significant. All but one of these hepatic neoplasms were hepatocellular adenomas and the one carcinoma had not metastasized. Other tumor types were not increased.

Animals↗
PubMed1984

Bacterial and mammalian cell mutagenesis, sister-chromatid exchange, and mouse lung adenoma bioassay with the antineoplastic acridine derivative amsacrine.

Amsacrine is a DNA intercalating agent with antineoplastic properties in lymphoproliferative disorders. This report describes a group of short-term tests with multiple endpoints to characterize the mutagenic and carcinogenic properties of this drug. In vitro studies included bacterial and mammalian cell mutagenesis, and sister-chromatid exchange and chromosome aberrations in mammalian cells. In vivo, mice were given amsacrine for 7 wk at 2, 5, and 10 mg/kg and were observed for an additional 17 wk. The standard bacterial assay revealed cytotoxicity at 2000 and 5000 micrograms/plate in the preincubation assay. No significant increase in revertants occurred in Salmonella strains, except for TA1537 in the activation phase. Amsacrine at 4.0 micrograms/ml was cytotoxic to V-79 cells in the cell mutation assay, and at lower dose levels was a direct-acting mutagen for the HGPRT locus. Sister-chromatid exchange rate of Chinese hamster ovary cells was increased more than twofold at 2 micrograms/ml without metabolic activation. Cell anomalies included changes in metaphase cell kinetics and chromosome damage. Mice in the lung adenoma bioassay failed to show increased numbers of tumors, while indicating lack of tolerance and survival beyond 5 mg/kg. The results indicate clear genotoxicity to mammalian cell systems with a spectrum of changes from point mutation and SCE induction to cell-cycle alterations, irrespective of exogenous metabolic activation. These results corroborate previous findings in animal and human cell systems in vitro. The reduction of genotoxicity in bacterial assays after exogenous metabolic activation may suggest some detoxification, and the magnitude of effects observed in mammalian cells indicates that exogenous metabolic activation is not required to manifest amsacrine's activity. The lack of tumor-inducing potential in mice may be attributed to strong cytotoxic effects in this species, or to an insensitivity of the target organ, or to assay systems that may mask the carcinogenic potential.

Adenoma↗
PubMed1983

Toxicology studies with a stable intravenous formulation of nitroglycerin.

The preclinical toxicologic profile of Nitrostat, a stable parenteral formulation of nitroglycerin, was determined in mice, rats, rabbits and dogs. Single-dose i.v. studies in rodents yielded LD50 values of 17.3 and 18.2 mg kg-1 in male and female mice, and 24.4 and 23.2 mg kg-1 in male and female rats, respectively. Subacute i.v. studies in rats at doses of 2.5, 5.0 and 10.0 mg per kg per day, and in dogs at doses 1.0 and 3.0 mg per kg per day for two weeks, elicited minimal reactions. In rats, suppression of body-weight gain and food consumption occurred among treated and vehicle-control animals. Mild tissue irritation at injection sites was noted in treated and vehicle-control groups. There were no clearly drug-related clinical or pathological findings in dogs. In rabbits, repeated intravenous administration of Nitrostat did not induce significant local venous irritation. The results of these studies indicated that the stabilized parenteral formulation of nitroglycerin did not elicit unusual toxic properties in intravenous infusion studies.

Animals↗
PubMed1983

Interaction of Ia antigen-bearing polymorphonuclear leukocytes and murine splenocytes.

Polymorphonuclear leukocytes (PMN) were induced in the peritoneum of a Balb/c mouse by ip injection of Fusobacterium nucleatum (FN) (greater than 95% PMN). A subpopulation of PMN harvested bore Ia surface antigens and stimulated a mixed lymphocyte reaction (MLR) when cultured with C57B1/6J splenocytes. The reaction was blocked by a short prior incubation of PMN with anti-Ia antibody or PMN cell depletion by the same antibody plus complement. The Ia antigen-bearing PMN were capable of antigenic modulation since incubation of PMN for 24 h rendered the cells incapable of stimulating an MLR. The Ia antigen-bearing PMN produced a soluble material that enhanced the phytohemagglutinin (PHA) response of murine splenocytes and the active material was a product of live cells since the supernatants contained no detectable lactate dehydrogenase activity. The data suggest that murine PMN subpopulations, defined by surface Ia antigen, can modulate mitogenic responses by production of an enhancing factor(s).

Animals↗
PubMed1982

Effects of supernatants of polymorphonuclear neutrophils recruited by different inflammatory substances on mitogen responses of lymphocytes.

Two different substances, glycogen and thioglycollate, were used to recruit early peritoneal exudate cells (4h). In the acute phase of the inflammatory response the cellular infiltrate is large, and the predominant cell (greater than 95%) is the polymorphonuclear neutrophil. Supernatant had differing effects on lymphocyte responses to the mitogens PHA and LPS, also carried out in serum-free media, depending on recruiting substance and time of culture. While glycogen-recruited PMN supernatant (GPMN-S) always enhanced splenocyte responses to PHA, thioglycollate-recruited cells (TPMN-S) did not produce an enhancing factor until the cells had been in culture for 24 h. Whereas GPMN-S enhanced the splenocyte response to LPS only after 1 or 4 h of culture, TPMN-S failed to have any significant effect. Thymocyte responses to PHA were facilitated by all supernatants. Dilution of the soluble PMN factors resulted in a suppressive effect on splenocyte responses to both PHA and LPS, regardless of whether PMN were recruited by the thioglycollate or glycogen or of the time of cell incubation. These results indicate that PMN-rich cell populations of different types of activity are recruited by glycogen and thioglycollate and that these cells produce factors capable of potentiating, enhancing, or suppressing responses to T- or B-cell mitogens by normal syngeneic lymphocytes.

Animals↗