Diperdipine (ethyl-(beta-piperidinoethyl)-2,6-dimethyl-4- (3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, CAS 149543-07-7), a new
calcium antagonist, will be used for the treatment of
hypertension,
angina pectoris and dysrhythmic conditions. The studies conducted were carried out to evaluate the risk following oral and intravenous application of
diperdipine. In accordance with the administration route envisaged for man the
drug was applied by oral and
intravenous administration. Studies were performed on the acute and subchronic toxicity, local tolerance and mutagenic potential. The single application of
diperdipine to mice and rats by gavage caused intolerance reactions starting at the lowest tested dose level of 200 mg/kg b.w. p.o. (mice) and at 250 mg/kg b.w. p.o. (rats). After single
intravenous injection intolerance reactions occurred starting at the lowest tested dose level of 10 mg/kg b.w. for mice and rats. The test substance proved to be only mildly toxic after repeated (up to 3 months)
oral administration. In the rat, toxic effects occurred from 15 mg
diperdipine/kg b.w./day p.o. onwards. Target organ is the liver with a miliary/submiliary hepatocellular
necrosis. No mutagenic potential was observed. The therapeutic index (ratio of the toxic dose in animals and the therapeutic human dose) for
oral administration of
diperdipine is at least 20, for i.v. administration at least 40 depending on animal species, frequency of administration, dose levels employed and the toxicological question posed.