Biomedical subjects

T Nishimura

Publications and source records attributed to T Nishimura.

At least 217 records · Page 12Linked to original sources

PubMed1998

A novel method for determination of alpha1,6fucosyltransferase activity using a reducing oligosaccharide from egg yolk as a specific acceptor.

A new method for determination of alpha1,6fucosyltransferase activity has been described. Recently, the disialyl-biantennary undecasaccharide was prepared in high yield from egg yolk [(1996), Carbohydr Lett 2: 137-42]. By treatment of this oligosaccharide with neuraminidase and beta-galactosidase, we readily obtained an asialo-agalacto-biantennary heptasaccharide (GlcNAcbeta 1,2Manalpha1,6[GlcNAcbeta1,2Manalpha1,3]Manbeta1 ,4GlcNAcbeta1,4GlcNAc). Using this asialo-agalacto-oligosaccharide as an acceptor, fucosyltransferases from human plasma and extracts of various human hepatoma cell lines were assayed in the presence of GDP-[3H]fucose. The reaction mixture was applied to a column of GlcNAc-binding, Psathyrella velutina lectin coupled gel. All the fucosylated acceptor were bound to the column which was eluted with 50 mM GlcNAc. Structural analyses revealed that only the innermost GlcNAc residue of the acceptor was fucosylated through an alpha1,6-linkage, and the oligosaccharide prepared could be used as a specific acceptor for alpha1,6fucosyltransferase. The present method was used to screen plasma alpha1,6fucosyltransferase in several patient groups, and significantly elevated activities were found in samples from patients with liver diseases, including chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma.

Acetylglucosamine↗

PubMed1998

Intrathoracic and intraabdominal wall implantation of a centrifugal blood pump for circulatory assist.

An implantable centrifugal pump (ICP) 320 ml in volume and 830 g in weight has been developed for prolonged circulatory assist. The antithrombogenicity of the ICP is provided by a balancing hole in the center of the impeller. The watertightness and histocompatibility of the ICP are supported by its silicone ring seal and its casing of titanium and acrylic resin, respectively. The total efficiency of the ICP was 30% at a 5 L/min flow rate and a 100 mm Hg head. The heat generation, watertightness, and anatomical fitting of the ICP were assessed in an intrathoracic implantation in a goat (66 kg) and in an intraabdominal wall implantation in a goat (70 kg). Warfarin was given for anticoagulation in each experiment to keep the prothrombin time around 1.7 times that of the control. The temperatures of the pump surface, the pleura, and the room were measured every 3 h. Anatomical fitting was evaluated by pathological observation after the termination of the experiment. The ICP could run for 40 days in the chest cavity and for 11 days in the abdominal wall. The temperature of the motor remained about 1.8 degrees C higher than the reference in both experiments. The ICP was completely covered by a layer of smooth fibrous tissue. The moisture content of the seals remained normal. Although a small amount of atelectasis was found in the lingula, neither lung adhesion nor necrotic change of the chest wall was observed. The inflammation of the surrounding tissue including foreign body reaction and thermal burn was minimal. In conclusion, the ICP has satisfied in vivo testing of its watertightness, exothermicity, and anatomical fitting.

Abdominal Muscles↗

PubMed1998

Prolonged nonpulsatile left heart bypass with reduced systemic pulse pressure causes morphological changes in the aortic wall.

We investigated the morphological changes in the aorta due to reduced systemic pulse pressure in prolonged nonpulsatile left heart bypass (LHB). Nineteen adult goats were divided into 3 groups, the nonpulsatile group in which nonpulsatile LHB was conducted, the pulsatile group in which pulsatile LHB was conducted, and the control group used as the normal control. The average aortic pulse pressures were 12, 47, and 37 mm Hg, respectively. The descending aorta was subjected to morphological examination. In the nonpulsatile group, the wall was significantly thinner, and the volume ratio of smooth muscle cells (SMCs) was much lower. In terms of the SMC type classification, the proportion of SMCs with low activity and low contractility was higher, and the cell density of the SMCs was increased compared to those in the other groups. These results indicate that prolonged nonpulsatile LHB causes morphological atrophic changes in the aorta.

