Watanabe K, Terazawa K, Terabayashi M, Kuramoto S, Yokomoto Y, Otani K, Sato K, Kurotori M, Shimamura K, Yamashita K
Research Laboratories, Torii and Co., Ltd., Chiba, Japan.
J Toxicol Sci. 1992 Dec;17 Suppl 4:61-99. doi: 10.2131/jts.17.supplementiv_61.
A subacute oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethanesulfonate (FUT-187), a new protease-inhibiting agent, was carried out in beagle dogs of both sexes. FUT-187 was administered to dogs at daily oral doses of 15, 50 and 150 mg/kg. Dogs in 150 mg/kg group were given twice a day in a.m. and p.m.. The results were as follows: 1. Changes of physical sign attributed to FUT-187, consisted of vomiting, diarrhea, salivation, decrease of locomotor activity, sedation and hyperemia of eye mucosa. These changes expect vomiting vanished within about 2 hours after treatment. One male given 150 mg/kg died on day 19 and two females given 150 mg/kg were sacrificed on day 55 and 67 due to deterioration of systemic conditions. 2. Body weight gain was suppressed in males given 150 mg/kg and females given 50 mg/kg or more. 3. In hematological examinations, some changes suggesting anemia or inflammation were observed in a few animals received 50 mg/kg or more 4. In serum biochemical examinations, dogs given 50 mg/kg or more had decrease of albumin, total protein, A/G ratio and total cholesterol, increase of GPT activity. In liver function test, decrease of function was observed in a few animals in 150 mg/kg group. These changes diminished by the end of recovery period. 5. In autopsy findings, ulcer formation and desquamation of mucosa in the digestive tract were observed in dead or sacrificed animals and survived animals given more than 50 mg/kg. In sacrificed animals, liver was yellow in color and intussusception was seen. 6. Plasma levels of intact FUT-187 and metabolites on the day 37 or 83 were higher than that on the first day of administration. 7. In histopathological examinations, ulcer formation, desquamation, degeneration and/or atrophy of mucosa in the digestive tract were observed in the animals from 50 mg/kg and 150 mg/kg groups. In addition, fatty deposition in hepatocytes was observed in one dead animal and two sacrificed animals.(ABSTRACT TRUNCATED AT 400 WORDS)
对新型蛋白酶抑制剂6-脒基-2-萘基4-[(4,5-二氢-1H-咪唑-2-基)氨基]苯甲酸酯二甲磺酸盐（FUT-187）进行了一项比格犬亚急性经口毒性研究。将FUT-187以每日15、50和150mg/kg的口服剂量给予犬。150mg/kg组的犬在上午和下午各给药一次。结果如下：1. 归因于FUT-187的体征变化包括呕吐、腹泻、流涎、运动活动减少、镇静和眼黏膜充血。除呕吐外，这些变化在治疗后约2小时内消失。一只给予150mg/kg的雄性犬在第19天死亡，两只给予150mg/kg的雌性犬因全身状况恶化分别在第55天和第67天被处死。2. 给予150mg/kg的雄性犬和给予50mg/kg及以上的雌性犬体重增加受到抑制。3. 在血液学检查中，接受50mg/kg及以上剂量的少数动物出现了一些提示贫血或炎症的变化。4. 在血清生化检查中，给予50mg/kg及以上剂量的犬白蛋白、总蛋白、A/G比值和总胆固醇降低，GPT活性升高。在肝功能测试中，150mg/kg组的少数动物出现功能降低。这些变化在恢复期结束时减轻。5. 在尸检结果中，在死亡或被处死的动物以及给予50mg/kg以上剂量的存活动物中观察到消化道黏膜溃疡形成和脱落。在被处死的动物中，肝脏呈黄色，可见肠套叠。6. 在第37天或第83天，完整FUT-187和代谢物的血浆水平高于给药第一天。7. 在组织病理学检查中，50mg/kg和150mg/kg组的动物出现消化道黏膜溃疡形成、脱落、变性和/或萎缩。此外，在一只死亡动物和两只被处死动物中观察到肝细胞脂肪沉积。（摘要截断于400字）
