HYPERSENSITIVE TOXICITY OF 5-n-BUTYL-1-CYCLOHEXYL-2, 4, 6-TRIOXOPERHYDROPYRIMIDINE IN THE PREGNANT RAT

Abstract

5-n-Butyl-l-cyclohexyl-2,4,6-trioxoperhydropyrimidine (BCP), a new antipyretic antiphlogistic agent, has been reported to differ from aminopyrine and phenylbutazone in lack of central convulsion in mice and rats as well as in mildness of the convulsion caused by the toxic doses in rabbits and dogs (1). Respiratory depression was the usual cause of death following excessive doses of BCP. The oral subchronic toxicity of BCP, amino pyrine and phenylbutazone in rats was reported by Okamoto (2) and Araki (3). Accord ing to their results, BCP in the daily doses above 800 mg/kg produced slight degeneration and destruction of the convoluted tubular epithels in the kidney, while phenylbutazone in the lesser doses resulted not only in the similar changes in the kidney, but also in obvious degeneration of the liver cells and the cardiac muscle fibers.The necessary prerequisite of a clinically available drug should be superiority of the main pharmacological effects and also minority of the side effects. During the toxicolo gical studies of the anti phlogistics, the present author found that the lethal dose of BCP in the pregnant rats was markedly different from that in the non-pregnant ones. There fore, attemt has been made in the present report whether the lethal response to the com pound is conditioned by sex or gestation. METHODSAdult male and female rats (4-5 months of age) of Wistar strain were used. The animals were housed in the individual cage at room temperature of 22±2°C and at humidity of 40-70%, and were fed a commercial powdered diet (CLEA OA-2, supplied by the Japan CLEA Co.) and water ad libitum.Pregnant rats : Previously unmated two female rats were placed in a cage with a male overnight. Those found to have vaginal plugs were isolated and the day when the females showed the positive smear was regarded as zero day of pregnancy.Drug administration : BCP, aminopyrine and phenylbutazone were suspended in water at various concentration with carboxymethyl cellulose and administerd via stomach tube. The non-pregnant rats were treated with a single dose of 1.0, 1.5 and 2.0 g/kg of BCP and were observed for 7 days. In next series of experiments, BCP in doses of 100

Effect of Antiphlogistics on the Level of Blood Glucose in the Rat

“…These metabolic effects including inhibition of corticosteroid biotransformation, uncoupling of oxidative phosphorylation, glycogenolysis, alteration of electrolyte balance and inhibition of mucopolysaccharide biosynthesis seem to merit attention in relation to their antiphlogistic activities (1-3). Tanabe and his co-workers (4,5) have shown that a death caused by larger doses of phenylbutazone and 5-n-butyl-l-cyclohexyl-2, 4, 6-trioxoperhydropyrimidine (BCP) is probably due to the decompensation of adrenocortical function, since repeated administrations of these agents produce the diffuse hemorrhage and proliferation of adrenal cortex in the rat. Korus et al (6) have reported that in the inactivation process of cortisone phenylbutazone not only inhibits the transformation of the a,f-unsaturated ketonic group of ring A, but also the degradation of the ce-ketolic side chain of ring D. However, Dirscherl and Lutzmann (7) have observed only the inhibitory effect of aminophenazone on the reduction of ring A.…”