Animals↗

PubMed1998

Immunohistochemical examination of NOS and SOD in nasal mucosa.

An immunohistochemical examination was performed to detect the localization of neural-type nitric oxide synthase (nNOS), endothelial-type NOS (eNOS) and inducible-type NOS (iNOS) in the human and mouse nasal mucosa. nNOS-immunoreactive nerve fibers were found in the subepithelial layer and around the seromucous glands of mice. In these fibers, immunodouble staining revealed co-localization of nNOS and superoxide dismutase (SOD). In the human nasal mucosa of normal subjects, strong eNOS immunoreactivity and weak iNOS immunoreactivity were found in the columnar epithelium.

Animals↗

PubMed1998

Changes in rat liver cytochrome P450 enzymes by atrazine and simazine treatment.

1. We examined the effect of two chloro-s-triazines (atrazine and simazine) on hepatic microsomal cytochrome P450 enzymes in rat. Rats were treated intraperitoneally with atrazine or simazine daily for 3 days with 100, 200 and 400 mumol/kg. 2. Among the P450-dependent monooxygenase activities, testosterone 2 alpha-hydroxylase (T2AH) activity in rat, which is associated with CYP2C11, was significantly decreased at all doses of atrazine and simazine. The levels relative to control activities were 59-46 and 60-32% respectively. Similarly, oestradiol 2-hydroxylase (ED2H) activity was also significantly decreased by 28-51% by atrazine and simazine at all doses. However, no change in CYP2C11 protein level by either chloro-s-triazine was observed. K(m) for T2AH was significantly increased only by simazine (200 mumol/kg), whereas the Vmax and Cl(int) for T2AH were significantly decreased by atrazine and simazine at all doses. 3. 7-Ethoxyresorufin O-deethylase (EROD), 7-methoxyresorufin O-demethylase (MROD) and 7-pentoxyresorufin O-depentylase (PROD) activities were significantly increased by 1.4-1.6-, 1.7-3.2- and 1.5-2.2-fold respectively, by both chloro-s-triazines at 200 or 400 mumol/kg. Lauric acid omega-hydroxylase (LAOH) was also increased by 1.4-fold by simazine at 200 and 400 mumol/kg. Immunoblotting showed that only simazine induces CYP1A2 and CYP4A1/2 protein expression. 4. The activities of 7-ethoxycoumarin O-deethylase (ECOD), bufuralol 1'-hydroxylase (BF1'H), chlorzoxazone 6-hydroxylase (CZ6H), testosterone 6 beta-hydroxylase (T6BH) and testosterone 7 alpha-hydroxylase (T7AH) were not affected by either chloro-s-triazine. 5. These results suggest that the pattern of changes in P450 isoforms by chloro-s-triazines differs between atrazine and simazine, that these herbicides change the constitutive and/or male specific P450 isoform(s) in rat liver, and that these changes closely relate to the toxicity of chloro-s-triazines.

Animals↗

PubMed1998

Changes in hepatic cytochrome P450 enzymes by cis- and trans-1,2-dichloroethylenes in rat.

