Toxicological investigations with nimodipine. Summary of relevant studies

The tolerance of the new dihydropyridine derivative nimodipine (Bay e 9736, Nimotop) was investigated in a series of toxicological studies. The following results were obtained: The maximum tolerated oral doses in subchronic toxicity studies (13 weeks) were 100 mg/kg in rats and 3 mg/kg in dogs. In chronic toxicity studies in rats (2 years), the no-effect dose was 300 ppm in the food (approx. 40-60 mg/kg). With chronic administration for 12 months, dogs tolerated oral dose levels up to 2.5 mg/kg. The only important alterations found after repeated administration of nimodipine are left ventricular papillary muscle lesions in dogs. These changes develop from hypoxia, which is most pronounced in the area of the papillary muscles and which is due to a marked drop in blood pressure, leading to a strong compensatory tachycardia. Those lesions, induced by exaggerated pharmacodynamic actions, are known to occur with various hypotensive vasodilatory drugs. The drug showed no effect on fertility, or embryonic/fetal development and did also not interfere with peri/postnatal development. Nimodipine had no mutagenic effects. Therefore, toxicological studies indicate relative safety of nimodipine.