Accumulation of fluphenazine enanthate (FE) and fluphenazine decanoate (FD), long-acting neuroleptic durgs, after repeated administration was investigated by means of their inhibitory effect on the discriminated avoidance response in rats. When FE 0.13 mg/kg, and FD 0.13 and 0.25 mg/kg were given i.m. once a day, the inhibitory effect enhanced progressively until about the 10th and 30th day in the cases of FE and FD, respectively. The maximum levels of suppression were maintained during the later medication periods. After the withdrawal of the drugs, the avoidance response recovered gradually and returned to each pre-drugged level on about the 20th, 30th and 100th day in the cases of FE 0.13, FD 0.13 and FD 0.25 mg/kg/day, respectively. When 1 and 2 mg/kg of each FE and FD were given i.m. once a week for 8 weeks, a progressive enhancement of the avoidance-suppressing effect was observed until the 3rd and 6th injection in the cases of FE and FD, respectively, and thereafter almost the same weekly variation pattern of the avoidance response was repeated. The present results suggest that the enhancement of the avoidance-suppressing effect after repeated administration of FE and FD is resulted from the accumulation of these drugs, and that the absorption and metabo1ism of the drugs in the body reach a steady state after 10-15 days in the former and 30-35 days in the latter, independently of the dose and administration intervals.

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The effects of paraquat on human embryonic somatic cells were studied. Monolayer cultured cells, from several different organs, were exposed to various concentrations of paraquat. Then, the cells were stained with nigrosine and Sudan IV to demonstrate dead or damaged cells and fatty granules, respectively. The lowest paraquat concentration that caused morphological changes varied from 1 to 10ppm, and the lowest concentration that caused fatty degeneration varied from 1 to 5 ppm. In both types of staining, the lowest degenerative concentration was lower as the culture generation was younger, and the degree of degeneration did not differ with the cell origin. The protein content per cell in paraquat-treated cells was not significantly decreased in comparison with control cells.

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Kinetic studies on the inhibition of the activity of glucose-6-phosphate dehydrogenase with mercuric chloride (MC) and methylmercuric chloride (MMC) have revealed that MC inhibited the enzyme non-competitively, while MMC inhibited it competitively. The Km value was 5.26×10^-5 M for glucose-6-phosphate and Ki value of MC was 2.17×10^-3M, while that of MMC was 4.35×10^-3M. The strong complex formation of nicotinamide adenine dinucleotide phosphate (NADP) or amino acids (cysteine, cystine, histidine, tryptophan or tyrosine) with MC was demonstrated in the presence of phosphate buffer as compared with that of MMC in the same buffer.

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The acute toxicity of photodecomposed products of Erythrosine, Eosine, Phloxine and Rose Bengale were studied, since it was found that toxicity of these dyes to fish increased after the dyes had been photoirradiated. Photodecomposed products of the dyes were isolated and identified with UV, IR, NMR spectra and the acute toxicity of those compounds were determined by TLm test. As results of these studies, it became clear that the toxicity of photo-decomposed organic products (dehalogenated compounds of dyes) were lower than the mother compounds. The increases in toxicity of the xanthene dyes by photo-irradiation were attributed to the liberated halogens by irradiation.

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Mutagenicity test of Methimazole (MMI) was performed by means of dominant lethal mutation test in the male mice. Male mice were treated with a single s.c. injection of 45 mg/kg or 90 mg/kg MMI. Mean body weights were slightly decreased and mating rates were low immediately after treatmrnt of MMI. Mean numbers of living implants at any periods examination up to 6 weeks after the treatment were compared with Salin Control, indicating lack of dominant lethality of MMI. On the other hand, EMS and MMC known mutagens and reference agents used in the present study, induced dominant lethalities at a single s.c. injection respectively.

