Nakano S, Yada H, Irimura K, Asanoma H, Hirota T, Terazawa K
Drug Safety Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
J Toxicol Sci. 1992 Dec;17 Suppl 4:163-99. doi: 10.2131/jts.17.supplementiv_163.
A chronic 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 using male and female beagle dogs. FUT-187 was orally administered to the dogs at dose levels of 7.5, 15, 30 and 60 mg/kg/day for 52 weeks, followed by 5 weeks' recovery period. Results are summarized as follows: 1. In general conditions, vomiting, salivation and the passage of mucousy stools were observed in dogs given 15 mg/kg/day or more, and diarrhea was observed at 30 mg/kg/day or more. One male given 15 mg/kg/day showed transient pallidity of the oral mucosa, and another male in the same group showed apnea and abdominal breathing. In addition, one male given 30 mg/kg/day was euthanatized due to extreme weakness, as weight loss and pallid oral mucosa, and another male in the same group died after showing acute toxic symptoms such as hyperpnea, tonic convulsion and ataxic gait. 2. Weight gain was slightly suppressed in females given 60 mg/kg/day. No significant changes in food consumption were observed. 3. Hematological examination revealed no statistically significant changes. Decreases in RBC counts, Ht values and Hb concentrations, and increased reticulocyte counts were observed in one male of 15 mg/kg/day group, which also showed pallid oral mucosa, and in one male of the 30 mg/kg/day group, which was euthanatized in a moribund state. 4. Blood biochemistry revealed increased GPT activity in males given 15 and 30 mg/kg/day and females given 60 mg/kg/day, which was accompanied by sporadic increases in GOT, A1P and/or gamma-GTP activities. Males given 30 mg/kg/day or more showed decreased total protein. 5. Hepatic function testing (ICG test) showed no statistically significant changes. One female given 60 mg/kg/day showed increased accumulating concentration of ICG. 6. There were no toxicological changes in urinalysis, fecal occult blood, renal function (PSP clearance), ophthalmological and electro-cardiographic examinations. 7. In pathological examination, inflammatory cell infiltration and microgranuloma formation in liver were noted periportally or perivenularly in both sexes given 15 mg/kg/day or more (except for 30 mg/kg/day males). In the some cases, atrophy, degeneration and necrosis of hepatocytes and/or fibrosis around inflammatory cells and microgranuloma were observed. In the spleen, one male given 15 mg/kg/day and one female given 60 mg/kg/day showed increased plasma cells in the red pulp. In the case sacrificed in a moribund condition, findings in the liver and spleen similar to those in surviving cases were detected, but were more severe, and the liver showed diffuse fibrosis.(ABSTRACT TRUNCATED AT 400 WORDS)
使用雄性和雌性比格犬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]苯甲酸二甲磺酸盐（FUT-187）进行了一项慢性经口毒性研究。以7.5、15、30和60 mg/kg/天的剂量水平对犬口服给予FUT-187，持续52周，随后有5周的恢复期。结果总结如下：1. 一般情况方面，给予15 mg/kg/天及以上剂量的犬出现呕吐、流涎和排出黏液便，给予30 mg/kg/天及以上剂量时出现腹泻。一只给予15 mg/kg/天的雄性犬出现口腔黏膜短暂苍白，同一组的另一只雄性犬出现呼吸暂停和腹式呼吸。此外，一只给予30 mg/kg/天的雄性犬因极度虚弱（体重减轻和口腔黏膜苍白）而被安乐死，同一组的另一只雄性犬在出现呼吸急促、强直性惊厥和共济失调步态等急性中毒症状后死亡。2. 给予60 mg/kg/天的雌性犬体重增加略有抑制。未观察到食物摄入量有显著变化。3. 血液学检查未发现有统计学意义的变化。在给予15 mg/kg/天剂量组的一只雄性犬（该犬也出现口腔黏膜苍白）以及给予30 mg/kg/天剂量组的一只雄性犬（该犬在濒死状态下被安乐死）中观察到红细胞计数、血细胞比容值和血红蛋白浓度降低，网织红细胞计数增加。4. 血液生化检查显示，给予15和30 mg/kg/天的雄性犬以及给予60 mg/kg/天的雌性犬谷丙转氨酶活性升高，同时谷草转氨酶、碱性磷酸酶和/或γ-谷氨酰转肽酶活性有散在升高。给予30 mg/kg/天及以上剂量的雄性犬总蛋白降低。5. 肝功能测试（吲哚菁绿试验）未发现有统计学意义的变化。一只给予60 mg/kg/天的雌性犬吲哚菁绿蓄积浓度增加。6. 尿液分析、粪便潜血、肾功能（酚红清除率）、眼科和心电图检查均未发现毒理学变化。7. 在病理检查中，给予15 mg/kg/天及以上剂量的两性（给予30 mg/kg/天的雄性犬除外）肝脏门静脉周围或静脉周围均可见炎性细胞浸润和微肉芽肿形成。在某些情况下，观察到肝细胞萎缩、变性和坏死以及/或炎性细胞和微肉芽肿周围的纤维化。在脾脏中，一只给予15 mg/kg/天的雄性犬和一只给予60 mg/kg/天的雌性犬红髓中的浆细胞增多。在濒死状态下处死的病例中，肝脏和脾脏的发现与存活病例相似，但更严重，肝脏出现弥漫性纤维化。（摘要截断于400字）
