Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677481 (urinary frequency)
 1,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A subacute toxicity study of propiverine hydrochloride (P-4), a new anti-pollakiuria agent, was carried out using male and female Wistar rats. P-4 was orally administered to rats at dose levels of 2, 10, 50 and 150 mg/kg/day for 13 weeks, followed by 5 weeks recovery period. The results obtained are as follows: 1. In the general conditions, transient salivation was observed immediately after administration and blotted fur at lower abdomen was noted in rats given 50 mg/kg/day or more. There were no deaths related to P-4. 2. Body weight gain was depressed in males given 50 mg/kg/day or more and females given 150 mg/kg/day. No significant changes in food consumption were observed. Water consumption increased in the groups of 50 mg/kg/day or more. 3. Urinalysis revealed an increase of urine volume, decreases of osmotic pressure, protein and urobilinogen, and a slight increase in excretion of electrolyte in rats given 50 mg/kg/day or more. 4. Hematological examinations revealed slight changes such as an increase in erythrocyte count and a shortening of APTT in rats given 150 mg/kg/day. 5. Serum biochemical examinations showed a decrease in triglyceride and increases in gamma-GTP and AlP activities, and urea nitrogen in males given 50 mg/kg/day or more and females given 150 mg/kg/day. Additionally, decreases in total and free cholesterol, and phospholipid for males and an increase of total cholesterol and a decrease of cholinesterase activity for females were detected. 6. At autopsy, atrophy of thymus and spleen was observed in rats given 50 mg/kg/day or more, but without histopathological correlation. Histopathological examinations revealed hypertrophy and fatty degeneration of hepatocytes, which were accompanied with increases of absolute and/or relative liver weight, in males given 50 mg/kg/day or more and females given 150 mg/kg/day. Electron-microscopy showed proliferation of smooth endoplasmic reticulum in the same groups. In the kidney, eosinophilic and intranuclear inclusions in the tubular epithelium were detected, in which cytoplasm there were no toxic injuries, in males given 10 mg/kg/day or more and females given 50 mg/kg/day or more. 7. After 5 weeks recovery period, above-mentioned changes were generally disappeared, suggesting that these were reversible. 8. The non-effective dose levels and the toxic dose levels of P-4 were estimated to be 2 mg/kg/day for males and 10 mg/kg/day for females, and 50 mg/kg/day for males and 150 mg/kg/day for females, respectively.
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PMID:[Thirteen-week oral toxicity study of propiverine hydrochloride in rats]. 260 52

NS-21, (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate, is a new drug for the treatment of urinary frequency and incontinence. To evaluate acute toxicities of its related compounds including the optical isomers of NS-21 ((S)NS-21 and (R)NS-21), the active metabolite of NS-21 ((R/S)RCC-36), the optical isomers of (R/S)RCC-36 ((S)RCC-36 and (R)RCC-36), the hydrolysis products of NS-21 (RCC-32 and RCC-38) and the bi-product of NS-21 (RCC-66), single-dose intraperitoneal toxicity studies were conducted in ddY mice. The LD50 values of these compounds in male and female mice were as follows: 199 and 184 mg/kg for (S)NS-21, 261 and 240 mg/kg for (R)NS-21, 74 and 100-150 mg/kg for (R/S)RCC-36, 93 mg/kg for (S)RCC-36 in both sexes, 83 and 104 mg/kg for (R)RCC-36, higher than 510 mg/kg for RCC-32 in both sexes, 340-510 mg/kg for RCC-38 in both sexes, and 1000-2000 mg/kg for RCC-66 in both sexes, respectively. The clinical signs included decreased spontaneous locomotor activity, prone or lateral position, ataxic gait, clonic convulsion, hypopnea, hypothermia, pale skin, mydriasis, abdominal distention and unkempt fur for (S)NS-21, (R)NS-21, (R/S)RCC-36, (S)RCC-36 and (R)RCC-36, decreased spontaneous locomotor activity, prone position, ataxic gait, clonic convulsion, tail elevation and hypopnea for RCC-32 and RCC-38, and decreased spontaneous locomotor activity and unkempt fur for RCC-66. Body weight was decreased or its gain was suppressed for every compound examined. Pathological examination of the dead mice showed atrophy of the thymus and spleen, intestinal distention with the retention of dark red contents, white spots or white materials in the abdominal fatty tissue for (S)NS-21, (R)NS-21, (R/S)RCC-36, (S)RCC-36, (R)RCC-36 and RCC-66, but no treatment related change for RCC-32 and RCC-38. Adhesion between the abdominal organs was observed in survivors treated with (S)NS-21, (R)NS-21, (S)RCC-36, (R)RCC-36, RCC-32 and RCC-66.
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PMID:[Intraperitoneal single-dose toxicity studies of active metabolite, optical isomers, hydrolysis products and bi-product of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence, in mice]. 917 Jun 1

