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Biomedical subjects

N Sumi

Publications and source records attributed to N Sumi.

At least 19 recordsLinked to original sources
PubMed2001

Spontaneous neoplastic lesions in aged Sprague-Dawley rats.

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.

Adenoma↗
PubMed2000

Interpeak latency of auditory event-related potentials (P300) in senile depression and dementia of the Alzheimer type.

Most studies on event-related potentials (ERP) in psychiatric illness or dementia have focused on the single-peak latency of ERP components. In the present study, not only peak latencies of ERP components (N1, P2, N2, and P3) but also interpeak latencies (IPL; N1-P2, P2-N2, and N2-P3) were analyzed using the auditory oddball task. Thirty-five senile depressed patients and 34 patients with dementia of the Alzheimer type (DAT) were compared to 39 age-matched healthy volunteers. The mean latencies of P2 and P3 were shorter in patients with senile depression than in controls. In DAT patients, the N2 and P3 latencies were longer. When the IPL was assessed, however, only the mean IPL of N1-P2 was shorter in patients with senile depression, while the P2-N2 IPL were longer in those with DAT. The IPL results suggest that in senile depression the early cognitive process is hastened and in DAT the middle process is disturbed. Based on these results, we conclude that IPL of the auditory ERP might be used to reveal the disturbed steps within the cognitive process.

Aged↗
PubMed2000

RIKEN integrated sequence analysis (RISA) system--384-format sequencing pipeline with 384 multicapillary sequencer.

The RIKEN high-throughput 384-format sequencing pipeline (RISA system) including a 384-multicapillary sequencer (the so-called RISA sequencer) was developed for the RIKEN mouse encyclopedia project. The RISA system consists of colony picking, template preparation, sequencing reaction, and the sequencing process. A novel high-throughput 384-format capillary sequencer system (RISA sequencer system) was developed for the sequencing process. This system consists of a 384-multicapillary auto sequencer (RISA sequencer), a 384-multicapillary array assembler (CAS), and a 384-multicapillary casting device. The RISA sequencer can simultaneously analyze 384 independent sequencing products. The optical system is a scanning system chosen after careful comparison with an image detection system for the simultaneous detection of the 384-capillary array. This scanning system can be used with any fluorescent-labeled sequencing reaction (chain termination reaction), including transcriptional sequencing based on RNA polymerase, which was originally developed by us, and cycle sequencing based on thermostable DNA polymerase. For long-read sequencing, 380 out of 384 sequences (99.2%) were successfully analyzed and the average read length, with more than 99% accuracy, was 654.4 bp. A single RISA sequencer can analyze 216 kb with >99% accuracy in 2.7 h (90 kb/h). For short-read sequencing to cluster the 3' end and 5' end sequencing by reading 350 bp, 384 samples can be analyzed in 1.5 h. We have also developed a RISA inoculator, RISA filtrator and densitometer, RISA plasmid preparator which can handle throughput of 40,000 samples in 17.5 h, and a high-throughput RISA thermal cycler which has four 384-well sites. The combination of these technologies allowed us to construct the RISA system consisting of 16 RISA sequencers, which can process 50,000 DNA samples per day. One haploid genome shotgun sequence of a higher organism, such as human, mouse, rat, domestic animals, and plants, can be revealed by seven RISA systems within one month.

Animals↗
PubMed2000

[The prevalence of virulence-related genes, eaeA, aggR and astA, of localized and aggregative-adherent Escherichia coli (EPEC and EAggEC) in healthy children and age-matched patients with diarrhea].

The prevalence of virulence-related genes of localized- and aggregated-adherent Escherichia coli (EPEC and EAggEC), such as eaeA, aggR and astA was compared between E. coli isolated from 0 to 5 year old children with and without diarrhea in Saga Prefecture. In the case of eaeA, 233 cases in Aichi Prefecture were included. The subjects were 74 diarrheal patients from which no diarrheagenic bacteria were detected besides E. coli. The control subjects were 304 nursery school children without diarrhea, and E. coli was isolated from 278 children in which 105 strains were of 0-serotype. EaeA-positive E. coli was isolated from nine (12.2%) Saga cases, 19 (8.2%) Aichi cases and 6 (5.7%) control subjects; aggR-positive E. coli was isolated from 10 (13.5%) cases and 6 (5.7%) control subjects and astA-positive E. coli from 10 (13.5%) cases and 14 (13.3%) control subjects. No significant difference (p > 0.05) was observed in the prevalence of eaeA, aggR and astA between healthy and diarrheal children, even in age-matched and 0-serotypable E. coli limited comparisons. The pathogenicity of EPEC and EAggEC should be investigated, considering other known or unidentified factors.

