Biomedical subjects

J L Schardein

Publications and source records attributed to J L Schardein.

At least 19 recordsLinked to original sources

PubMed1997

[Reproductive and developmental toxicity studies of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence (1). Fertility study in rats by oral administration].

Fertility and developmental toxicity study of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was conducted in Crl:CD rats. Male rats were given NS-21 orally from 60 days before mating to the day of necropsy, and female rats were given NS-21 orally from 14 days before mating to day 7 of pregnancy. The dose levels for both males and females were 0 (control), 2, 30 and 500 mg/kg. On day 20 of pregnancy, the females were sacrificed and their fetuses examined. At the 500 mg/kg dosage level, one male and one female died. Salivation and dilated pupils occurred at the 30 and 500 mg/kg dosage levels, and rales occurred at 500 mg/kg. Body weights and food consumption were decreased, and water consumption was increased in both males and females at the 500 mg/kg dosage level. Decreases in the numbers of corpora lutea and implantations per litter and a lower number of live fetuses per litter were found at the 500 mg/kg dosage level. However, the incidence and number of postimplantation loss per litter were comparable among the treatment and control groups. These results demonstrate that the NOAEL (no observed adverse effect level) of NS-21 is 2 mg/kg for general toxicity in parental animals, and 30 mg/kg for reproductive function of the parent animals and for embryo-fetal development.

Administration, Oral↗

PubMed1997

[Reproductive and developmental toxicity studies of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence (2). Teratogenicity study in rats by oral administration].

A study of teratogenicity and developmental toxicity of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was conducted in Crl:CD rats. Female rats were given NS-21 orally at dose levels of 0 (control), 2, 25 and 300 mg/kg from day 7 to day 17 of pregnancy. Twenty-two female rats per dose level were sacrificed on day 20 of pregnancy for examination of their fetuses, and the remaining pregnant rats (twenty-three per dose level) were allowed to deliver naturally for postnatal examination of their offspring. At the 300 mg/kg dosage level, rales, partially closed eyes and reduced activity were observed in pregnant rats. Decreases in body weight gain, food consumption and water consumption were observed in the dams at the 300 mg/kg dosage level. Fetal body weights were decreased at the 300 mg/kg dosage level. The drug never altered the numbers of corpora lutea and implantations, fetal mortality, the number of live fetuses, sex ratio, placental weight, and external, visceral and skeletal development of fetuses. NS-21 did not affect the delivery of dams, the number of live newborns, birth index, body weight or survival index. Nor did NS-21 have any adverse effect on the postnatal development of the offspring, including physical and functional development, emotionality, motor activity, learning ability and reproductive performance. These results demonstrate that the NOAEL (no observed adverse effect level) of NS-21 is 25 mg/kg for general toxicity in mother animals. 300 mg/kg for reproductive function in mother animal and 25 mg/kg for developmental toxicity.

Administration, Oral↗

PubMed1997

[Reproductive and developmental toxicity studies of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence (3). Teratogenicity study in rabbits by oral administration].

Administration, Oral↗

PubMed1997

[Reproductive and developmental toxicity studies of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence (4). Perinatal and postnatal study in rats by oral administration].

A study of the effect of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was conducted in Crl:CD rats during the perinatal and lactational periods. Female rats(thirty-three per dose level) were given NS-21 orally at dose levels of 0 (control), 2, 25 and 300 mg/kg from day 17 of pregnancy to day 21 after delivery. All pregnant rats were allowed to deliver naturally for postnatal examination of their offspring. At the 300 mg/kg dosage level, reduced activity, salivation and rales were observed in dams, and five dams died. Decreases in body weight gain, food consumption and water consumption were also observed in the dams at the 300 mg/kg. The number of remaining implantation sites was increased at 300 mg/kg, indicating fetal mortality. The number of live newborns, birth index and survival index at the birth were decreased at the 300 mg/kg dosage level. Reduced activity, paleness in color and/or discoloration were observed for many pups at the 300 mg/kg on lactation day 0. Body weights of male and female offspring at the birth were also decreased at the 300 mg/kg dosage group. Survival index at the 4 days was decreased at the 300 mg/kg dosage level. Body weight gains of male and female offspring were decreased at the 300 mg/kg during the lactational period and after weaning. NS-21 did not affect the postnatal development of the offspring, including physical and functional development, motor activity, emotionality, learning ability and reproductive performance. These results demonstrate that the NOAEL (no observed adverse effect level) of NS-21 is 25 mg/kg for general toxicity and reproductive function in mother rats and 25 mg/kg for developmental toxicity of their offspring.

