Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0013911 (emaciation)
 1,059 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S-1, an antineoplastic formulation of a fluorinated pyrimidine derivative containing tegafur (FT), CDHP, and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1, was recently developed by Taiho Pharmaceutical Co., Ltd., with the aim of prolonging the effective plasma concentration of 5-fluorouracil (5-FU) over that produced by FT alone and reducing its dose-limiting gastrointestinal toxicity. As a part of the S-1 toxicity study, the single-dose toxicity of S-1 as well as that of its components, CDHP and Oxo, was investigated in mice, rats, and dogs. The following results were obtained. 1. In mice and rats, excretion of diarrheal stools, salivation, and alopecia were observed after S-1 administration. In severe cases, the animals subsequently showed emaciation due to weight loss or suppressed weight gain, decreased spontaneous motor activity, an anemic appearance, bradypnea, prone position, and death. In the CDHP and Oxo treatment groups of rats, the only toxic signs were soft or diarrheal stools on the dosing day. 2. In dogs, vomiting and excretion of diarrheal, mucous, or soft stools was observed after S-1 administration. In the CDHP and Oxo treatment groups, excretion of soft and diarrheal stools and vomiting were observed relatively frequently from the dosing day until day 1. 3. In the pathological examination of the animals given S-1, mice and rats showed pulmonary congestion/edema, dark red discoloration of the mesenteric lymph nodes, atrophy of lymphatic tissues such as the thymus and lymph nodes, decreases of lymphocytes in the splenic white pulp and mesenteric lymph nodes, a decrease in bone marrow cells, congestion of the glandular stomach, and aggregates of bacteria in the lung, liver, or spleen. In dogs, abnormal changes were observed mainly in the lymphatic organs such as the thymus and lymph nodes. 4. The LD50 values of S-1 in terms of the amount FT they contained were estimated to be 549 mg/kg for mice(male), 441-551 mg/kg for rats (both sexes) and about 53 mg/kg for dogs (male). The LD50 values of CDHP and Oxo were 2000 mg/kg or higher for both rats (both sexes) and dogs (male). 5. Hematopoietic and lymphatic impairments, immunosuppression associated with respiratory were considered to be the cause of death from S-1. The toxicity of S-1 reflects the toxicity of 5-FU and was not found the different toxicity by the addition of CDHP and Oxo.
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PMID:[Oral single-dose toxicity study of a new antineoplastic agent S-1, and its components, CDHP, and Oxo]. 902 58

S-1, an antineoplastic formulation of a fluorinated pyrimidine derivative containing tegafur (FT), CDHP, and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1, was recently developed by Taiho Pharmaceutical Co., Ltd., with the aim of prolonging the effective plasma concentration of 5-fluorouracil (5-FU) over that produced by FT alone and reducing its dose-limiting gastrointestinal toxicity. As a part of the S-1 toxicity study, a 13-week oral repeated dose toxicity study and a recovery study using male and female rats was conducted. Doses of S-1 were adjusted to deliver 1.5, 5, and 15 mg/kg/day as doses of FT, and FT was given at 15 mg/kg/day. The following results were obtained. 1. In clinical observation, edema of the limbs and face or swelling of the auricle of the ear and an anemic appearance were observed in both sexes in the 15 mg/kg/day group as dose of FT. Subsequently, males in this group developed severe anemia, decreased spontaneous motor activity, emaciation, and subnormal skin temperature, and many males died. In the survivors, keratosis of the palm, sole, or tail was observed, with necrosis and loss of the tail tip in the severe cases. 2. Body weight gain was suppressed from about week 2 of treatment in both sexes in the 15 mg/kg/day group as dose of FT, and there was almost no weight gain after week 4-5. Food consumption was consistently less than the control value for males in the 15 mg/kg/day group as dose of FT throughout the treatment period. 3. No marked changes were observed in water intake and on opthalmologic examination. 4. In the fecal test for occult blood, a positive tendency was observed in both sexes in the 15 mg/kg/day group as dose of FT. 5. Urinalysis disclosed a slight increase in protein and decrease in sodium, potassium, and chloride in males, and an increase in protein in females in the 15 mg/kg/day group as dose of FT. 6. Hematologically, both sexes in the 15 mg/kg/day group as dose of FT showed decreases in red blood cell count, hemoglobin, and hematocrit, and increases in platelet count and fibrinogen, with a slight decrease in white blood cell count in males. 7. In the blood biochemical test, abnormal findings included increases in total cholesterol and free cholesterol, and decreases in non-esterified fatty acid and albumin in both sexes in the 15 mg/kg/day group as dose of FT. 8. In organ weight measurement, abnormal changes included a decrease in thymus weight in both sexes in the 5 mg/kg/day or higher dosage groups and a decrease in the testis weight in males and an increase in the liver weight in females in the 15 mg/kg/day group as dose of FT. 9. Histopathologically, both sexes in the 15 mg/kg/day group as dose of FT showed a decrease in the red pulp of the bone marrow, atrophy of the thymus, white pulp of the spleen, and testes. degeneration of the renal tubules, and ulcerative changes of the skin or oral mucosa. 10. The findings were unremarkable in the FT group. 11. During the recovery study, all the toxic effects tended to reverse. 12. The NOAEL of S-1 was estimated to be 1.5 mg/kg/day as dose of FT for both sexes.
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PMID:[A 13-week oral repeated dose toxicity study of a new antineoplastic agent S-1 in rats]. 902 59