1. We examined the effect of cis- and trans-1,2-dichloroethylenes (DCEs) on hepatic microsomal cytochrome P450 (P450) enzymes in the male and female rat. Rats were treated intraperitoneally with 7.5 mmol/kg cis- or trans-1,2-DCE daily for 4 days. 2. Among the hepatic microsomal P450-dependent monooxygenase activities tested, testosterone 2 alpha-hydroxylase (T2AH) activity in the male rat, which is associated with CYP2C11, was decreased by both cis- and trans-1,2-DCE isomers. The levels to control activities were 53 and 63% respectively. Furthermore, immunoblotting showed that both isomers significantly reduced the CYP2C11/6 protein level in liver microsomes from the male. The levels of testosterone 6 beta-hydroxylase (T6BH) activity and CYP3A2/1 protein in the male rat were reduced by cis-1,2-DCE but not trans-1,2-DCE. 3. cis-1,2-DCE decreased ethoxycoumarin O-deethylase (ECOD), benzyloxyresorufin O-debenzylase (BROD), chlorzoxazone 6-hydroxylase (CZ6H) and testosterone 7 alpha-hydroxylase (T7AH) activities in the male rat by 29, 28, 34 and 27% respectively. On the other hand, trans-1,2-DCE significantly increased 7-ethoxyresorufin O-deethylase (EROD) and 7-methoxyresorufin O-demethylase (MROD) activities in the male rat 1.4- and 1.9-fold respectively. Immunoblotting showed that cis-1,2-DCE reduced CYP1A1/2 and CYP2B1/2 protein levels, whereas trans-1,2-DCE increased CYP1A1/2 and CYP2B1/2 protein levels in the male rat. 4. The activities of other P450-dependent monooxygenases, namely benzphetamine N-demethylase (BZND), aminopyrine N-demethylase (APND), erythromycin N-demethylase (EMND) and lauric acid omega-hydroxylase (LAOH), in the male rat were hardly affected by either 1,2-DCE isomer. In the female rat there were no apparent changes in P450-dependent monooxygenase activities upon treatment with the 1,2-DCE isomers. 5. These results suggest that 1,2-DCEs mainly affect male-specific P450 isoforms in the rat liver and that these changes may relate to the toxicity of 1,2-DCEs.

Animals↗

PubMed1998

Ex vivo evidence for asymmetric tyrosine phosphorylation of ZAP-70 on double-positive thymocytes in the positive selection process.

Antigen stimulation via TCR in mature T cells provides rapid induction of tyrosine phosphorylation of intracellular substrates including ZAP-70. To study the potential involvement of tyrosine phosphorylation in CD4+CD8+ [double-positive (DP)] thymocytes in the positive selection process in vivo, we isolated and analyzed them in the presence of phosphatase inhibitor. DP thymocytes were obtained from TCR transgenic mice (TCR-Tg) expressing MHC class I- or class II-restricted TCR in selecting and non-selecting MHC backgrounds respectively. The phosphorylation of ZAP-70 in DP thymocytes of class I-restricted TCR-Tg was significantly higher in the positively selecting background than in the non-selecting one. However, such a phosphorylation difference between selecting and non-selecting TCR-Tg was found to be considerably less in class II-restricted TCR-Tg. A similar bias for ZAP-70 phosphorylation was also observed on selecting DP thymocytes when I-A(beta) deficient- and beta2-microglobulin-deficient mice were compared. These ex vivo studies suggest that TCR-mediated signaling on DP thymocytes induces ZAP-70 phosphorylation under a different manner of engagement of TCR to class I and class II molecules in the positive selection process.

Animals↗

PubMed1998

Patterns of care study of radiation therapy for cervix cancer in Japan: the influence of the stratification of institution on the process.

BACKGROUND: To improve the quality of radiation oncology in Japan, Patterns of Care Study (PCS), a widely known quality assurance (QA) program in the USA, was introduced. The feasibility was tested by collecting nationwide data by extramural audit for cervix cancer. METHODS: From July 1996 through February 1997, PCS audits were performed for 29 institutions nationwide. On the basis of the facility survey by Tsunemoto, 13 institutions were classified as A1 (university hospital/cancer center), 10 as B1 (other institutions treating >120 patients/year) and six as B2 (other institutions treating <120 patients/year). Medical charts for the patients treated for cervix cancer between 1992 and 1994 were reviewed based on the data format of the US PCS. The total number of patients surveyed was 432. RESULTS: Simulation was used for >90% of the patients in both A1 and B1-2 institutions. However, in B1-2, planning for 5% of the patients was performed with only a clinical set-up (p = 0.0287). A daily fraction with a size of 200 cGy was given to >65% of patients in A1 and to <47% in B1-2. On the other hand, >50% of those in B1-2 were treated with daily fractions of 180 cGy and less compared with 25% in A1 institutions (p < 0.0001). Brachytherapy was utilized more frequently for patients in Stages II (p = 0.0365), III (p = 0.0015) and IV (p = 0.0483) in A1 than in B1-2. As for external beam equipment, linear accelerators with 10 MV or more were used for 83% of the patients in A1. However, in B1-2 institutions, machines with lower energy were used for 38% of the patients (p < 0.0001). The median number of full-time-equivalent (FTE) radiation oncologists was 2.7 in A1, 0.65 in B1 and 0.2 in B2. CONCLUSIONS: Institutional stratification, including equipment and personnel, was found to affect significantly the patterns of care for cervix cancer. Therefore, to improve the quality of radiation therapy nationwide, improvements in equipment and in supply of FTE personnel are extremely important. PCS was found to have great potential for a practical evaluation of how much improvement will be required in Japan.