Administration, Oral↗

PubMed1994

Developmental toxicity of the HMG-CoA reductase inhibitor, atorvastatin, in rats and rabbits.

The developmental toxicity of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, atorvastatin, was investigated in pregnant rats and rabbits given daily oral doses during organogenesis. Rats received 0, 10, 100, or 300 mg/kg on days 6-15 of gestation, and rabbits received 0, 10, 50, or 100 mg/kg on days 6-18 of gestation. Maternal and fetal parameters were evaluated on day 20 (rats) or 29 (rabbits) of gestation. Live fetuses were examined for external, visceral, and skeletal malformations and variations. At 300 mg/kg in rats, 1 treatment-related death occurred on day 12 of gestation, and maternal body weight gain and food consumption were decreased during treatment (43% and 23%, respectively). In addition, 1 animal at 300 mg/kg had total litter resorption. Increased postimplantation loss (not statistically significant) and slightly decreased fetal body weight (statistically significant only in males) were also observed at 300 mg/kg. There were no significant differences between treated and control groups in the incidence of fetal malformations or variations. No maternal or developmental toxicity was observed in rats at 10 or 100 mg/kg. In rabbits, marked maternal toxicity (7 deaths, body weight loss during and after treatment, and decreased food consumption) and abortion occurred at 100 mg/kg. At 50 mg/kg, maternal toxicity (2 deaths and 72% body weight gain suppression) and abortion also occurred. There were no treatment-related effects on live litter size or sex ratio. At 50 and 100 mg/kg, nonstatistically significant increases in postimplantation loss and decreases in gravid uterine weight were observed, and at 100 mg/kg, decreases in fetal body weight were observed relative to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗

PubMed1994

Reproductive and developmental toxicity studies of silicone gel Q7-2159A in rats and rabbits.

Studies reported here assessed the potential adverse effects of silicone gel, Dow Corning Q7-2159A, on general reproduction and fetal development in male and female Charles River CD rats and New Zealand white rabbits. Two control and three treatment groups of 30 male and 30 female rats and 25 female rabbits per group were used in the one-generation reproduction and developmental toxicity studies, respectively. The silicone gel was implanted subcutaneously in two flank sites at dosage levels of 3, 10, and 30 ml/kg. The highest dose was selected on the basis of likely human body burden. Control groups received either sterile saline or carboxymethylcellulose solution in two flank implantation sites. The control and test articles were implanted in male and female rats 61 and 47 days, respectively, prior to mating (in the rat reproduction study) and approximately 42 days prior to insemination of female rabbits (in the rabbit developmental toxicity study). There were no treatment-related effects on F0 parental general conditions and reproductive performance, F1 neonatal viability, or growth in the rat reproduction study. No maternal nor developmental effects, including teratogenicity, were observed in rabbits in the groups implanted with Q7-2159A gel in the developmental toxicity study.

Abnormalities, Drug-Induced↗

PubMed1994

Reproductive and developmental toxicity studies of silicone elastomer Q7-2423/Q7-2551 in rats and rabbits.

The purpose of these studies was to assess the potential adverse effects of silicone breast implant envelope elastomer on general reproduction and fetal development in rats and rabbits. One control and one treatment group of 30 male and 30 female Charles River CD rats and 25 inseminated New Zealand white rabbits per group were used in the one-generation reproductive and developmental toxicity studies, respectively. Two 1.2-cm discs of silicone elastomer were subcutaneously implanted in one site in the left flank and one site in the right-flank of the treated group of rats, while four 2.5-cm discs were implanted in two sites in the left flank and two sites in the right flank of the treated group of rabbits. The size of the elastomer implants was chosen to approximate the expected body burden of women with breast implants. The control animals in both studies received subcutaneous implantation of either 1.2- or 2.5-cm discs of polyethylene of the same number in the same locations. The control and test articles were implanted in the male and female rats at 61 and 47 days, respectively, prior to mating (in the rat reproduction study) and approximately 42 days prior to insemination of female rabbits (in the rabbit developmental toxicity study). Subcutaneously implanted discs of silicone breast implant envelope elastomer did not induce maternal or developmental toxicity before or during pregnancy or during lactation, did not cause any adverse effects on the parents or neonates, and did not impair reproductive performance in the rat reproduction study. No maternal toxicity or adverse developmental effects, including teratogenicity, were observed in the treated groups in the rabbit developmental toxicity study.

