Acute and subacute toxicity of 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)-1 ,4-dihydropyridine (PP-1466).
The acute and subacute oral toxicity of 2,6-dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)-1,4 -dihydropyridine (PP-1466) was investigated in several animal species in comparison with nifedipine and nicardipine. A clear species difference in LD50 values was found in acute toxicity of PP-1466, and rabbits were the most sensitive between animal species used, then dogs, mice and rats in order. Prominent acute circulatory failure and associated secondary changes were noticed in toxic signs and autopsy findings. PP-1466 as well as nifedipine was apparently less toxic than nicardipine. In the subacute toxicity studies in rats, deaths occurred only in the 2000 mg/kg/d treated groups of both sexes of PP-1466 and nifedipine. Major changes in various observations and examinations were focussed on the cardiovascular system and liver. On the cardiovascular system, it was revealed as congestion and hemorrhage in the various organs and tissues on autopsy finding in dead rats during the test period. A dose-dependent increase in heart weight was observed in rats sacrificed at the termination of the test period. On the liver, it was revealed as a dose-dependent increase in liver weight, changes in liver lipid levels, changes in several serum biochemistry parameters, such as GOT, GPT and ALP (alkaline phosphatase) activities and lipid levels measured at the termination of the test period. These changes were toxicologically mild and functional except the autopsy findings in dead rats. Female rats were slightly more sensitive than males, and PP-1466 was slightly less toxic than nifedipine on subacute oral toxicity in rats.
D000284:Administration, Oral; D000818:Animals; D001774:Blood Chemical Analysis; D001835:Body Weight / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000633:toxicity*; D004285:Dogs; D005260:Female; D007928:Lethal Dose 50; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009529:Nicardipine; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000633:toxicity; D009929:Organ Size / Q000187:drug effects; D011524:Protoporphyrins / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors; D013045:Species Specificity; D013997:Time Factors
D002121:Calcium Channel Blockers; D011524:Protoporphyrins; D009529:Nicardipine; D009543:Nifedipine; C045912:ryodipine