RESUMEN
Montirelin hydrate (NS-3), a new drug for the treatment of disturbance of consciousness, was examined for mutagenicity in the reverse mutation test, the chromosome aberration test in vitro, and the micronucleus test in mice. The reverse mutation test was performed at dose range of 156.25-5,000 micrograms/plate using Salmonella typhimurium strains, TA1535, TA100, TA1537, and TA98, and Escherichia coli WP2uvrA. The drug did not increase revertant colonies significantly in any of the test strains with or without metabolic activation system (S-9mix). The chromosome aberration test was carried out at dose range of 300-4,800 micrograms/ml using cultured Chinese hamster lung cells (CHL/IU). No significant increases of the frequencies of cells with chromosomal aberrations were observed with or without metabolic activations. The micronucleus test was conducted in the bone marrow cells of Slc:ddY male mice. Mice were given the drug by a single intraperitoneal administration at doses of 0, 250, 500, 1,000, and 2,000 mg/kg. There were no significant increases in the frequencies of micronucleated polychromatic erythrocytes at any dose levels. These results show that montirelin hydrate has no mutagenic activity in vitro or in vivo.
Asunto(s)
Pruebas de Mutagenicidad , Hormona Liberadora de Tirotropina/análogos & derivados , Animales , Células Cultivadas , Aberraciones Cromosómicas , Cricetinae , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Pruebas de Micronúcleos , Ratas , Hormona Liberadora de Tirotropina/toxicidadRESUMEN
We used 13-week repeated oral administration of lactitol as part of a study to clarify the mechanism by which lactitol induces the proliferation of adrenomedullary chromaffin cells. There was a marked increase in urinary calcium (Ca) excretion even though the lactitol administration had no effect on the blood Ca level. A tendency for an increase in adrenal venous blood epinephrine (EPI) and norepinephrine (NE) concentrations was seen. Organ weight measurement of adrenal glands revealed a tendency for an increase in absolute weight and a significant increase in relative weight. Morphometric analysis of adrenomedullary chromaffin cells showed a tendency for an increased total cell volume and a decreased numerical density; but, there was no conspicuous change in the total cell number. Determinations of the anti-bromodeoxyuridine (BrdU) and antiproliferative cell nuclear antigen (PCNA) antibody-positive cell counts showed a tendency for an increased proliferation rate for adrenomedullary chromaffin cells. Electron microscopy showed a slight increase in the number of Golgi apparatuses in these cells. Because the marked increase in urinary Ca excretion was concomitant with morphological changes that suggested the hyperfunction of chromaffin cells in the adrenal medulla and a tendency for an increased cell proliferation rate, we assume that persistent hyperfunction of the adrenomedullary chromaffin cells, which was mediated by enhanced Ca absorption from the intestinal tract, may have induced proliferative lesion.
Asunto(s)
Médula Suprarrenal/efectos de los fármacos , Catárticos/toxicidad , Alcoholes del Azúcar/toxicidad , Médula Suprarrenal/patología , Médula Suprarrenal/ultraestructura , Animales , Calcio/metabolismo , División Celular/efectos de los fármacos , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
The single dose toxicity studies of lactitol, a hepatic encephalopathy drug, were performed in ddY mice and SD rats of both sexes by administering the drug orally, intravenously or subcutaneously. The drug was administered as a single dose followed by a 14-day observation. Oral LD50 values of lactitol were estimated to be between 23 and 30 g/kg in male mice, approximately 30 g/kg in female mice, and more than 30 g/kg in male and female rats. Lethal dose was more than 10 g/kg intravenously and subcutaneously in mice and rats of both sexes. The signs of toxicity in mice and rats observed following the administration of this drug included the following: decreased spontaneous movement [p.o., i.v., s.c.]; diarrhea, oligopnea or prone position, transient decreased body weight [p.o]. There were no treatment-related changes in gross examination. Based on these results, it was found that lactitol had a very low acute toxicity when administered by a single dose method in mice and rats.
Asunto(s)
Alcoholes del Azúcar/toxicidad , Administración Oral , Animales , Diarrea/inducido químicamente , Femenino , Inyecciones Intravenosas , Inyecciones Subcutáneas , Dosificación Letal Mediana , Masculino , Ratones , Ratones Endogámicos , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Alcoholes del Azúcar/administración & dosificación , Pérdida de Peso/efectos de los fármacosRESUMEN
Male beagle dogs were orally given lactitol, a hepatic encephalopathy drug, in a single dose of 7.5, 15.0 or 30.0 g/kg. Vomiting was seen within 30 minutes after dosing in all treated groups. Diarrhea was observed 3 or 5 hours after dosing in the 15.0 and 30.0 g/kg dose groups. There were no drug related effects on survival, food and water consumption, body weight gain or tissues and organs.
Asunto(s)
Alcoholes del Azúcar/toxicidad , Administración Oral , Animales , Diarrea/inducido químicamente , Perros , Masculino , Alcoholes del Azúcar/administración & dosificación , Vómitos/inducido químicamenteRESUMEN
Twenty male and 20 female Slc : SD rats were orally given lactitol, a hepatic encephalopathy drug, for 13 weeks at doses of 0, 0.625, 2.5 or 10 g/kg/day. A 5 week recovery test was conducted after the discontinuation of the drug treatment. Soft stool and decreased food consumption were seen in the 2.5 and 10 g/kg groups. In the 10 g/kg group, there were diarrhea, soiled fur, abdominal distention, salivation, piloerection, decreased body weight gain and increased water consumption. Urinalysis showed decreased urine volume and K+ excretion in the 10 g/kg group. In this dose group, biochemical examination showed decreased ALP, total cholesterol, triglyceride, glucose, Ca, Na+, Cl- and total protein. In the pathological examination, the cecum weight was increased in all dose groups. In the 2.5 and 10 g/kg groups, cecum distention with mucosal hyperplasia was observed. The adrenal weight was increased in the 10 g/kg group and hypertrophy of zona fasciculata of adrenal gland were seen in the 2.5 and 10 g/kg groups. The thymic weight was decreased in the 10 g/kg group. Ophthalmoscopic and hematologic examinations failed to reveal any drug induced changes. The increased cecum weight in the 0.625 g/kg group was regarded as toxicologically insignificant because of the failure of the association with any clinical or morphological findings. The above mentioned changes were satisfactorily reversible except for those in the cecum. Based on the results obtained, the NOAEL of this study was suggested to be 0.625 g/kg/day.
