之江菌素的毒性实验

之江菌素对ＩＣＲ小鼠灌胃，ＬＤ５０为１１５３．８ｍｇ／ｋｇ，属低毒物质。致畸致突变试验阴性。亚慢毒性试验表明，大鼠饲喂含之江菌素４００ｐｐｍ的饲料连续２８ｄ，对生长发育、饲料利用率、血液及生化指标、病理组织学观察均无明显不良影响     

Teratogenic Effects of Antiepileptic Drugs: Implications for the Management of Epilepsy in Women of Childbearing Age

Summary: Exposure to antiepileptic drug (AED) treatment in utero occurs in 1 of every 250 newborns. The absolute risk of major malformations in these infants is about 7–10%, ˜3–5% higher than in the general population. Specific risk factors include high maternal daily dosage or serum concentrations of AED, low folate levels, polytherapy, and generalized seizures during pregnancy. Adverse pregnancy outcomes, including congenital heart malformations, facial clefts, spina bifida aperta, hypospadias, growth retardation, and psychomotor and mental retardation, are associated with, although not necessarily caused by, AED exposure. Specific cognitive defects, hypertelorism, and nail hypoplasia can be causally related to specific AED exposures. To prevent teratogenic side effects, the prospective mother should be treated with AEDs only when absolutely necessary. Monotherapy with the AED that is most effective in the lowest possible daily dose (divided into at least two or three administrations) should be prescribed. High-dose folate supplementation (4–5 mg/day) reduces the risk of a neural tube defect in a child whose sibling had such a defect, but its impact on the specific teratogenic risks of AEDs is unknown. A substantial proportion of fetal malformations may be secondarily prevented by prenatal diagnosis, consisting of a fetal structural ultrasound examination at weeks 18 and 20 of gestation and, with VPA or CBZ administration, an α₁-fetoprotein analysis of amniotic fluid at week 16. Determination of a specific defect prevention strategy depends largely on parental attitudes toward prenatal diagnosis and termination of pregnancy, which should be discussed before conception. The availability of many new AEDs, many of which will be used in polytherapy, will make prospective evaluation of large numbers of pregnancy outcome on a population basis even more important in the future.     

Comparative embryolethal effect of bromofenofos and dephosphate bromofenofos in rats

Bromofenofos (BF) and dephosphate bromofenofos (DBF) were administered at equimolar doses to rats on day 10 of pregnancy. The dams were killed on day 21, and the fetuses were removed, weighed and examined by routine teratological methods. BF caused a significant increase in fetal resorptions at 58.2 mg/kg. Approximately 69% of the implants were resorbed at this dose level. In rats given DBF equimolar to 58.2 mg/kg BF, the resorption rate was 81.9%. Administration of BF resulted in a dose-dependent decrease in fetal body weights which was significant at 29.1 mg/kg or more. DBF caused a significant decrease in fetal body weights, beginning at 25.1 mg/ kg equimolar to 29.1 mg/kg BF, and the decreased fetal body weights were almost the same between BF and DBF. BF at 58.2 mg/kg induced significant gross and skeletal malformations, with incidences of 35.6 and 27.6%, respectively. In rats given DBF equimolar to 58.2 mg/kg BF, gross and skeletal malformations were seen in 54.5 and 61.5% of the fetuses, respectively. There were similarities in the types of malformations observed between BF and DBF. Both compounds induced no significant internal malformations. It was concluded from these results that the embryolethal and teratogenic effects of BF is due to its metabolite, DBF, which cannot respond to cholinesterase inhibition.     

Dose-response relationship of cadmium embryotoxicity in cultured mouse embryos

Mouse embryos were exposed in vitro to 1.2 to 2.2 μM cadmium, and effects on embryotoxicity were examined after 39 h of culture. Teratogenic responses similar to in vivo were obtained at 1.2 to 2.2 μM with concomitant reduction in embryonic protein, while embryo deaths were increased from 13.8 to 93.3% at 2.0 to 2.2 μM. The response data of both teratogenicity and growth parameters, including embryonic protein, head lenght, crown-rump lenght, somite number, and protein and diameter of yolk sac, were acceptably fitted to a cadmium is a critical parameter in the manifestation of teratogenic potential, (b) as an estimation of interference in the growth of embryos, embryonic protein is one of the most sensitive endpoints while somite number is an insensitive criterion, and (c) a linear log-probit regression is applicable to the analyses of embryotoxicity data, including growth parameters in whole-embryo culture systems.     

Teratology study of two isoglutamine derivatives

The embryotoxicity and teratogenicity of N-phthalyl isoglutamine (2), a metabolite of thalidomide, and of K-2004-1c, 2-(bicyclo[2.2.1]heptane-2-endo-3-endodicarboximido)-glutaric acid 1-amide (4), the main metabolite of the test compound K-2004 (proposed generic name: biglumide), a nonteratogenic congener of thalidomide, have been investigated in mice and rats. Whereas 2 proved to be highly teratogenic and embryotoxic, 4 showed none of these activities in the dose range from 50 to 400 mg/kg.     