Adhesins, Bacterial↗
PubMed1999

Activation of p38 mitogen-activated protein kinase and caspases in UVB-induced apoptosis of human keratinocyte HaCaT cells.

Exposure of human keratinocyte HaCaT cells to ultraviolet B-irradiation induced apoptotic morphologic changes. In this study, we found that the ultraviolet B irradiation (0.25 J per cm2) induced phosphorylation of p38 mitogen-activated protein kinase and c-jun N-terminal protein kinase, and also significant activation of caspase-3 (CPP32-like protease) and a small increase of caspase-1 (ICE-like protease) activity in the early stages of ultraviolet B-induced apoptosis. Pretreatments of the cells with a p38 mitogen-activated protein kinase inhibitor, SB203580, and a caspase-3 inhibitor, Ac-Asp-Met-Gln-Asp-1-aldehyde, suppressed the ultraviolet B irradiation-induced apoptosis by approximately 60% as estimated by nuclear staining and DNA laddering. Pretreatment with caspase-1 inhibitor, Ac-Tyr-Val-Lys-Asp-aldehyde was without effect. Ultraviolet B-induced caspase-3 activation resulted in cleavage of poly(ADP) ribose polymerase, which was abolished by the caspase-3 inhibitor. SB203580 pretreatment prevented activation of caspase-3 and caspase-1, and also suppressed the cleavage of poly(ADP) ribose polymerase. Neither ceramide generation nor sphingomyelinase activation (neutral and acid) was observed in the ultraviolet B-irradiated HaCaT cells. Also various antioxidants did not affect the caspase activation induced by ultraviolet B irradiation. These results indicated that activation of p38 mitogen-activated protein kinase upstream of caspases may play an important part in the apoptotic process of keratinocytes exposed to ultraviolet B irradiation.

Apoptosis↗
PubMed1998

Identification and characterization of STK12/Aik2: a human gene related to aurora of Drosophila and yeast IPL1.

Mutations in aurora of Drosophila and related Saccharomyces cerevisiae IPL1 protein kinases are known to cause abnormal chromosome segregation. We earlier isolated a cDNA encoding a novel human protein kinase Aik which shares high amino acid identity with the Aurora/Ipl1 protein kinase family. In the present study, a second human cDNA highly homologous to aurora/IPL1 (Aik2) was identified and the nucleotide sequence was determined (gene symbol STK12). The C-terminal kinase domain of the STK12 encoded protein shares high amino acid sequence identity with those of mouse STK-1 (90%), rat AIM-1 (90%), human Aik (69%), mouse IAK1/Ayk1 (69%), Xenopus pEg2 (68%), Drosophila Aurora (62%), and yeast Ipl1 (45%), whereas the N-terminal domain of the STK12 protein shares little homology with those of Aurora/Ipl1 family members except for AIM-1 and STK-1. Northern blotting analyses revealed that STK12 expression was high in thymus, while low level expression was detected in small intestine, testis, colon, spleen, and brain. The STK12 protein content in HeLa cells is low in S phase, but it accumulates during M phase. STK12 was mapped to human chromosome 17p13.1 by fluorescence in situ hybridization. The chromosome location of STK12 was further defined using a radiation hybrid panel (Stanford G3), that showed a linkage with marker WI-7901 (LOD Score 7.83) located between D17S938 and D17S786.

Animals↗
PubMed1997

Cell cycle-dependent expression and spindle pole localization of a novel human protein kinase, Aik, related to Aurora of Drosophila and yeast Ipl1.

