Teratological study of the antioxidant stobadine in rats.

The potential teratogenicity of the antioxidant stobadine (STO) was studied in Wistar rats. Daily oral doses of 5, 15 and 50 mg/kg STO were given from the 6th day of gestation up to weaning of pups--day 21 post partum. No significant differences between the STO treated groups and the control group were found in litter size, pre- and postimplantation losses and foetal body weight. External, skeletal and internal examinations of the foetuses revealed no evidence of teratogenesis. The offspring from the STO treated dams exhibited a high survival rate in their postnatal development. It can be concluded that STO had no adverse effects on the pre- and postnatal development of the offspring in rats.

Determination of selective biochemical parameters in pregnant and lactating rats after stobadine administration.

The effect of oral administration of stobadine, a cardioprotective drug, was studied on the basis of determination of selective biochemical parameters in pregnant and lactating rats. Stobadine was administered orally at a dose of 50 mg/kg from day 15 of gestation until day 21 of lactation. We determined creatinine and urea in serum, acidity, protein, glucose, ketones, bilirubin, urobilinogen, blood, and creatinine in urine from females on days 15 and 20 of gestation and 7, 14, and 21 of lactation. In the biochemical parameters investigated no significant differences between control and experimental animals were recorded on any of the days studied. Histopathological examination of kidney tissue did not reveal kidney damage after stobadine administration.

Teratological assessment of stobadine after single and repeated administration in mice.

Teratological studies were performed with stobadine, a compound with antiarrhythmic and antihypoxic activity. Single i.v. injections of stobadine in the form of dihydrochloride (DH 1011) to ICR mice on days 3, 6, 9 or 12 of gestation at doses of 1 and 3 mg kg-1 had no teratogenic effect. Slight fetal toxicity was manifested by decreased fetal weight after treatment on days 3 and 6, increased incidence of rudimentary ribs after treatment on days 9 and 12 of gestation and non-significantly increased postimplantation loss after injection on day 6 of gestation. The effect of repeated oral administration in the form of dipalmitate salt (DP 1031) was studied in doses of 12.2, 61.0 and 122.0 mg kg-1 on days 4-16 of gestation. Oral exposure to 61.0 mg kg-1 DP 1031 resulted in significant reduction of implantations, live fetuses and litter weight, and after 122.0 mg kg-1 DP 1031 the fetal weight was significantly decreased. External and skeletal examinations of the fetuses revealed no evidence of teratogenesis. The relevance of the two routes of stobadine administration for risk involvement is discussed.

Teratogenicity of cyclophosphamide in New Zealand white rabbits.

Pregnant rabbit does received daily oral doses of 6.2 or 18.6 mg/kg cyclophosphamide (CP) on days 6-20 of gestation. On day 29, shortly before term, the uterine content was removed by Caesarean section. At the dose of 6.2 mg/kg CP maternal mortality was 2/9 does and at 18.6 mg/kg CP one abortion was recorded. Body weight gain of pregnant females was essentially unaffected by CP treatment. Both doses of CP elicited significant dose-dependent decrease of fetal body, organ (heart, lung, liver, kidney) as well as placental weight. After treatment with 18.6 mg/kg CP, gross examination of fetuses revealed significantly increased incidence of exophthalmos, cleft palate/lip, syndactyly, and brachycardia. Skeletal anomalies and malformations, significantly increased after the higher CP dose, included sternebrae, back-bone and limb defects. Oral administration of CP to rabbits in the dose of 18.6 mg/kg during organogenesis resulted in pronounced embryotoxic and teratogenic changes.

Teratological study of stobadin after single and repeated administration in rats.

The toxic developmental potential of the anti-arrhythmic drug stobadin was assessed after single intravenous or repeated oral doses to pregnant rats. Stobadin was studied in the form of dihydrochloride (DH 1011) at doses of 2 and 6 mg/kg, given in single intravenous injections on days 3, 6, 9, or 12 of gestation. Immediately after injection of the 6-mg/kg dose of DH 1011 to pregnant rats, saccade abdominal respiration, tremor of hindlimbs, and sedative behaviour were observed on each day of medication. No deaths of females occurred in either the control or experimental groups. Slight foetal toxicity was manifested by significantly decreased foetal weight only after treatment on day 3 of gestation at 6 mg/kg and by significantly increased incidence of delayed ossification of the parietal and supraoccipital bone also at 6 mg/kg DH 1011 given on day 12 of gestation. The effect of repeated oral treatment in the form of dipalmitate salt (DP 1031) was studied in doses of 5, 15, and 45 mg/kg from days 2-15 of gestation. Oral exposure to 45 mg/kg DP 1031 resulted in significant reduction of maternal body weight gain and in embryofoetal toxicity, namely, increased preimplantation foetal loss, anomalies of sternebrae, and, after 15 and 45 mg/kg DP 1031, significantly decreased foetal weight and smaller litter size. The relevance of the two routes of stobadin administration for risk extrapolation is discussed.

Effect of the cardioprotective agent stobadine on reproduction in rats.

The cardioprotective drug stobadine in the form of dipalmitate salt DP 1031 was evaluated for its effects on perinatal and postnatal development in the rat. Doses of 5, 15 and 50 mg/kg/day representing approximately 1, 3, and 10 times the anticipated maximum daily human therapeutic dose were administered to rats orally in aqueous suspension. Treatment of pregnant rats with stobadine continuously from day 15 of gestation through parturition and lactation had no adverse effects on reproductive parameters of dams or on survival and development of F1 offspring at any dose used. There were only signs of slight maternal toxicity at 50 mg/kg/day, which consisted of sedated behaviour, reduced liver weight and reversible histopathological changes in kidney tissue. (Tab. 3, Fig. 4, Ref. 24).

