Experimental studies on the toxicity of diperdipine following oral and parenteral application.
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.
Herzog
R
R
Henning Berlin GmbH, Germany.
Leuschner
J
J
D000284:Administration, Oral; D000818:Animals; D001772:Blood Cell Count / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000633:toxicity*; D005128:Eye Diseases / Q000139:chemically induced / Q000473:pathology; D005260:Female; D007275:Injections, Intravenous; D007509:Irritants / Q000633:toxicity; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009153:Mutagens / Q000633:toxicity; D009568:Nitrendipine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D002121:Calcium Channel Blockers; D007509:Irritants; D009153:Mutagens; C056837:diperdipine; D009568:Nitrendipine