Abnormalities, Drug-Induced↗

PubMed1993

Neurotoxicity evaluation of N,N-diethyl-m-toluamide (DEET) in rats.

The neurotoxic potential of N,N-diethyl-m-toluamide (DEET) was evaluated following acute oral administration or following multigeneration plus chronic dietary administration to the rat. For the acute study, rats were administered undiluted DEET at dose levels of 50, 200, or 500 mg/kg by gavage. A dose level of 500 mg/kg was considered to be the highest practical dose that could be evaluated in this study based upon observations of overt toxicity at 500 mg/kg and mortality at 1000 mg/kg in a dose range-finding study. The two measures of neurotoxicity evaluated in the acute study were functional observational battery (FOB) and motor activity measurements. An apparent treatment-related effect in thermal response time (increased) was noted for both sexes 1 hr after dosing at the 500 mg/kg dose level. A questionable effect on rearing activity (decreased) also was noted at the same dose level. For the multigeneration plus chronic dietary administration study, rats were administered DEET at dietary concentrations of 0, 500, 2000, or 5000 ppm continuously over two generations and then chronically for 9 months. A dietary concentration of 5000 ppm meets the criteria for a maximum tolerated dose (MTD) based on traditional chronic toxicology assessments. Evaluations included FOB, motor activity, discriminative acquisition and reversal in an M-maze, acoustic startle habituation, passive avoidance acquisition and retention, and microscopic examination of central and peripheral nervous tissue. The only effect that was considered to be possibly treatment-related was a slight increase in exploratory locomotor activity at the 5000 ppm dose level. Based on the results of these studies, the nervous system does not appear to be a selective target when DEET is administered to rats either as a single oral dose at high dose levels or chronically at the MTD.

Acoustic Stimulation↗

PubMed1991

A two-generation reproduction study in rats receiving diets containing hexamethylenediamine.

Rats received diets containing average daily doses of 0, 50, 150, and 500 mg/kg/day of hexamethylenediamine over two generations. Although no treatment-related mortality was observed in any of the groups, the weight gain of adults and pups was slightly reduced in the high dose group. While the litter size was also slightly reduced at birth in the high dose group, there was no adverse effect on survival during lactation in any of the treated groups. Thus, the dietary administration of up to 150 mg/kg/day of hexamethylenediamine over two generations did not adversely affect reproduction or fertility in rats.

Animals↗

PubMed1991

The effect of piroctone olamine on reproduction of male and female rats.

The purpose of this study was to determine the effect of piroctone olamine, an antidandruff active, on reproductive performance, fertility, parturition, and neonatal viability and growth. Piroctone olamine was administered orally by gavage to three groups of 35 male Sprague-Dawley rats each beginning 64 days prior to mating and continuing until euthanized and to three groups of 35 female Sprague-Dawley rats each beginning 14 days prior to mating and continuing until euthanized. Animals in the treated groups received piroctone olamine in a combination of 1.0% methylcellulose and polyethylene glycol 400 as a single daily dose at levels of 0, 10, 100, and 250 mg/kg/day, at a volume of 2.5 ml/kg. The control group received the vehicle only. Ten randomly selected females/group were mated and underwent a uterine examination on Gestation Day 13; the remaining females were allowed to deliver. Because earlier studies reported hematological effects, blood samples were collected from all parental animals during acclimation and prior to euthanasia for hematological and blood chemistry (Gestation Day 13 females) characterization. The parental animals were necropsied and tissues were grossly examined. Systemic effects induced by the test article were seen at the mid- and high-dose levels but only among the male rats. These effects were reduced body weight and decreased liver weights. Hematological findings representative of anemia occurred at the high-dose level, as did rales in several animals. Offspring growth was inhibited for the high-dose group as evidenced by significantly reduced mean weight values throughout lactation. The remaining parameters assessed, including mating ability and reproductive performance, were not affected by treatment at any dosage level tested. In summary, the no observable effect level of piroctone olamine with respect to systemic toxicity was considered to be 10 mg/kg/day. Neonatal growth was not affected at 100 mg/kg/day or less, and the no observable effect level with respect to reproductive parameters, including fertility, was 250 mg/kg/day.