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.
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PMID:[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 novel drug for urinary frequency and incontinence, in rats followed by a 5-week recovery test]. 917 Jun 2

Oral single-dose and 13-week repeat-dose toxicity studies of (+/-)-4-ethylamino-1, 1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride (RCC-36), an active metabolite 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, were conducted in male and female Sprague-Dawley rats. In the single-dose toxicity study, rats were given the drug at doses of 0 (control), 400, 600, 900, 1350 and 2030 mg/kg. In the 13-week repeat-dose toxicity study, rats were given the drug for 13 weeks at doses of 0 (control), 3, 30 and 300 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted. In the single-dose toxicity study, death occurred in the 600 mg/kg group and over, and LD50 values were 735 mg/kg in both sexes. The major clinical signs observed following the administration of this drug were mydriasis, salivation, decreased spontaneous locomotor activity, ataxic gait, lacrimation and urorrhea in the 400 mg/kg group and over, hypopnea and soft feces in the 600 mg/kg group and over. In addition, prone or lateral position and tonic or clonic convulsion were observed in the dead animals. Rats showed a decrease in body weight or a suppression of its weight gain in the 400 mg/kg group and over. Macroscopic findings in the dead animals were congestion in lung and retention of foamy mucinous fluid in trachea. The animals alive showed no abnormalities attributable to the treatment. In the 13-week repeat-dose toxicity study, 13 cases of death occurred in the 300 mg/kg group. Main pathological findings in these cases were congestion and edema in lung. Mydriasis was seen in the 30 mg/kg group and over. Lacrimation, salivation, wheezing, emaciation [corrected] wasting and unkempt fur were seen in the 300 mg/kg. A suppression of body weight gain and a decrease in food consumption were observed in the 300 mg/kg group. An increase in water consumption was seen in the 30 and 300 mg/kg groups. Ophthalmologic examination confirmed the mydriasis in the 30 mg/kg group and over. Urinalysis showed an increase in urine volume and a decrease in Na+ excretion in the 30 and 300 mg/kg groups and decreases in K+ and Cl- excretions in the 300 mg/kg group. Hematological examination showed decreases in hemoglobin, hematocrit, MCV and MCH, and an increase in MCHC in the 300 mg/kg group. Blood chemical examination showed decreases in triglyceride and glucose, and an increase in total protein in the 300 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy associated with hyperplasia of smooth-ER, a decrease in number of glycogen granules and an increase in number of lipofuscin in the 300 mg/kg group. Stimulated thyroid follicles were seen in the 300 mg/kg/group. In kidney, an increase in number of hyaline droplets in the proximal tubular epithelium, in which lysosomes and dense bodies were increased, was observed in the 300 mg/kg group. Dense bodies were increased also in the glomerular epithelium. In this dose group, adrenocortical hypertrophy was also 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 3 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of RCC-36 is 3 mg/kg for 13-week oral toxicity in rats.
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PMID:[Oral single-dose and 13-week repeat-dose toxicity studies of RCC-36, the active metabolite of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a novel drug for urinary frequency and incontinence, in rats]. 917 Jun 4