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By using male and female JCL:SD rats, the subacute toxicity and recovery from toxic phenomena were tested on M73101, which was newly developed as an analgesic and anti-inflammatory drug. The drug was compulsively administered perorally in doses of 250, 500 and 1, 000 mg/kg/day for six weeks. One female rat in the highest dose group died from intoxication. None of the animals of both sexes given 250mg or 500mg died during the experimental periods. No other toxic signs than an increased salvation were observed in the rats of these groups. In the groups of 1, 000 mg/kg/day, a slight inhibition was induced in the growth curve and in the food efficiency. An increase in water consumption was observed in all of the medicated groups, being more remarkable in female than in male. In the highest dose groups, male rats showed proteinuria, while female rats showed an increase in urinary output. There were no significant changes in the histological appearances of blood and bone marrow. As to biochemical profiles of serum, the highest dose groups showed an increase in the albumin-globulin ratio and activity of GPT in both sexes, and an increase in alkaline phosphatase activity and the contents of cholesterol and neutral fat was observed only in female rats. Pathological examinaton revealed a dose-dependent increase in liver weight and a hypertrophy of hepatocytes due to proliferation of smooth endoplasmic reticulum. These changes were more intense in female than in male rats suggesting the presence of a sex difference in the effect of the drug. An increase in the weight of kidneys was also noted. Histologically, swelling and vacuolation of proximal tubular epithelial cells were observed, and single cell degeneration or necrosis was also found electron-microscopically. A conspicuous change in the gastro-intestinal tracts was ulcer formation due to swelling and subsequent desquamaton of mucous epithelial cells; however, the ulcers did not develop beyond lamina muscularis mucosae (grade I ulcus or erosion). In the recovery experiments, the symptoms and pathological changes mentioned above almost disappeared one month after the cessation of the drug administration, except that a hypertrophy of hepatocytes still remained histologically to some extent in female. It was concluded that the target organs of M73101 were regarded virtually to be the liver, kidneys and gastro-intestinal tracts. The largest non-toxic dose of the drug was considered to be 125 mg/kg body weight/day in male and 30-60 mg/kg body. weight/day in female rats (according to a supplement experiment). Furthermore, it was suggested that the greatest safety dose was 250 mg/kg body weight/day in male, while it was 125mg/kg in female rats,

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生後8ヵ月令以上のJW-NIBS系ウサギについて, M73101の50, 120および300mg/kgを器官形成期 (妊娠6日目より18日目まで) に経口投与し, 母体および胎仔におよぼす影響をaspirin の200 mg/kg投与群と比較検討し次の結果を得た。1. 妊娠母体に対し, M73101の300mg/kg群では投与期間中体重増加抑制, 摂餌量および飲水量の減少などの影響がみられ, 2例の死亡例も認められた。しかし投与終了後には著明な回復がみられ妊娠末期には特に変化がみられなかった。一方aspirin群では1例の死亡例がみられたのみで特記すべき変化は認められなかった。2. M73101投与群およびaspirin群とも吸収死亡胎仔の増加がなく,胎仔体重に著変がみられず, また薬物の影響によると考えられる奇形の出現もみられなかった。以上の結果より, 本実験条件下においてM73101はウサギ胎仔の発生に対し致死作用, 発育抑制作用および催奇形性作用を持たないものと判断される。

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JCL : SD系ラットについて M73101の100, 250および600 mg/kgを器官形成期(妊娠7日目より17日目まで)に経口投与し, 胎仔および新生仔におよぼす影響を対照群およびポジティブ対照であるaspirin群(225 mg/kg)と比較検討して次の結果を得た。1. 妊娠母体に対しM73101の250および600mg/kg群で投与初期に体重増加抑制, 摂餌量の減少などの影響が認められたが, 投与日数が進むにつれて漸欠軽減する傾向を示し, 投与終了後には順調な経過を示した。一方aspirin群でも同様の変化が認められ, さらに妊娠後期には母体体重の増加抑制が著明であった。2. M73101はF₁胎仔に対し致死作用および発育抑制作用を示さなかったが, aspirin には明らかな致死作用および発育抑制作用が認められた。3. M73101の影響と考えられる奇形の発現は認められなかったが, aspirinには著明な催奇形性作用が認められた。4. M73101はF₁新生仔の生後発育および生殖能力などに対し障害作用がなく, またF₂胎仔および新生仔に対してもなんら影響を与えなかった。一方aspirinは死産仔の増加, 生存率の低下などF₁仔に対する障害作用を示したが, F₂胎仔および新生仔には影響をおよぼさなかった。以上の結果より, 本実験条件下ではM73101の器官形成期投与はF₁胎仔に対し, 致死作用, 発育抑制作用および催奇形性作用を示さず, またF₁新生仔の生存, 成長, 発達および生殖能カへの障害作用やF₂胎仔および新生仔の生存と発達への障害作用はないものと判断される。

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