Intravenous single and repeated dose toxicity studies of cimadronate (YM175), a novel bisphosphonate, in rats.

Cimadronate (YM175) is a novel bisphosphonate with potent inhibitory activity on bone resorption under development for the treatment of tumor-induced hypercalcemia, metastatic bone disease and osteoporosis. We conducted toxicity studies of cimadronate intravenously, single dose, 30-day repeated dose and 26-week weekly dose in F344 rats. In the single dose study, cimadronate was administered to rats and the animals were observed for 14 days. Major toxic symptoms were decreased motility and piloerection and LD50 values were 23 mg/kg for males and 21 mg/kg for females. In the 30-day study, the animals received cimadronate at doses of 0, 0.16, 0.31, 0.62 or 1.25 mg/kg/day. At 0.16 mg/kg/day or more, an increased amount of primary spongiosa was observed in the femur. At 0.62 mg/kg/day or more, renal and testicular/epididymal toxicity were observed. After a 30-day recovery period, the finding in the kidney disappeared, but the findings remained in the bone, testis and epididymis. In the 26-week weekly dose study, animals received cimadronate at doses of 0, 0.31, 0.62 and 1.25 mg/kg/week. At 0.31 mg/kg/week or more, an increased amount of primary spongiosa was seen in the femur. Renal and testicular/epididymal toxicity, however, were not observed.

Intravenous single and repeated dose toxicity studies of cimadronate (YM175), a novel bisphosphonate, in beagle dogs.

Cimadronate (YM175) is a novel bisphosphonate with potent inhibitory activity on bone resorption under development for the treatment of tumor-induced hypercalcemia, metastatic bone disease and osteoporosis. We conducted intravenous single and repeated dose toxicity studies of cimadronate in beagle dogs. In the single dose study, animals received a single dose of 0.3, 1, 3 or 10 mg/kg of cimadronate and the animals were observed for at least 14 days. At 10 mg/kg, both the male and female dog showed toxic signs such as vomiting, decreased locomotor activities and hypothermia and were killed in extremis within a week after dosing. In the 30-day study, animals received cimadronate at a dosage of 0 (vehicle), 0.03, 0.1, 0.3 or 1 mg/kg/day. At 0.03 mg/kg/day or more, histological findings indicated an increased amount of primary spongiosa in the rib and ilium. At 1 mg/kg/day, degenerative nephropathy, aggregation of spermatozoa and glandular hypoplasia of the prostate gland were observed. On day 16 of dosing one male animal died of acute renal failure. In the 26-week study, animals received cimadronate once weekly at a dosage of 0 (vehicle), 0.31, 0.62, or 1.25 mg/kg. Histopathological examination showed an increased amount of primary spongiosa in the rib at all dosage levels. In addition, similar findings were observed in the lumbar vertebrae at 1.25 mg/kg/week. Histopathological changes in the kidney and male reproductive organs were not observed.

Reproductive toxicity studies of ademetionine.

S-Adenosyl-L-methionine sulphate-p-toluene sulphonate (ademetionine, SAMe), a donor of methyl groups, was examined for effects upon embryofoetal toxicity following both premating treatment and treatment during pregnancy and for peri- and post-natal toxicity in the rat at dosages of 0, 100, 200 and 400 mg/kg/d SAMe ion by subcutaneous or intravenous administration. Embryofoetal toxicity was also examined in the New Zealand White rabbit at dosages of 0, 10, 20 and 40 mg/kg/d SAMe by intravenous administration. Treatment was considered to be without adverse effect upon any of the reproductive parameters examined on either F0 or on the untreated F1 generations. There was no indication that treatment adversely affected the litter parameters including the incidences of malformations, anomalies and skeletal variants. Some slight changes in the activity of the F1 females derived from F0 animals given 400 mg/kg/d were considered to be of minimal importance. In contrast to the above, adverse effects upon the parents were noted at 400 mg/kg/d including local tissue reaction at the injection sites and retardation of body weight gain. In the intravenous studies some rigidity and dyspnoea were noted following administration. Following subcutaneous premating treatment there was also evidence of histopathological change to the kidney of the female rat. Increased water consumption was noted in this latter study and amongst females rearing offspring in the embryo foetal toxicity study in which the compound was administered intravenously. At the lower dosages administered to the rat some local tissue reaction was evident as was some retardation of body weight gain, minimal at the lowest intravenous dose.(ABSTRACT TRUNCATED AT 250 WORDS)