Mutations in Aurora of Drosophila and related Saccharomyces cerevisiae Ipl1 kinase are known to cause abnormal chromosome segregation. We have isolated a cDNA encoding a novel human protein kinase of 402 amino acids with a predicted molecular mass of 45.9 kDa, which shares high amino acid identities with the Aurora/Ipl1 protein kinase family; hence the cDNA is designated as aik (aurora/IPL1-related kinase). Amino acid sequence of C-terminal kinase domain of Aik shares 86, 86, 72, 59, and 49% identity with those of Xenopus XLP46APK and XLP46BPK, mouse STK-1, Aurora of Drosophila, and yeast Ipl1, respectively, whereas N-terminal domain of Aik shares high homology only with those of XLP46APK and XLP46BPK. Northern and Western blotting analyses revealed that Aik is expressed highly in testis and various proliferating cells including HeLa cells. In HeLa cells, the endogenous levels of aik mRNA and protein contents are tightly regulated during cell cycle progression. Both of these levels are low in G1/S, accumulate during G2/M, and reduce rapidly after mitosis. Its protein kinase activity is also enhanced at mitosis as inferred by exogenous casein phosphorylation. Immunofluorescence studies using a specific antibody have shown that Aik is localized to the spindle pole during mitosis, especially from prophase through anaphase. These results strongly suggest that Aik is a novel member of a protein kinase family possibly involved in a centrosome function(s) such as chromosome segregation or spindle formation.

Amino Acid Sequence↗
PubMed1997

Enhancement of the clastogenicity of N-nitrosodialkylamines plus near-ultraviolet irradiation by ethanol in Chinese hamster lung fibroblasts.

Early work from our laboratory showed a synergistic action of N-nitrosodialkylamines and near-ultraviolet light (UVA, 320-400 nm) to cause mutations in bacteria and phages. Recently we reported that N-nitrosodialkylamines + UVA induces chromosome aberrations in Chinese hamster lung cells in culture. We have now found that ethanol can potentiate this clastogenic action of N-nitrosodialkylamines + UVA. When the cells were treated with N-nitrosopyrrolidine (NPYR) or N-nitrosodiethylamine (NDEA) + UVA for 2 hours in the presence of 1% ethanol, approximately 2-fold increase in the numbers of cells with aberrant chromosomes was observed, compared to those found without the ethanol. NPYR/NDEA only ethanol only, or ethanol + UVA did not cause the aberrations. The enhancement was dependent on the concentration of ethanol. Treatment of cells with ethanol before the NPYR + UVA was ineffective. By contrast, treatment of cells with NPYR-UVA and then with ethanol was as effective as with the simultaneous treatment. Methanol showed synergistic effects similar to those of ethanol, but mannitol did not. Intracellular hydrogen peroxide was found to be increased twofold over that in the background by a treatment with ethanol + UVA. The alcohol-mediated enhancement of the clastogenic action of N-nitrosodialkylamines + UVA may be a consequence of an increase in intracellular oxidative stress, or simply due to increased membrane permeability.

Animals↗
PubMed1997

cDNA cloning, characterization, and chromosome mapping of UBE2E2 encoding a human ubiquitin-conjugating E2 enzyme.

A cDNA encoding a human ubiquitin-conjugating enzyme (E2) with N-terminal extension (UBE2E2/UbcH8) was isolated. Amino acid sequence within the UBC domain of UBE2E2 shares over 90% identity with human UbcH6, mouse UbcM2, and Drosophila UbcD2, whereas the N-terminal region shows little amino acid sequence similarity with known proteins. The UBE2E2 gene is transcribed in various tissues as a 1.9-kb transcript. The UBE2E2 protein formed a thioester bond with ubiquitin in an E1-dependent manner, indicating that the gene product is a functional E2 enzyme. The UBE2E2 gene was assigned to human chromosome 3p24.2 by fluorescence in situ hybridization.

Amino Acid Sequence↗
PubMed1997

[Single-dose toxicity studies 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, rats and dogs].

Comparative single-dose toxicity studies 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 ddY mice and Sprague-Dawley rats after oral(p.o.),intraperitoneal(i.p.) and subcutaneous(s.c.) administration, and in Beagle dogs after p.o. administration. The p.o. LD50 values of NS-21 were 852 and 1167 mg/kg for male and female mice, 2839 and 1739 mg/kg for male and female rats, respectively. The i.p. LD50 values were 324 and 390 mg/kg for male and female mice, and 423 and 359 mg/kg for male and female rats, respectively. No death occurred in mice and rats at doses up to s.c. 5000 mg/kg. Minimum lethal dose for dogs could not be determined because of vomiting. Mydriasis was noted in all three species tested without regard to administration route. In addition, decreased spontaneous locomotor activity, prone or lateral position, hypopnea, hypothemia, ataxic gait, twitch and clonic convulsion were observed in mice and rats after p.o. and i.p. administration. In rats, salivation was observed after p.o. administration and lacrimation was observed after p.o. and i.p. administration. After s.c. administration, scab formation at the site of injection was observed in mice and rats. In dogs, vomiting, hyperemia of both conjunctiva and oral mucosa, prone position, tremor and clonic convulsion were observed after p.o. administration. Body weight was decreased or its gain was suppressed in mice and rats without regard to administration route. Body weight and food consumption were decreased in dogs after p.o. administration. Pathological examination showed congestion of lung in dead mice and rats after p.o. and i.p. administration. Distention of small intestine was observed in dead mice and rats after p.o. administration and in sacrificed rats after p.o. administration. Adhesion between the abdominal organs was observed in sacrificed mice and rats after i.p. administration. Thymic atrophy associated with a decrease in its organ weight was observed in dogs after p.o. administration.

