RESUMEN
Neoplastic lesions were observed in untreated aged Sprague Dawley (SD) rats throughout their lifespan starting at 5 weeks. Their mean survival times were 89 to 105 weeks of age. The total tumor incidences were 70 to 76.7% and 87 to 95.8% in males and females, respectively. The common neoplasmas were pituitary adenoma and adrenal pheochromocytoma in both sexes, testicular Leydig cell tumor in males and mammary gland tumors, thyroidal C-cell adenoma and uterine stromal polyp in females.
Asunto(s)
Envejecimiento , Neoplasias/veterinaria , Enfermedades de los Roedores/epidemiología , Adenoma/epidemiología , Adenoma/veterinaria , Neoplasias de las Glándulas Suprarrenales/epidemiología , Neoplasias de las Glándulas Suprarrenales/veterinaria , Animales , Femenino , Tumor de Células de Leydig/epidemiología , Tumor de Células de Leydig/veterinaria , Masculino , Neoplasias Mamarias Animales/epidemiología , Neoplasias/epidemiología , Feocromocitoma/epidemiología , Feocromocitoma/veterinaria , Neoplasias Hipofisarias/epidemiología , Neoplasias Hipofisarias/veterinaria , Pólipos/epidemiología , Pólipos/veterinaria , Ratas , Ratas Sprague-Dawley , Neoplasias Testiculares/epidemiología , Neoplasias Testiculares/veterinaria , Neoplasias de la Tiroides/epidemiología , Neoplasias de la Tiroides/veterinaria , Neoplasias Uterinas/epidemiología , Neoplasias Uterinas/veterinariaRESUMEN
A 13-week oral repeated dose toxicity study of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a new drug for the treatment of urinary frequency and incontinence, was conducted in Sprague-Dawley rats. Male and female rats were given the drug orally for 13 weeks at doses of 0 (control), 6, 30, 150 and 750 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted at doses of 0, 30, 150 and 750 mg/kg. Nine cases of death occurred in the 750 mg/kg group. Main pathological findings in these cases were congestion and edema in lung. Mydriasis, salivation, lacrimation and a decrease in body weight or a suppression of its weight gain were seen in the 30 mg/kg group and over. Piloerection and an increase in water consumption were seen in the 150 and 750 mg/kg groups. In addition, a decrease in spontaneous locomotor activity, abdominal distention, unkempt fur, soft stool, diarrhea and decreases in feces and food consumption were seen in the 750 mg/kg group. Ophthalmologic examination confirmed mydriasis and lacrimation in the 30 mg/kg group and over. Urinalysis showed decreases in Na+ and K+ excretions in the 30 mg/kg group and over, an increase in urinary protein in the 150 and 750 mg/kg groups, and a decrease in urine volume in the 750 mg/kg group. Hematological examination showed decreases in hemoglobin and hematocrit in the 150 and 750 mg/kg groups, and a decrease in lymphocytes in the 750 mg/kg group. Blood chemical examination showed an increase in total protein in the 30 mg/kg group and over, a decrease in triglyceride in the 150 and 750 mg/kg groups, and an increase in BUN in the 750 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy caused by hyperplasia of smooth-ER in the 30 mg/kg group and over, and a decrease in number of glycogen granules in the 150 and 750 mg/kg groups. Stimulated thyroid follicles were seen in the 30 mg/kg group and over. Increases in incidence and severity of chronic progressive nephropathy were observed in the 150 and 750 mg/kg groups. Ultrastructual features of the renal lesions were swelling and foot process loss of the glomerular epithelial cells, absorption droplets in the glomerular epithelial cells, increase of lysosomes in the proximal tubular cells and hyaline casts in the tubular lumen. Adrenocortical hypertrophy was seen in the 150 and 750 mg/kg groups. In the 750 mg/kg group, a decrease of hematopoietic tissue in bone marrow and thymic and testicular tubular atrophy were observed. The recovery test showed that the above-mentioned changes were satisfactorily reversible or the degree and frequency of these changes were lowered. No treatment-related effects were seen in the 6 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of NS-21 is 6 mg/kg for 13-week oral toxicity in rats.
