RESUMEN
The toxicological evaluation of urinary human epidermal growth factor (u-hEGF) included mutagenicity, single and repeated dose general toxicity, and teratogenicity studies in various animal species. The mutagenic potential of u-hEGF was tested in vitro (Ames test, chromosome aberration in human lymphocytes, unscheduled DNA synthesis in HeLa cells) and in vivo (chromosome aberration in Chinese hamster bone marrow and micronucleus test in rat bone marrow). No mutagenic or clastogenic effects were found. The acute toxicity of u-hEGF was evaluated in mice and rats, using single subcutaneous (sc) or intravenous (i.v.) injection of 15 mg/kg. No toxic effects were observed Four-week i.v. daily administration of u-hEGF at the doses of 0.3, o.9, and 3 mg/kg in the SD rat followed by 2 wk of compound withdrawal induced pronounced and generally dose-related effects (i.e., epithelial hyperplasia) in a wide range of tissues and organs, at all doses. However, these effects were not apparently detrimental to the general health of the rats. The repeated sc administration of u-hEGF to cynomolgus monkeys for 4 wk at the same doses as used in the rat study resulted in lethality after about 7 days of treatment in the 2 higher dose groups or after 14 days at the lowest dose. The main clinical signs observed were gastrointestinal effects, respiratory distress, sedation, marked loss of body weight, and cutaneous desquamation. At histology, hyperplasia of most epithelia was seen in all groups. In addition, atrophy of the ovarian follicles and necrosis of the uterine endometrium were noted. Changes considered secondary to physical distress were atrophy of the hemopoietic and lymphatic system and hepatic steatosis. The embryofetal toxicity and teratogenicity of u-hEGF was tested, using the i.v. route in the SD rat and the i.v. and sc routes in the New Zealand White rabbit. In both species, the compound was administered at the doses of 0, 0.3, 0.9, and 3 mg/kg/day, from day 6 to 15 of pregnancy in rats and 6-18 in rabbits. In the rat, an increase in body weight was noted in the dams and fetuses at the 2 high doses. No embryotoxic or teratogenic effects were observed. In the rabbit studies, mortality and severe clinical signs involving various systems, with marked effects on the eyes, were observed at all doses tested during the first days of treatment by both routes. From the reproductive point of view, most of the surviving treated gravid females showed only resorptions.
Asunto(s)
Factor de Crecimiento Epidérmico/toxicidad , Animales , Cricetinae , Factor de Crecimiento Epidérmico/orina , Femenino , Humanos , Macaca , Masculino , Ratones , Pruebas de Mutagenicidad/métodos , Conejos , Ratas , Especificidad de la Especie , Teratología/métodos , Pruebas de Toxicidad/métodosRESUMEN
Pregnancy termination was obtained in both Beagle and mongrel bitches after a single s.c. or i.m. injection of 2-(3-ethoxy-phenyl)-5,6-dihydro-s-triazole[5,1-a]isoquinoline (DL 204-IT) dissolved or suspended in an oily vehicle. The activity of the compound was dependent on the dose and time of pregnancy. The optimal time of treatment was found to be day 20 of gestation, at which time the smallest effective dose was 6.25 ng/kg. Pregnancy arrest normally occurs during the first stage of embryonic development (between day 25 and 30) due to the degeneration and subsequent resorption of the products of fertilization. Pregnancy termination is never accompanied by intrauterine or placental hemorrhage. After pregnancy arrest the animals return to estrus within a normal interval of time; they exhibit normal mating behaviour and their ability to conceive is not impaired. Later, pregnancies can be interrupted again by the same treatment. After subeffective doses normal parturition occurs at the expected time and the pups do not have any external malformations. High doses given every 15 days for more than one year are well tolerated and do not inhabit either the return of estrous cycle or fertility. Studies of the mechanism of action suggest that the primary site of action is the uteroplacental complex.