[A 13-week subacute oral toxicity study of 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethanesulfonate (FUT-187) in rats].

The toxicity of FUT-187, a synthetic protease inhibitor, was investigated in Sprague-Dawley rats. FUT-187 was given orally to the rats at doses of 2, 10, 50, 250 and 1250 mg/kg/day for 13 weeks, then the drug was withdrawn for 5 weeks for recovery. The results are summarized as follows: In the 1250 mg/kg/day group, 9 out of 20 males died with decreased body weight and exhaustion. Histopathological examination revealed renal papillary necrosis, ulcer in the urinary bladder, hemostatic lesions in the lungs and liver, ulcer or erosion in the stomach, duodenum and jejunum. The surviving animals in this group showed swelling of the limbs due to synovitis, transient salivation immediately after administration, suppression of growth with decreased food consumption. Urinalysis revealed a low pH, increased ketones and bilirubin excretion, dark yellowish change in color, the appearance of "leaflet-shaped" crystals and increased red blood cells and epithelial cells in the urinary sediment, increased water intake, decreased specific gravity and decreased sodium, potassium and chloride in the urine. Hematologically, there was an increase in the white blood cell count. A biochemical analysis of the blood revealed decreased amylase activity, glucose and total protein levels and increased GOT activity and inorganic phosphorus levels. Pathological changes were observed in the pancreas, kidney, digestive tract, urinary bladder and liver. The pancreas showed macroscopical enlargement and increased organ weight. Histopathologically, there were several alterations in the acinar cells, such as vacuolization due to increased fat droplets, nuclear irregularity, prominent nucleoli, irregular arrangement and vesiculation of rough endoplasmic reticulum (rER), dilatation of developed Golgi apparatus and increased free ribosomes. In the kidney, increased weight and pigmentation in the proximal tubular epithelium were noted. Electron microscopically, these pigments were recognized as secondary lysosomes containing filamentous material and electron dense granules within a lucent matrix. In the digestive tract, ulcer or erosion in the stomach and duodenum, and villous proliferation in the small intestine were observed. Furthermore, hyperplasia and vacuolization were noted in the mucosal epithelium of the urinary bladder. In addition, loss of perilobular fat droplets in the liver and increased adrenal weight without histological change were observed. After a 5-week recovery period, these changes disappeared almost completely. In the 250 mg/kg/day group, slight suppression of growth the appearance of "leaflet-shaped" crystals in the urinary , sediment, increased water intake and decreased sodium in the urine were observed. The pancreas showed enlargement, increased weight, acinar cell hypertrophy with increased zymogen granules, fine vacuolization, slight derangement and vesicular of rER, and dilatation of Golgi apparatus.(ABSTRACT TRUNCATED AT 400 WORDS)