Animals↗

PubMed1991

Fertility and perinatal/postnatal studies in rats with the angiotensin-converting enzyme inhibitor, quinapril.

Quinapril, an inhibitor of angiotensin-converting enzyme (ACE) and an antihypertensive agent, was evaluated in rats for effects on fertility, reproduction, and perinatal and postnatal development. In a fertility study, male rats were treated by gavage for 60 days prior to and during mating and female rats were treated by gavage for 14 days prior to mating, during mating and gestation, and during lactation with doses of 0, 10, 50, or 100 mg quinapril/kg body wt. There were no significant effects on body weight, food consumption, fertility indices, fetal development, or neonatal growth, survival, development, behavior, or reproduction. In a perinatal/postnatal study, administration of quinapril to females at doses of 25, 75, or 150 mg/kg during late gestation and lactation had no effects on parturition, lactation, or postnatal development, but a significant decrease in neonatal body weight during the suckling period was observed at all doses. In a subsequent study, female rats were given 150 mg/kg during late gestation, lactation, or late gestation and lactation. No adverse effects were seen in the dams or the offspring, and no reduction in neonatal body weight was observed. Kidneys from pups whose mothers received quinapril during gestation and/or lactation had minimal juxtaglomerular cell hypertrophy, characteristic of treatment with ACE inhibitors. Low levels of quinaprilat (the major and pharmacologically active metabolite of quinapril) were detected in fetal blood and in neonatal blood, indicating offspring exposure to quinapril. Milk quinaprilat concentrations were 3-5% of the plasma concentrations 3-5 hr after dosing. These studies demonstrate no adverse effects of quinapril on fertility, reproduction, or perinatal and postnatal development.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1989

Inhalation developmental toxicity study of propylene oxide in Fischer 344 rats.

The developmental toxicity potential of propylene oxide (PO) was evaluated in Fischer 344 rats following inhalation exposure. Four groups of 25 mated female rats were exposed to 0, 100, 300, and 500 ppm of PO for 6 hr per day on Gestation Days 6 through 15, inclusive. Cesarean sections were performed on all females on Gestation Day 20 and the fetuses removed for morphological evaluation. Exposure to propylene oxide did not adversely affect survival, appearance, or behavior at any of the exposure levels tested. Maternal body weight gain and food consumption were reduced significantly among the females at the 500 ppm level during the exposure period. No exposure-related effects were noted with respect to maternal water consumption, organ weights, cesarean section, or fetal morphological observations with the sole exception of increased frequency of seventh cervical ribs in fetuses at the maternally toxic exposure level of 500 ppm. In summation, the no-observable-adverse-effect level (NOAEL) of propylene oxide, when administered to Fischer 344 rats via whole-body inhalation exposure, was considered to be 300 ppm.

Administration, Inhalation↗

PubMed1989

Evaluation of the developmental toxicity of succinate tartrates in rats.

The potential for succinate tartrates (ST) to induce developmental toxicity in Sprague-Dawley CD rats has been evaluated. ST dose levels of 250, 500 and 1000 mg/kg body weight/day were administered in the drinking-water on days 6-15 of gestation. Control animals received distilled water. Caesarean sections were performed on gestation day 20 and the foetuses were removed for teratological evaluation. No significant maternal or developmental toxicity was observed at any dose level. Based on these observations, the no-observed-effect level for ST developmental toxicity is greater than or equal to 1 g/kg/day, which was the highest dose tested.

Abnormalities, Drug-Induced↗

PubMed1989

Potential human developmental toxicants and the role of animal testing in their identification and characterization.

