Promoting effect of quercetin in the intestinal tract was examined in Sprague-Dawley strain rats. The rats were injected with methy-lazoxymethanol acetate (MAM) in saline solution at 25 mg/kg body weight once a week for 3 weeks and fed a diet containing 1% quercetin for the following 459days. Most tumors found in this experimental group were also found in the group injected with MAM alone and there was no significant difference in tumor incidence between these two groups. No tumors were found in the group fed the 1% quercetin diet alone. Thus, quercetin was shown to lack of promoting activity on MAM-induced intestinal carcinogenesis in Sprague-Dawley rats.

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In order to explore the effects of metals upon the subsequent onset of several clinical events in SMON, a retrospective cohort study was attempted. Study subjects were 216 "exposed" patients and 149 "unexposed" patients. "Exposure" was defined as the simultaneous ingestion of metal-containing drugs with clioquinol before the onset of neurological disorders. These two cohorts were identified from 531 patients among 832 patients, collected by the nationwide survey in 1975 and 1976. Effects provoked by ingestion of five metals (alminum, calcium, magnesium, copper and bismuth) were evaluated by relative risks with and without adjustment of the total amount of clioquinol ingested. Adjusted relative risks were estimated by maximum likelihood method. Significance of relative risk was determined by its 95% confidence interval. Following major findings emerged from the present analysis. (1) Simultaneous ingestion of Al-, Ca-, Mg-, Cu- or Bi-containing drugs with clioquinol significantly reduced the risk of developing motor disturbances. (2) Risk of developing visual disturbances were favorably modified by Al-containing drugs. (3) Clinical severity was significantly reduced by ingestion of Al-, Ca-, Mg- or Bi-containing drugs. (4) About 2-fold increase in risk of unfavorable clinical course was demonstrated by Al-containing drugs. (5) Onset of both green-fur on the tongue and relapse appeared unrelated to the metal-containing drugs ingested. (6) Combined ingestion of two kinds of metal-containing drugs with clioquinol appeared to yield more favorable effects than single ingestion of metal-containing drugs. (7) Al- or Bi-containing drugs demonstrated the strongest association with clinical features of SMON, followed by the drugs containing Mg or Ca. Cu-containing drugs had little association.

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In this study, allopurinol toxicity was investigated in the liver and the kidney in the rat. Allopurinol was intraperitoneally administered to rats, once a day, for 1, 3 or 10 days, in doses of 3, 10, 30 and 100 mg/kg body weight/day. At the 24th hour after the last administration, the rat was sacrificed, and blood and tissue samples were taken for analyses. In doses of 30 mg/kg/day and more, decreases of the body weight and the liver weight were observed, while the kidney weight increased. The plasma activities of alkaline phosphatase, glutamic oxaloacetic and glutamic pyruvic transaminases showed no increases, while the blood urea nitrogen and creatinine increased. These changes were the most remarkable in the 3 day administration, whereas they approached the control level thereafter. In doses of 10 mg/kg/day and less, no significant changes were observed in comparison to the control. These results denote that the minimal toxic dose ranges between 10 and 30 mg/kg/day, and that the kidney is more sensitive than the liver. In addition, these results also denote that the renal and hepatic failures are reversively restored even when allopurinol is further administered later than the 3 day. This fact suggests not only that the capacity inactivating allopurinol in the body is increased, but also that the enzymatic induction in the allopurinol inactivation system is accelerated.

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The relationship between natriuresis and glucosuria produced by administration of 6-aminonicotinamide (6-AN), was investigated in the rat. After intraperitoneal administration of 6-AN (75mg/kg), urine was collected at intervals of 2 hours using a metabolic cage for assays. Sodium and glucose were excreted maximally into the urine at 2 to 4 and at 4 to 6 hours, respectively, after the administration of 6-AN, with a time delay being recognized between sodium and glucose in the peaks of their urinary excretions. This dissociation of the patterns on the urinary excretion between sodium and glucose led to the following conclusion that the natridiuresis induced by 6-AN was not mainly ascribed to the osmotic diuresis for glucose, but to the direct effect on the sodium transport in the kidney. Furthermore, additional experiments were carried out by loading animals with glucose after administration of 6-AN. The tolerance for glucose in the body was clearly depressed in rats in the 6-AN group, while no significant difference in the renal threshold concentration for glucose was shown in either group. The renal tubular transport maximum for glucose was also depressed in the 6-AN group. It is, accordingly, speculated that the glucosuria induced by 6-AN was not only due to the hyperglycemia, but also due to the decreased capacity of the renal tubular reabsorption for glucose.

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ACの26週間尾静脈内投与による慢性毒性試験及び13週間回復試験をラットを使用して実施し, 以下の結論を得た。なお, ACの投与量は30, 100, 300及び1000 mg/kg/dayの4段階とした。1. いずれの群にも死亡例はみられず, また重篤な障害も発現しなかった。2. 1000 mg/kg群には体重増加の抑制, 摂水量, 尿量及び尿中電解質排泄の増加, 腎の尿細管変性及び随伴する検査値の変動, 貧血傾向, 血清生化学的検査及び臓器重量の変動が雌雄の双方あるいは一方に認められた。3. 300 mg/kg群には, 前記の1000 mg/kg群の変動の一部が軽度に観察された。4. 100 mg/kg群及び30 mg/kg群には特に障害を意味する変化は認められなかった。5. 回復試験の結果, 1000 mg/kg群の変動は一部が残存して認められたが, 300 mg/kg群の変化は概ね回復した。6. 以上の結果を総合し, ACの本試験における最大無毒性量は100 mg/kg/dayであることが推測された。

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The effects of sodium iodate (SI), iodoacetic acid (IAA) and ethambutol (EB) on the electroretinogram (ERG) and the visual evoked potential (VEP) were examined in unrestrained rats. 1. A single intravenous dose of SI at 25 mg/kg caused depression of amplitudes of the ERG a-wave and oscillatory potentials 24 hrs after dosing. Following these changes, the amplitude of the ERG b-wave decreased. The depression of the VEP was observed in parallel with the depression in amplitude of the ERG. 2. A single intravenous dose of IAA, even at a dose of 60 mg/kg which induced death of the rats, did not cause any significant abnormality in the ERG and VEP. 3. Repeated subcutaneous dose of EB at 500 mg/kg/day depressed the amplitude of the P₁-N₁ wave and prolonged the peak latency of the P₁ and N₁ waves of the VEP without affecting the ERG after administration for 5 to 6 weeks. These abnormalities of the VEP appeared almost in parallel with ataxic gait. 4. Neither gross behavioral changes suggesting visual disturbances nor abnormal ocular fundus was revealed in any rat receiving SI or EB even when marked depression of the ERG and/or VEP was observed. 5. These results indicate that SI damages retinal function and EB does the conduction pathways from the retina to the visual cortex. In addition, the simultaneous recordings of both the ERG and VEP in unrestrained rats were found to be useful for evaluating the visual toxicity, and to furnish useful information on the site of toxic action of drugs.

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