Animals↗
PubMed1997

[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 dogs followed by a 5-week recovery test].

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 beagle dogs. Male and female dogs were given the drug orally for 13 weeks at doses of 0 (control), 5, 25 and 125 mg/kg. After discontinuation of the treatment, a 5-week recovery test was also conducted. No effects related to the treatment were observed on survival. Mydriasis and a decrease in body weight or a suppression of its weight gain were seen in the 25 and 125 mg/kg groups. Vomiting, salivation and a decrease in food consumption were seen in the 125 mg/kg group. Ophthalmologic examination confirmed the mydriasis in the 125 mg/kg group. Electrocardiographic examination and urinalysis showed no abnormalities attributable to the treatment. Hematological examination showed an increase in number of platelets in the 125 mg/kg group. Blood chemical examination revealed increases in GPT and ALP and a decrease in albumin in the 25 and 125 mg/kg groups, and an increase in triglyceride in the 125 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy in the 125 mg/kg group, hyperplasia of smooth-ER and concentric lamellar bodies derived from the smooth-ER, and bile pigments in the bile capillary, hepatocyte and stellate cells of Kupffer in the 25 and 125 mg/kg groups. Megakaryocytes in mesenteric lymph node were observed in the 25 and 125 mg/kg groups. 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 5 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of NS-21 is 5 mg/kg for 13-week oral toxicity in dogs.

Administration, Oral↗
PubMed1997

[A 12-month 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 dogs followed by a 2-month recovery test].

A 12-month 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 beagle dogs. Male and female dogs were given the drug orally for 12 months at doses of 0 (control), 3, 17.5 and 100 mg/kg. After discontinuation of the treatment, a 2-month recovery test was also conducted. No effects related to the treatment were observed on survival and water consumption. Mydriasis, vomiting and a decrease in body weight or a suppression of its weight gain were seen in the 17.5 and 100 mg/kg groups. Salivation and a decrease in food consumption were seen in the 100 mg/kg group. Ophthalmologic examination confirmed the mydriasis in the 17.5 and 100 mg/kg groups. Electrocardiographic and hematological examinations and urinalysis showed no abnormalities attributable to the treatment. Blood chemical examination revealed increases in GPT and ALP in the 17.5 and 100 mg/kg groups, increases in GOT and triglyceride and a decrease in total protein in the 100 mg/kg group. Pathological examination disclosed hepatocellular hypertrophy and concentric lamellar bodies derived from the smooth-ER in the 100 mg/kg group, and hyperplasia of smooth-ER, an increase in number of lysosomes and bile pigments in the bile capillary, hepatocyte and stellate cells of Kupffer in the 17.5 and 100 mg/kg groups. The recovery test showed that the above-mentioned changes were satisfactorily reversible or the degree and frequency of these changes were lowered. The serum concentrations of NS-21 and its active metabolite. RCC-36, in the treated groups were increased in a dose-dependent manner. No treatment-related effects were seen in the 3 mg/kg group. These results show that the NOAEL (no observed adverse effect level) of NS-21 is 3 mg/kg for 12-month oral toxicity in dogs.

Administration, Oral↗
PubMed1997

[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].

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.

Animals↗
PubMed1997

[Toxicokinetics 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 and rats during 13-week dietary administration].