Some 50 chemicals have been identified from environmental, occupational, or therapeutic exposure data as being potential developmental toxicants in humans. The toxicity pattern of these chemicals in humans has been characterized and correlated with developmental toxicity end points in laboratory animal models in order to determine the relevance and predictiveness of the results of testing in animals in extrapolation to human data. In general, animal developmental toxicity data closely paralleled human outcomes, and while humans in most cases were more sensitive than animals, the data support the concept that, imperfections aside, studies in animals serve a vital role in the hazard identification process.

Animals↗

PubMed1988

Teratologic testing: status and issues after two decades of evolution.

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Animals↗

PubMed1987

Approaches to defining the relationship of maternal and developmental toxicity.

Maternal and developmental toxicities reported in the literature were examined in an attempt to define more clearly their relationship. Relationships were difficult to ascertain because maternal toxicity end points are not clearly defined, or even assessed, in every study. However, maternal toxicity accompanied by developmental toxicity is the most common outcome of in vivo testing. Approaches to define these associations have included assessment of acute maternal toxicity and teratogenicity; evaluation of maternal toxicity and its association to developmental toxicity in general, and to malformations, specifically; and examination of developmental variations, embryolethality, and altered growth. None has demonstrated an unequivocal relationship between specific maternal and developmental toxicities: Developmental disruption appears not to result unconditionally from maternal toxicity. Maternal "stress" appears to have some impact on development but resists further definition at this time. Variations in association may be due to the extent to which maternal homeostasis has been compromised. Several quantitative approaches to relating maternal toxicity and developmental toxicity in animal systems (ie, relative teratogenic index, adult/developmental toxicity ratio) may provide the most satisfactory means of evaluating developmental toxicity testing for assessment of hazard.

Abnormalities, Drug-Induced↗

PubMed1987

Teratogenic response of dimethylacetamide in rats.

Pregnant CD rats (25/group) were used to determine the teratogenic potential of dimethylacetamide (DMAC). DMAC was administered in deionized water once a day by gavage on Days 6 through 19 of gestation at dosages of 0, 65, 160, and 400 mg/kg/day. Cesarean sections were performed on all females on Gestation Day 20. No treatment-related effects were observed in survival, appearance, or behavior at necropsy. Mean maternal body weight gain was reduced significantly only at the 400 mg/kg/day level. Fetotoxicity manifested by increased postimplantation loss was seen at the 400 mg/kg/day level while reduction in mean fetal body weights was noted at the 160 and 400 mg/kg/day test levels. Developmental variations (reduced ossification and unossified skeletal variations) were increased at the 400 mg/kg/day test level and corresponded to the reduced fetal body weights which were observed. Treatment-related malformations of the heart, major vessels and oral cavity, and anasarca were seen at the 400 mg/kg/day DMAC level. No teratogenic effect of DMAC treatment was observed at or below dosage levels of 160 mg/kg/day.

Acetamides↗

PubMed1987

Inhalation teratology studies of n-butyl mercaptan in rats and mice.

n-Butyl mercaptan (n-BM) is used as a solvent and a chemical intermediate. Pregnant Charles River CD-1 mice and COBS CD rats were randomly assigned to a control group and to three n-BM-exposed groups of 25 rats and 25 mice each. The animals were exposed by whole-body inhalation to mean n-BM concentrations of 10, 68, or 152 ppm on a 6-hr daily exposure schedule. Rats were exposed on Gestation Days 6-19 and mice on Gestation Days 6-16. The control group was exposed to filtered air only on a comparable regimen. Cesarean sections were performed on all surviving mice on Gestation Day 17 and on all rats on Gestation Day 20. Seventeen of the n-BM-treated mice died: 8 at the 68-ppm level and 9 at the 152-ppm level; none of the n-BM-treated rats died. An increased postimplantation loss and increased early resorption occurred in mice exposed at 68 and 152 ppm, indicating embryotoxicity. An increased incidence of cleft palate was observed in mice exposed to 10 or 68 ppm which was not statistically significant. Total fetal abnormalities were statistically significantly different from controls at 68 ppm where maternal lethality was observed when based on the fetal unit although not when based on the litter unit. Rats exposed to 152 ppm or less demonstrated no terata.

Abnormalities, Drug-Induced↗