Thrombophlebitis similar to that which is frequently observed following i.v. injection of irritative drugs in clinical treatment has been successfully reproduced in experimental animals by utilizing a newly devised technique. Thrombophlebitis at a high rate resulted within a few days by allowing the sample to remain in the sealed section of the V. retroauricularis in rabbits for 3 min after injection. The effects of several drug preparations on the thrombus as well as on the inflammation formed by means of this technique were examined, and the results were in good parallel with clinical cases reported in medical literature. Histopathologically, it was observed that each thrombus was formed by the irritative effect of drugs on the portion on the veneous wall damaged when needles had been inserted.

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An in vivo study was made on the effect of linoleic acid hydroperoxide on the formation of lipid peroxide in rat liver mitochondria, and results are as follows: There were no changes in contents of lipid peroxide and total sulfhydryl in rat liver mitochondria after daily administration of linoleic acid hydroperoxide (10 mg/kg, i.p.) for 3 or 7 days. Changes in the fatty acid composition in plasma and liver after i.p. administration of linoleic acid hydroperoxide for one week were not observed as compared to that of control animals. In addition, no appreciable change was found in the fatty acid composition of phosphatidylserine and phosphatidylinositol in liver mitochondria from rats treated with linoleic acid hydroperoxide. After treatment with linoleic acid hydroperoxide for 3 days, content of plasma triglycerides increased, but no effect was observed in liver triglycerides. However, plasma triglycerides returned to the control level and triglycerides in liver increased by treatment with linoleic acid hydroperoxide for one week. Free fatty acids decreased in plasma but not in the liver from rats treated with linoleic acid hydroperoxide for 3 or 7 days.

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Three sodium polyacrylates (PAS) with different viscosities were examined for antiulcerogenic properties. Rats were fed with sugar containing a PAS for 4 hr and subjected to 12 hr reserpinization or stress by water immersion. Lower incidence of ulceration and larger amount of stomach content after the experiment were found in the PAS administered groups. The higher viscous PAS was more effective in prevention of ulceration and in prolongation of gastric emptying. Intragastric administration of the drugs to pylorus ligated rats reduced forestomach ulceration. However, differences in the antiulcerogenic activity of three drugs were not observed. The effects on the gastric secretion of three PAS (50 mg) were also examined, using pylorus ligated (6 hr) rats. In PAS groups, the free acid in the gastric juice was reduced to some extent. There was, however, no relation between the antiacid effect and viscosity. The drugs inhibited the peptic digestion in vitro, but the difference of viscosity was not related to the antipeptic effect. It is concluded that prolongation of gastric emptying may be a major factor in the antiulcerogenic activity of PAS.

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Physical dependence on narcotics is induced in laboratory animals by intermittent parenteral administration (2 ?? 3 times daily). However, inducing of dependence on pethidine has been unsuccessful using the parenteral method. Recently, it has been reported that physical dependence on pethidine can be induced by continuous infusion methods (5.6). In the present experiment, pethidine was administered to rats (n=5 ?? 6) by ingestion of pethidine-admixed food preparations (0.5 ?? 4.0 mg/g of feed). The results indicated that (a) when rats are allowed free access to two food preparations (0.5 mg/g vs. 1 mg/g of food) for 7 weeks, spontaneous intake ratios of food (1 mg/g of food) gradually increased from 15% to 30% after 3 weeks. (b) Abrupt withdrawal for 48 hr after a 10 day administration period (2mg/g of food on day 1 ?? 3 and 4mg/g of food on day 4 ?? 10) resulted in a loss of body weight in the next 24 hr, and the prewithdrawal level of body weight was recovered in 48 hr. (c) The time course of body weight and food intake during the first 24 hr withdrawal period demonstrated the characteristic pattern of abstinence syndrome of pethidine, viz. early onset (12 ?? 13 hr) and rapid recovery (within 48 hr), as compared to morphine withdrawal. (d) Suppression of pethidine abstinence by both a single injection of morphine (10 mg/kg, s.c.) and substitution for morphine-admixed food was also realized. (e) When levallorphan (5 mg/kg, s.c.) was administered to both pethidine and morphine dependence rats, the maximal decrease in body weight was less than that in morphine dependent rats. These data indicate that pethidine possesses about one fifth the dependence liability of morphine and the maximal abstinence syndrome appears within 24 hr after withdrawal. Conclusively, application of a drug-admixed food preparation in drug dependence tests in rats has proven to be a useful method, particularly in the case of pethidine-like drugs which rapidly disappear from the blood.

