Subacute toxicity of ebrotidine in rats and dogs.

Subacute toxicity studies of ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl]methyl] thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) were performed in Spragu-Dawley rats and Beagle dogs. Both animal species were administered with the same dose levels (50, 200 and 500 mg/kg) for 4 and 7 weeks, respectively. In a previous 4-week subacute toxicity study in the rat, ranitidine and cimetidine at 500 mg/kg were used as reference drugs. The results indicated that ebrotidine was well tolerated at 50 mg/kg, while there were dose-related effects at 200 and 500 mg/kg. Probably due to its pharmacokinetics, ebrotidine was more toxic in dogs than in rats, since the most severe effects were the death or sacrifice in extremis of two dogs from the high dose group which had undergone rectal prolapse, while no deaths occurred in the rats. The changes that were very likely related to treatment (500 mg/kg) were a lower weight in both species, a slight decrease of hematocrit and red blood cells in rats, single increments of transaminases, alkaline phosphatase and lactate dehydrogenase in dogs (some animals of the 200 mg/kg dose group were also affected) and a higher liver weight. These effects with a few exceptions were found to be common to cimetidine and ranitidine.

Chronic toxicity of ebrotidine in rats and dogs.

The results obtained in the chronic toxicity studies of ebrotidine (N-[(E)-[[2-[[[2-[(diaminomethylene)amino]-4-thiazolyl] methyl]thio]ethyl]amino]methylene]-4-bromo-benzenesulfonamide, CAS 100981-43-9, FI-3542) by oral route in rats and in Beagle dogs are reported. Rats were administered for 6 months and dogs for 12 months. The doses were 50, 200 and 500 mg/kg in rats and 50, 200 and 400 mg/kg in dogs. The dose of 400 mg/kg was reduced to 350 mg/kg after 3 months of treatment, due to its toxicity. The effects probably related to the administration of ebrotidine were as follows: three dogs from the high dose group died after 3, 4.5 and 8 months of treatment (in rat there was no mortality); occult blood in faeces; lower weight gain in the high dose group (in rats only females were affected); lower food consumption in rats from the high dose group (and also females from the middle dose group); reduction of erythrocyte count and packed cell volume, only in rats and at the end of the study; alkaline phosphatases increment in rats and dogs; proteinemia decrease in rats; and a tendency to decrease in the testicular weight, which was not statistically significant (p > 0.05). The only histopathological changes observed were moderate erosions or ulcerations in the intestinal mucosa of some dogs from the high dose group. These effects coincide with those published for other competitive H2-receptor inhibitors. The maximum toxic effect-free level was 50 mg/kg for both rats and dogs, which provides a wide safety margin with respect to the therapeutic dose.