Ameltolide. I: Developmental toxicology studies of a novel anticonvulsant.

Ameltolide, a novel anticonvulsant agent, has been shown in animal models to be effective in controlling seizures. The developmental toxicity of ameltolide was evaluated in two species. Naturally mated rats and rabbits were dosed once daily by gavage on gestation days (GD) 6-17 and 6-18, respectively. Rats were given doses of 0, 10, 25, or 50 mg/kg; rabbits were given 0, 25, 50, or 100 mg/kg. Laparotomy was performed on rats on GD 20 and on rabbits on GD 28. In rats, maternal toxicity was indicated at the 25- and 50-mg/kg dose levels by depressed body weight gain. Fetal body weight was depressed at the 50-mg/kg dose level. Fetal viability and morphology were not affected. The no-observed effect levels (NOEL) for adult and developmental toxicity in the rat were 10 and 25 mg/kg, respectively. In rabbits, maternal toxicity was indicated by a net loss in body weight at the 50- and 100-mg/kg dose levels. Fetal viability and body weight were depressed at the 100 mg/kg dose level. Shortened digits occurred on the right forepaw of one fetus at the 50-mg/kg dose level (in conjunction with severe maternal toxicity) and on the hindpaws of two fetuses from separate litters at the 100-mg/kg dose level. Incomplete ossification of the phalanges occurred on the forepaws of nine fetuses from four litters at the 100-mg/kg dose level. Ameltolide was weakly teratogenic in the rabbit. The NOEL for adult and developmental toxicity in the rabbit was 25 mg/kg.

Patulin mycotoxicosis in the rat: toxicology, pathology and clinical pathology.

Patulin, a secondary metabolite produced by species of the genera Penicillium and Aspergillus, was administered to male Sprague-Dawley rats, weighing 50-60 g, by the oral, sc and ip routes. The 72-hr LD50 values (in mg/kg weight) were: oral, 55.0; sc, 11.0; ip, 10.0. Mortality was greatest 0-24 hr after administration by the oral and sc routes and 49-72 hr after ip dosing. Gross alterations consisted of gastric and intestinal hyperaemia and distention. Histopathological alterations consisted principally of ulceration and inflammation of the stomach. Patulin was administered orally to rats daily or every other day for 2 wk at doses of 50 or 75% of the oral LD50. Mortality in the treated groups was greater than in controls but was similar for all treated groups. No evidence of cumulative toxicity was found and the gross and histopathological alterations were similar to those found in the LD50 studies. Clinicopathological alterations included metabolic alkalosis with respiratory compensation, oliguria, decreased serum sodium, elevated blood glucose, reduced plasma protein and an elevated total leucocyte count which differential leucocyte counts indicated to be due to neutrophilia. The inflammatory alterations observed in the gastro-intestinal tract may be due to the irritant properties of patulin or to an alteration in the gastro-intestinal flora by the antibiotic activity of patulin.