The toxicity and teratogenicity of mercuric mercury in the pregnant rat

Mercuric mercury (Hg²⁺), when injected IV into the pregnant Wistar rat, is retained mainly in the maternal compartment and uptake by the conceptuses is small. Thus if the dose is based on total body weight, the maternal body burden, particularly in late gestation, is greater than the whole body burden in the non-pregnant animal. The LD₅₀ of Hg²⁺ (mg/kg total body weight), however, remains essentially constant (1.0–1.2 mg Hg²⁺/kg) throughout pregnancy. It seems, therefore, that the rat becomes more resistant to Hg²⁺ with increasing gestational age. This increased resistance does not correlate with differences in (a) the uptake of Hg²⁺ by the kidneys, the target organs of toxicity, (b) the severity of the histopathologically detected renal damage and (c) the inhibition of glomerular filtration. Biochemical measurements, however, suggest that kidney function may become less susceptible to Hg²⁺ as pregnancy advances from conception to near term. During mid-gestation the minimum effective teratogenic dose of Hg²⁺ (0.79 mg/kg total body weight) is high in relation to the maternal LD₅₀ and the incidence of foetal malformations, mainly brain defects (23% in all live foetuses), is low. In rats of different gestational ages uptake of Hg²⁺ by the embryo/foetus at this dose level decreases sharply between day 12 and day 13. The teratogenic effects in the foetus and both the structural and functional damage to the maternal kidneys, however, are essentially the same in animals that are dosed with Hg²⁺ either immediately before, or immediately after these gestational ages. It is probable, therefore, that foetal defects result not from any direct action of Hg²⁺ on the conceptuses, but from either the inhibition of the transport of essential metabolites from the mother, or the maternal kidney dysfunction.     

Teratogenicity induced in cultured rat embryos by the serum of procarbazine treated rats

Male rats were injected with single intraperitoneal doses of 50–200 mg/kg of procarbazine hydrochloride (P). Their undiluted serum was then used as the culture medium for 9.5-day-old embryos to evaluate its teratogenic and toxic potential in vitro. A 48-h exposure to this medium resulted in a variety of dysmorphogenic effects. Somite, limb bud and otic vesicle deformities were seen at all dose levels, and neural tube and optic vesicle abnormalities were frequently observed in the 150 and 200 mg/kg groups. Embryonic growth and differentiation were only moderately affected at any dose levels.In a second set of experiments, embryos were directly exposed to 100–150 μg/ml P combined with a liver enzymatic activating system. No abnormalities were detected but toxicity occurred within narrow concentration ranges; 125 μg/ml affected growth and differentiation slightly, and 150 μg/ml suppressed the embryonic development severely. Exposure to 125 μg/ml P without the liver enzymatic activating system had no effect on embryonic growth and differentiation, suggesting that the metablites responsible for the toxic effect were generated by the liver enzymatic preparation.Our results indicate that stable metabolites of P, responsible for its teratogenic action, are formed only within body compartments, whereas the formation of these metabolites does not take place in vitro in the presence of hepatic enzyme preparations.     

Teratogenesis and reproductive safety evaluation of the retinoid etretin (Ro 10-1670)

Reproduction and teratology studies were performed with etretin, the free acid analog of the retinoid etretinate. The lowest teratogenic dose of etretin in mice, rats and rabbits was 3, 15 and 0.6 mg/kg, respectively. In all three species, the lowest dose which was embryolethal, fetolethal or reduced the survivability of the pups during lactation was 2–3 times higher than the above doses. In rats, the lowest effective dose of etretin was 3 mg/kg in both the study for fertility and general reproductive performance and the peri- and postnatal study. The main adverse effect in these two experiments was a reduced survival of the F₁-generation.     

Teratogenic effects of nitroimidazopyridazine on the CNS in fetal Wistar (WU) rats

Teratogenic effects caused by a new nitroimidazopyridazine were examined in Wistar (WU) rats after repeated oral administration of 0, 2.5, 10, and 40 mg/kg, given on days 6–17 post coitum (p.c.) (Day of mating = Day 0) in a regular study on embryo-fetal development according to ICH S5A. At day 20 p.c., fetuses were removed and carefully examined under a dissecting microscope for external, visceral and skeletal malformations. The exposure to the high dose of the test compound during the organogenesis and early histogenesis periods of prenatal development induced prominent CNS malformations (exencephaly, neural tube defects (NTD)) associated with external malformations (hyperflexion of the forelimbs). To support the data from this study additional histological evaluation of the brains was performed with the following results: disorganization of the cerebral cortex associated with ectopic subcommissural organs. Additionally, an in vitro test (whole embryo culture, WEC) showed alterations of the developing neural tube after the incubation of rat embryos with the test compound on gestation days 9.5–11.5. Our data demonstrated that nitroimidazopyridazine caused NTDs and limb malformations during organogenesis. Based on these data the further development of the test compound was stopped.