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In preliminary experiments to investigate the influence of masking the eyes of E1-mice on the rate of non-convulsions (RNC), it was suggested that the quantity of light as well as visibility itself played a role in inducing convulsions. The following experiments were thus carried out: (a) Both TSC (the threshold of number of shakings required for induction of convulsions) and RNC increased remarkably on the 5th day after enucleation of bilateral eyeballs from E1-mice, but 15 days later recovery to control level was observed. Moreover, TSC and RNC at 2 p.m. increased considerably compared with the control, however, the increase was rarely observed at 10 a.m.. (b) 2 groups of E1-mice reared intact under radiation of light plus different time schedules were shaken at 10 a.m. and 2 p.m., respectively. Consequently, TSC after radiation for 5 hours was less than that after radiation for 1 hour. When observed 9 hr after radiation, TSC could not be differentiated from TSC at 5 hr after the radiation. (c) E1-mice were reared under continuous lighting, continuous darkness or a normal lighting situation, after which TSC and RNC were examined. From our observations, the intensity of light appears to play a role in inducing convulsions. (d) When mice were shaken immediately after lighting, RNC decreased in inverse proportion to increase in the quantity of light. TSC was not influenced by the luminosity itself. One hour after lighting, however, the influence of lighting had disappeared. The intensity, quantity or irradiation time would not, however, influence the induction of El-mice convulsions so much as the cognizance of light by the individual animals. Such a conception is derived from the “cognitive theory” in psychology.

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It is well known that aniline and hydroxylamine derivatives induce methemoglobinemia in humans as well as various animal species. It was noticed that sulfhemoglobinemia was induced by subchronic admistration of N-(4-chlorophenyl)-β-(4-hydroxymethylphenoxy)ethyl urethane (HPU) to rabbits (p.o.), cats (i.p.) and mice (i.p.). Sulfhemoglobin (SHb) and methemoglobin (MHb) formation by various compounds structurally related to HPU were examined by a single and three consecutive intraperitoneal administrations to mice. It was found that by a single administration, methemoglobinemia was induced by phenylhydroxylamine (PHA), nitrobenzene (NB), aniline (A), 2-chloro-A (2-Cl-A), 3-Cl-A, 4-Cl-A, acetanilide (AA), phenacetin (PA), N-(4-chlorophenyl)ethylurethane (CPU), hydroxylamine (HA) and sodium nitrite (SN), and was not observed with phenylurethane, HPU, methylhydroxylamine (MHA), methylamine and nitromethane (NM). On the other hand, with sulfhemoglobinemia which appeared much more delayed than MHb, a single administration, was found to be induced by PHA, 3-Cl-A, 4-Cl-A, PA, CPU, MHA and SN. Futhermore, with three consecutive administrations, such was induced by NB, 2-Cl-A, AA, HPU and NM even though SHb was not demonstrated with a single administration. Structure-SHb forming property relationship and mechanism for SHb formation are discussed.

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A41 304 at 400 μg/kg produced depression of body weight gains in the rat dams but did not increase the number of the fetuses with gross malformations. At 400 μg/kg of dexamethasone, body weight gains of the rat dams were markedly depressed and fetuses presented cleft palate and depression of the placental weight, body weight and crown-rump length. As for the influence of both drugs upon the fetal skeleton, ossification of the odontoid process and metatarsus was delayed and lumbar ribs increased. Dexamethasone at 400 μg/kg, in addition to these findings, caused prominently delayed ossification of the caudal vertebrae. When A41 304 at 1600 μg/kg and dexamethasone at 400 μg/kg were given to pregnant mice, cleft palate occurred with high incidences, but neither visceral abnormalities nor skeletal malformations attributable to the drug administration were observed. The critical period of cleft palate which was noted in the mice given A41 304 was day 11 through day 15 of pregnancy, mainly days 11 ?? 13 of pregnancy. Cleft palate was seen in a doserelated manner in either A41 304-treated groups or dexamethasone-treated groups, but the incidence at the same dosage level was higher in dexamethasome-treated groups than in A41 304-treated groups.

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Toxicity of drugs to cultured cell line (RK13-, EL-cell line) were exposed to various concentrations/ ml medium for 48 hours and for 14 days. The morphologic changes of both cell lines observed included granulation and shrinkage of the cytoplasm, formation of long and narrow cytoplasmic projection, and appearance of giant like cells. ID50 values of ibuprofen, naproxen, Y-5554, diclofenac and aminopyrine to RK13 cell were found to be 130, 290, 200, 140 and >500 μg/ml respectively. On the other hand, ID50 values of each drug to FL-cell were found to be 105, >500, 180, 170 and <500 μg/ml respectively. Minimum concentration, caused by the detachment of the cell from the vessel wall, was as follows : to RK13 were ibuprofen 125 ?? 250, paproxen 250 ?? 500, Y-5554 125 ?? 250, diclofenac 62.5 ?? 125, aminopyrine 1000 ?? 2000 each μg/ml. On the other hand, to FL-cell were ibuprofen 62.5 ?? 125, naproxen 125 ?? 250, Y-5554 62.5 ?? 125, diclofenac 62.5-125 and aminopyrine 1000 ?? 2000 each μg/ml respectively.

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