[Pharmacotoxicologic characteristics of pentacaine]. / Farmakotoxikologická charakteristika pentakaínu.

Long-term administration of pentacaine to experimental animals in investigations of chronic toxicities confirmed that this substance is relatively safe in amounts of 10 mg/kg/day. Larger doses caused ECG changes, as well as changes of some clinical and biochemical indicators and histopathological findings which were independent on the dose and sex. The embryotoxic and teratogenic action of pentacaine was manifested only after large doses in mice (more than 20 mg/kg). Doses under 10 mg/kg per day did not produce toxic effects in mother and foetus, whereby the substance penetrates through the placenta and is distributed in the maternal and foetal organs of rabbits in a proportionate way. From the in vitro action of pentacaine ensues that it has a strong stimulating action on isolated cells which gradually changes into cytotoxic action. The results support the decision not to use pentacaine for intravenous, infiltration and conduction anaesthesia and to recommend only its oral administration.

Reproductive toxicity studies with cis-(-)-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1H-pyrido-[4,3-b]indole dipalmitate in rats.

cis-(-)-2,3,4,4a,5,9b-Hexahydro-2,8-dimethyl-1H-pyrido-[4,3-b]indole dipalmitate (stobadin dipalmitate; in the following briefly called STB) a new prospective cardioprotective drug, was evaluated for effects on fertility, general reproductive performance, prenatal and peri-postnatal development in the rat. Doses of 5, 15 and 50 mg/kg/d were administered orally in aqueous suspension to rats in all studies. Daily treatment of male rats for 70 days before mating and female rats for 14 days before mating and during gestation and lactation had no adverse effects on fertility, survival rate and weight gains of parental animals or on prenatal and postnatal development of pups. There was only evidence of slight adult toxicity late in the experiment, significant increase of anomalous foetuses in both the 15 and 50 mg/kg/d doses and decreased body weight of the young at 50 mg/kg/d on day 21 post partum. Daily oral treatment of pregnant rats with STB throughout organogenesis (day 4 to 16) had no overt effects on dams or on embryo-foetal development, except of increased incidence of some skeletal variations in all treated groups. In the peri-postnatal toxicity study treatment of pregnant dams with STB continuously from day 15 of gestation through parturition and lactation had no adverse effects on reproductive parameters of dams or on survival and development of F1 offspring at any dose used. There were only signs of slight maternal toxicity at 50 mg/kg/d, which consisted of sedated behaviour, reduced liver weight and reversible histopathological changes in kidney tissue. The results of these studies did not reveal serious developmental hazard potentials of STB administered to rats in doses up to 50 mg/kg/d.

[Characteristics of new approaches for evaluation of embryotoxic effects of chemical substances]. / Charakteristika nových prístupov k hodnoteniu embryotoxických úcinkov chemických látok.

New approaches to the evaluation of embryotoxic effects of xenobiotics are characterized in the light of mother--fetus interrelationship. The first part of the paper analyzes problems of evaluating maternal and embryofetal toxicity and substantiates the necessity of sensitive selection and precise evaluation of individual parameters of toxicity. The second part presents a survey of classical testing procedures and of alternative methods used in assessing the safety of new drugs. The third part characterizes methods of quantitative determination of risks inherent to chemical substances. A detailed description of the principles of the new method is presented which is based on the interrelationship of maternal and embryofetal toxicity (adult/developmental--A/D). The acceptability of the new method has been verified experimentally on evaluating some new prospective drugs according to standard teratological studies.

Teratological study of the hypolipidaemic drugs etofylline clofibrate (VULM) and fenofibrate in Swiss mice.

Teratological studies of the hypolipidaemic drugs etofylline clofibrate (VULM) and fenofibrate were carried out in mice. Pregnant mice were given etofylline clofibrate and fenofibrate in doses 11.7, 117.1, and 585.5 mg/kg orally from day 7 to 16 of gestation. Terminal maternal body weight was significantly decreased after all doses of etofylline clofibrate in a non-dose-related fashion compared to the control group. The foetuses were examined on day 19 of gestation. They were weighed and inspected for external, skeletal and visceral abnormalities. The low and middle doses of etofylline clofibrate and fenofibrate had no adverse effects on embryofoetal development. The highest etofylline clofibrate dose induced a significant decrease of foetal weight at term, likewise postimplantation loss was significantly increased after the highest dose of fenofibrate. The incidence of external, skeletal and visceral anomalies was not dose-dependent. In this study no teratogenic effects were detected, yet with the highest etofylline clofibrate and fenofibrate doses some foetotoxic effects were observed.

Teratological and cytogenetical evaluation of two antihistamines (pipethiadene and pizotifen maleate) in mice.

The teratogenic and cytogenetic effects of two drugs with antihistamine properties, Pipethiadene and Pizotifen maleate, were investigated. Three groups of pregnant mice were treated daily with oral doses (0.24, 0.6 and 1.2 mg/kg) of these drugs from day 4 to day 16 of gestation. The following parameters were investigated: reproductive health of the dams, external, skeletal and visceral malformations of fetuses and frequencies of micronuclei and chromosome aberrations in bone marrow cells of dams. Oral administration of Pipethiadene or Pizotifen maleate produced no teratogenic effects. No elevation was observed in the frequencies of micronuclei and chromosome aberrations. However, the significant reduction of fetal weight after all doses of Pipethiadene or Pizotifen maleate was found to correlate well with the decreased values of the mitotic indices of bone marrow cells of mice, suggesting a potential embryotoxic effect of the tested substances.