Toxicokinetics 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 studied in mice and rats during a 13-week dietary administration to determine the toxicokinetic profiles of NS-21 and its active metabolite (+/-)-4-ethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride (RCC-36) in dietary carcinogenicity studies. Male and female mice were given the drug in the diet at doses of 0(control), 30, 100 and 300 mg/kg/day, and male and female rats were given the drug at doses of 0(control), 10, 30 and 100 mg/kg/day. The chosen doses and means of administration were identical to those of a 78-week dietary carcinogenicity study in mice and 2-year dietary carcinogenicity study in rats. The plasma concentrations were measured on the first and the last day of the administration. For every treatment period, the plasma concentrations of NS-21 and RCC-36 increased with dose in mice and rats. The sum of the area under the concentration-time curve(AUC) of NS-21 and RCC-36 was 2694 to 8614 ng.hr/ml in the maximum dose of mice, and 2232 to 3593 ng.hr/ml in the maximum dose of rats through the administration period. These results show that, when compared with therapeutic dose in humans(682 ng.hr/ml at 10 mg/body/day), the total maximal exposure to NS-21 and RCC-36 in the earlier dietary carcinogenicity studies were estimated to be 4 to 13 times higher in mice, and 3 to 5 times higher in rats.

Administration, Oral↗
PubMed1997

[The mechanism of increased thyroidal function caused by (+/-)-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, administration in rats].

A study was conducted to elucidate the mechanism of the increased thyroidal function caused by oral administration 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, in rats. Rats were given 500 mg/kg of NS-21 orally for 13 weeks. Rats were also given 500 mg/kg of the drug and 15 micrograms/animal of thyroxine (T4) in order to assess the influence of T4 treatment. NS-21 caused decreases in both total and free T4 and increases in TSH and thyroxine uridine diphosphate glucuronyltransferase (T4UDP-GT). Morphological examination of thyroid gland revealed stimulated follicles indicating heightened thyroidal function. The treatment of T4 inhibited the stimulating effect of NS-21 on thyroid gland. These results show that the administration of NS-21 caused induction of T4UDP-GT, which resulted in a compensatory stimulation of the thyroidal function by the increased secretion of pituitary TSH in response to increased blood thyroid hormone metabolism.

Animals↗
PubMed1997

[Reproductive and developmental toxicity studies 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 (1). Fertility study in rats by oral administration].

Fertility and developmental 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 Crl:CD rats. Male rats were given NS-21 orally from 60 days before mating to the day of necropsy, and female rats were given NS-21 orally from 14 days before mating to day 7 of pregnancy. The dose levels for both males and females were 0 (control), 2, 30 and 500 mg/kg. On day 20 of pregnancy, the females were sacrificed and their fetuses examined. At the 500 mg/kg dosage level, one male and one female died. Salivation and dilated pupils occurred at the 30 and 500 mg/kg dosage levels, and rales occurred at 500 mg/kg. Body weights and food consumption were decreased, and water consumption was increased in both males and females at the 500 mg/kg dosage level. Decreases in the numbers of corpora lutea and implantations per litter and a lower number of live fetuses per litter were found at the 500 mg/kg dosage level. However, the incidence and number of postimplantation loss per litter were comparable among the treatment and control groups. These results demonstrate that the NOAEL (no observed adverse effect level) of NS-21 is 2 mg/kg for general toxicity in parental animals, and 30 mg/kg for reproductive function of the parent animals and for embryo-fetal development.

Administration, Oral↗
PubMed1997

[Reproductive and developmental toxicity studies 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 (2). Teratogenicity study in rats by oral administration].

A study of teratogenicity and developmental toxicity 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 Crl:CD rats. Female rats were given NS-21 orally at dose levels of 0 (control), 2, 25 and 300 mg/kg from day 7 to day 17 of pregnancy. Twenty-two female rats per dose level were sacrificed on day 20 of pregnancy for examination of their fetuses, and the remaining pregnant rats (twenty-three per dose level) were allowed to deliver naturally for postnatal examination of their offspring. At the 300 mg/kg dosage level, rales, partially closed eyes and reduced activity were observed in pregnant rats. Decreases in body weight gain, food consumption and water consumption were observed in the dams at the 300 mg/kg dosage level. Fetal body weights were decreased at the 300 mg/kg dosage level. The drug never altered the numbers of corpora lutea and implantations, fetal mortality, the number of live fetuses, sex ratio, placental weight, and external, visceral and skeletal development of fetuses. NS-21 did not affect the delivery of dams, the number of live newborns, birth index, body weight or survival index. Nor did NS-21 have any adverse effect on the postnatal development of the offspring, including physical and functional development, emotionality, motor activity, learning ability and reproductive performance. These results demonstrate that the NOAEL (no observed adverse effect level) of NS-21 is 25 mg/kg for general toxicity in mother animals. 300 mg/kg for reproductive function in mother animal and 25 mg/kg for developmental toxicity.

Administration, Oral↗