Asunto(s)
Fenilacetatos/toxicidad , Trastornos Urinarios/tratamiento farmacológico , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Masculino , Estructura Molecular , Fenilacetatos/química , Fenilacetatos/uso terapéutico , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Incontinencia Urinaria/tratamiento farmacológicoRESUMEN
A repeated dose toxicity study of prulifloxacin, a new antibacterial agent, was conducted in beagle dogs. Male and female dogs were given the test material orally for 13 weeks at doses of 0 (control), 20, 100 and 500 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted. Vomiting, salivation and decreased body weight gain or reduced body weight were seen in the 100 and 500 mg/kg groups. In the 500 mg/kg group, tremor, paresis of posterior limb associated with prone or sitting position and decreased food consumption were also observed. There were no treatment-related effects on survival and water consumption. Ophthalmoscopic, electrocardiographic and hematologic examinations, and urinalysis failed to show any abnormalities attributable to the treatment. Blood chemical examination showed increased GPT and decreased beta- and gamma-globulins in the 100 and 500 mg/kg groups, and increased GOT in the 500 mg/kg group. In pathological examination, cavitations and erosions were seen in the humeral and femoral articular cartilages in the 100 and 500 mg/kg groups. The above-mentioned changes were satisfactorily reversible except for erosions in the humeral and femoral articular cartilages in the 100 and 500 mg/kg groups. No toxicological findings were seen in the 20 mg/kg group. The results show that the NOAEL of prulifloxacin is 20 mg/kg for 13-week repeated dose toxicity in dogs.
Asunto(s)
Antiinfecciosos/toxicidad , Dioxolanos/toxicidad , Fluoroquinolonas , Piperazinas/toxicidad , Quinolonas/toxicidad , Administración Oral , Alanina Transaminasa/sangre , Animales , Antiinfecciosos/administración & dosificación , Aspartato Aminotransferasas/sangre , beta-Globulinas/metabolismo , Peso Corporal/efectos de los fármacos , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Dioxolanos/administración & dosificación , Perros , Discinesia Inducida por Medicamentos/etiología , Femenino , Masculino , Piperazinas/administración & dosificación , Quinolonas/administración & dosificación , gammaglobulinas/metabolismoRESUMEN
A repeated dose toxicity study of prulifloxacin, a new antibacterial agent, was conducted in Sprague-Dawley rats. Male and female rats were given the test material orally for 13 weeks at doses of 0 (control), 30, 170 and 1000 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted. Salivation, soft feces, reduced body weight gain and increased water consumption were seen in the 1000 mg/kg group. There were no treatment-related effects on survival and food consumption. Ophthalmoscopic and hematologic examinations failed to show any abnormalities attributable to the treatment. Urinalysis revealed increased urine volume and decreased K+ excretion in the 1000 mg/kg group. Blood chemical examination showed increased BUN, decreased triglyceride, K+, Cl- and total protein in the 1000 mg/kg group. Pathological changes caused by the treatment were as follows. Renal tubular nephrosis with crystalline substance was observed in the 170 and 1000 mg/kg groups. Renal weight was increased and crystalline substance was noted in the lumen of the urinary bladder in the 1000 mg/kg group. Cecal distention with increased its organ weight was observed in all dose groups and swelling of its absorptive cells was seen in the 170 and 1000 mg/kg groups. Swelling of jejunal goblet cells was observed in the 1000 mg/kg group. In femoral articular cartilage, focal accumulation of chondrocytes, small cavities and proliferation of fibrous tissue were seen in the 170 and 1000 mg/kg groups. The above-mentioned changes were reversible except for renal tubular nephrosis and cecal distention with its increased organ weight, of which the degree and frequency, however, were lowered. The cecal distention in the 30 mg/kg group was considered to be attributable to the pharmacological effect of the test material. The results show that the NOAEL of prulifloxacin is 30 mg/kg for 13-week repeated dose toxicity in rats.
Asunto(s)
Antiinfecciosos/toxicidad , Dioxolanos/toxicidad , Fluoroquinolonas , Piperazinas/toxicidad , Quinolonas/toxicidad , Administración Oral , Animales , Antiinfecciosos/administración & dosificación , Proteínas Sanguíneas/metabolismo , Nitrógeno de la Urea Sanguínea , Cartílago Articular/efectos de los fármacos , Cartílago Articular/patología , Ciego/efectos de los fármacos , Ciego/patología , Cloruros/sangre , Dioxolanos/administración & dosificación , Femenino , Necrosis Tubular Aguda/inducido químicamente , Necrosis Tubular Aguda/patología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Piperazinas/administración & dosificación , Potasio/sangre , Quinolonas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Triglicéridos/sangreRESUMEN
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
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 & dosificaciónAsunto(s)
Astrocitoma/veterinaria , Parálisis/veterinaria , Ratas Sprague-Dawley , Enfermedades de los Roedores , Neoplasias de la Médula Espinal/veterinaria , Animales , Astrocitoma/complicaciones , Miembro Anterior , Masculino , Parálisis/etiología , Ratas , Neoplasias de la Médula Espinal/complicacionesRESUMEN
An intracranial epidermoid cyst was identified within the fourth ventricle of a male 10-month-old beagle dog. The cyst, which exhibited a multilocular structure, was lined by a stratified squamous epithelium and filled with desquamated keratin. In the region of the roof of the fourth ventricle, choroid plexus adherent to the cyst wall and secondary compression of the cerebellum were also seen.