Asunto(s)
Alcoholes del Azúcar/toxicidad , Administración Oral , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/patología , Animales , Peso Corporal/efectos de los fármacos , Ciego/efectos de los fármacos , Ciego/patología , Diarrea/inducido químicamente , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Hipertrofia , Masculino , Tamaño de los Órganos/efectos de los fármacos , Potasio/orina , Ratas , Ratas Sprague-Dawley , Alcoholes del Azúcar/administración & dosificaciónRESUMEN
UNLABELLED: 13-week repeated dose toxicity studies were conducted on lactitol, a hepatic encephalopathy drug. In the experiment I, male and female dogs were orally treated with lactitol at doses of 0, 1.0, 2.5 and 6.25 g/kg/day for 13 weeks, followed by 4 weeks recovery period. In the experiment II, male and female dogs were orally treated with lactitol at doses of 0, 0.25, 0.50 and 1.0 g/kg/day for 13 weeks in order to require the no-toxic dose. RESULTS: 1. Soft stool and diarrhea were observed at the 0.50 g/kg group and above, and vomiting was observed at the 1.0 g/kg group and above. Increased water consumption was observed at the 6.25 g/kg group. No deaths occurred at all groups. 2. In urinalysis, increased urine volume was observed at the 6.25 g/kg group. 3. Blood chemistry showed decreased BUN at the 6.25 g/kg group. 4. There were no drug-related changes in body weight, food consumption, ophthalmological examination, electrocardiography, hematology and pathology. 5. At the end of the recovery period, all these changes observed at the end of the administration period were disappeared. Based on these results, it was considered that the no-toxic dose of lactitol is 0.25 g/kg/day.
Asunto(s)
Alcoholes del Azúcar/toxicidad , Administración Oral , Animales , Análisis Químico de la Sangre , Nitrógeno de la Urea Sanguínea , Diarrea/inducido químicamente , Perros , Ingestión de Líquidos/efectos de los fármacos , Femenino , Masculino , Alcoholes del Azúcar/administración & dosificación , Vómitos/inducido químicamenteRESUMEN
Twenty five male and 25 female Slc:SD rats were given orally lactitol, a hepatic encephalopathy drug, for 52 weeks at doses of 0, 0.4, 2 or 10 g/kg/day. A 9 week recovery test was conducted after the discontinuation of the drug treatment. Treatment related death, soft stool, diarrhea, decreased body weight gain and food intake and increased water consumption were observed in the 10 g/kg group. Urinalysis showed increased Ca excretion in the 2 and 10 g/kg groups. In the 10 g/kg group, there were increased Ca++ excretion and urine specific gravity and decreased K+ and Na+ excretion and urine volume. Hematologic examination showed decreased platelet count in the 10 g/kg group. Biochemical examination revealed higher A/G ratio in the 2 and 10 g/kg groups. In the 10 g/kg group, there were lowered level of total cholesterol, triglyceride, phospholipid, Na+, Cl- and total protein. Distention of the cecum with increased organ weight was seen pathologically in the 2 and 10 g/kg groups. In the 10 g/kg group, cecal mucosa was hyperplasic. The adrenal gland was hypertrophic in the zona glomerulosa in the 2 and 10 g/kg groups. In the 10 g/kg group, the adrenal weight was increased. Dilatation of renal tubules was also found in the 10 g/kg group. The above mentioned changes were satisfactorily reversible except for the increased cecum weight in the 10 g/kg group. Based on the results obtained, the NOAEL of this study was suggested to be 0.4 g/kg/day.
Asunto(s)
Alcoholes del Azúcar/toxicidad , Administración Oral , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/patología , Animales , Diarrea/inducido químicamente , Dilatación Patológica , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Femenino , Hiperplasia , Hipertrofia , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , Masculino , Recuento de Plaquetas/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Alcoholes del Azúcar/administración & dosificación , Aumento de Peso/efectos de los fármacosRESUMEN
Five male and 5 female beagle dogs were orally given lactitol, a hepatic encephalopathy drug, for 52 weeks at doses of 0, 0.25, 1.25 or 6.25 g/kg/day. A 9 week recovery test was conducted after the discontinuation of the drug treatment. Soft stool, diarrhea, and vomiting were seen in the 1.25 and 6.25 g/kg groups. In the 6.25 g/kg group, bloody stool and increased water consumption were also observed. Urinalysis showed larger amount of the urine volume in the 6.25 g/kg group. The cecum weight of this group was increased without any morphological changes. There were no drug related effects on survival, body weight gain and food consumption. Electrocardiographic, ophthalmoscopic, hematologic and biochemical examinations failed to show any abnormalities related to the drug treatment. The above mentioned changes were satisfactorily reversible. Based on the results obtained, the NOAEL of this study was suggested to be 0.25 g/kg/day.