A comparative toxicity study with 6α-methylprednisolone 21-sodium succinate and hydrocortisone 21-sodium succinate in male rats revealed that the inhibiting effect of these two steroids on the pituitary-adrenal system was the same. No ulceration was observed in the gastro-intestinal tract of rats treated with these compounds.
DDVP (dichlorvos), an irreversible cholinesterase (ChE) inhibitor, was administered acutely and chronically to rats in order to investigate effects on the distribution of brain acetylcholine (ACh). In acutely treated animals (4 mg/kg, singly), cholinergic signs were evident and accompanied with a 100, 146, 113, and 61 per cent increase in total, free, labile-bound and stable-bound ACh content of the brain, respectively, and a 66 per cent decrease in acetylcholinesterase (AChE) activity 20min after injection. In no animals treated chronically with a low dose (0.2 mg/kg/day for 9 or 90 days, or 1 mg/kg/day for 9 or 30 days), any overt sign was shown during the experimental period, and the stable-bound ACh content of the brain was not altered. In the group given 0.2 mg/kg for 90 days and that given 1.0 mg/kg for 9 or 30 days, free ACh content increased slightly but significantly, and AChE activity decreased to 58 per cent. Total ACh content and labile-bound ACh content increased only in a group given 1 mg/kg of DDVP for 30 days. These results suggest that acute, as well as chronic, exposure to organophosphate may induce alterations in mobilization and storage of ACh in the central cholinergic nerves.
Cytotioxicity of methyl bromide on cultured mammalian cells was examined. Lethal concentrations of methyl bromide on HeLa cells and primary cultured muscle, kidney and brain cells were similar (10 μg/ml). Acute toxic effect was induced by methyl bromide itself. And its cytotoxicity was reduced in the presence of glutathione. The action of methyl bromide seemed to be nonspecific protoplasm-toxic.
The β-glucuronidase activity in liver of Wistar strain albino rats shows a sharp increase in 2-3 days after birth and indicates no longer extensive alterations in 50-90 days, after reaching the peak in about 20-30 days. In Gunn strain rats, the activity was detected to be low, as compared to that in Wistar strain albino rats. In kidney and intestine, the activity was observed in 12 days after birth or thereafter, but it was maintained at a certain level. In the study using Wistar strain albino rats, the β-glucuronidase activity showed an increase in liver, kidney and intestine at 500 mg/kg borneol oral administration. The same increase was noticed only in liver at 50 mg/kg chloretone administration and also in liver at 300 mg/kg barbital-Na administration. In Gunn strain rats, no notable increase was indicated even in the administration of any drugs.
1) Absorption, distribution and excretion of 14C-Dipyridamole (RA 8) were studied comparatively after the administration of single intravenous (5 mg/kg), single oral (10 mg/kg) and multiple oral (10 mg/kg, once a day for one week) dosages in rats. 2) The blood level of radioactivity after oral administration showed a monophasic slow elimination with a half-life (t1/2) of about 10 hrs. The apparent absorption rate was not so high (t1/2 : 0.72 hr), therefore, it took about 3 hrs to reach the maximum level. 3) When the drug was applied intravenously, radioactivity in blood decreased tri-phasically, but the terminal phase, which appeared 12 hrs after the application, showed the same elimination rate as that of p.o. application, i.e. t1/2 : about 10 hrs. 4) The observed values of radioactivity during and after the multiple dosing regimen fitted well on the simulation curve derived from the results of a single administration. 5) Radioactivity was mainly distributed in the alimentary canal, liver and kidney, which were isolated after single or multiple oral administration. No radioactivity was found in CNS. Whole body autoradiogram obtained after intravenous or oral administration also supported the results of distribution as above. 6) No considerable accumulation of radioactivity was recognized in any tissues after the multiple dose in the rat.
Subacute toxicity and recovery tests of labetalol hydrochloride, α-and β-adrenoceptor blocking agent, were carried out using male and female Wistar strain rats. The drug was orally administered at 50, 150, 450 or 1000 mg/kg/day for 1 month. In all the drug-treated groups, increase in salivation was observed from immediately to 15 minutes after dosing through the treatment period. Eight of the 10 males and 9 of the 10 females in the group treated with 1000mg/kg/day died of intoxication. Suppresion of body weight gain was observed in male rats in the 450 and 1000 mg/kg/day groups and in female rats in the 1000 mg/kg/day group. In the 150 mg/kg/day and higher dose groups, water comsumption showed a tendency to increase as compared with that of control group. Increase in urine volume was observed in female rats in the 450 mg/kg/day group. In the serum biochemical examinations, slight elevation in potassium levels was noted in the 150 and 450 mg/kg/day groups. In histopathological findings, some abnormalities were found in organs were; congestion and hypremia of various organs due to vasodilation, swelling of parenchymatous cells in liver and kidneys, and loose arrengement and change in the thickness of muscle fibers in cardiac and skeletal muscles. None of these abnormal findings was found in any examination in recovery tests. From these results, it was suggested that maximum non-toxic dose of labetalol hydrochloride was about 150 mg/kg/day in male and female rats.