Adult↗

PubMed1998

Reversible ischemia in hippocampal areas by retrograde cerebral circulation surgery for thoracic aortic aneurysm with Tc-99m ECD brain SPECT.

Because hippocampal neurons are quite vulnerable to the anoxic brain injury that sometimes occurs in aortic arch surgery in humans, hippocampal ischemia should be a sensitive indicator of global cerebral ischemia. It was concluded that the hypothermic retrograde cerebral circulation technique for aortic arch surgery could not only be performed safely with respect to the brain, but could also increase blood flow to the hippocampal areas, probably as a result of restoration of blood flow in the thoracic aorta.

Adult↗

PubMed1998

Decreased hippocampal blood flow related to memory impairment after cardiovascular surgery: assessment by reconstructed SPECT parallel to the longitudinal axis of the hippocampal formations.

Hippocampal damage has been linked to memory impairment. To clarify the relationship between decreased hippocampal blood flow and memory impairment in patients after cardiovascular surgery, the authors compared Tc-99m HMPAO SPECT findings and Mini Mental State Examination (MMSE) scores. Eight patients who had valve replacement, two who underwent aorto-coronary bypass, two who had aortic aneurysm replacement and one who had a ventricular septal defect closure were included in this study. Cerebral perfusion was estimated using reconstructed tomographic images, which were parallel to the longitudinal axis of the hippocampal formations. The hippocampal uptake ratios of Tc-99m HMPAO were calculated and normalized to that of the cerebellum. In three patients whose MMSE score decreased after surgery, the hippocampal uptake ratio was significantly reduced (0.69 +/- 0.09) compared with the remaining 10 patients whose MMSE scores did not decrease after surgery (0.91 +/- 0.02). These data suggest that SPECT imaging parallel to the longitudinal axis of the hippocampus is sensitive to decreased hippocampal blood flow, and decreased hippocampal blood flow is related to memory impairment in some patients after cardiovascular surgery.

Adolescent↗

PubMed1998

Comparison of dual-isotope acquisition of 201Tl and 99Tcm-tetrofosmin for the detection of ischaemic heart disease and determination of the optimal imaging time of 99Tcm-tetrofosmin.

Comparative studies of thallium-201 (201Tl) and 99Tcm-tetrofosmin for the detection of ischaemic heart disease (IHD) have previously been reported. These 201Tl and 99Tcm-tetrofosmin studies were usually performed separately with different exercise loads at an interval of several days. Here, we used a dual-isotope technique with exercise myocardial SPET (single photon emission tomography) in 17 patients with IHD and 10 patients with normal coronary arteries. The triple-energy window (TEW) method was applied for cross-talk correction. SPET imaging was performed at 10 and 70 min (S1 and S2) after the injection of 99Tcm-tetrofosmin (222 MBq) and 201Tl (74 MBq) at peak exercise to determine the optimal imaging time of 99Tcm-tetrofosmin. The S2 value was obtained 35 min after the subject drank a glass of milk to accelerate hepatobiliary clearance. Twenty-five minutes after S2, 37 MBq of 201Tl were reinjected at rest and SPET imaging (S3) was performed. Immediately after S3, 666 MBq of 99Tcm-tetrofosmin were reinjected and SPET imaging (S4) was performed 50 min later. Representative short and vertical long axis tomograms were divided into 17 segments. Each segment was assessed using a 4-point scoring system. The defect score was defined as the sum of each segmental score. The defect scores for imaging at exercise were 14.3 +/- 11.4 for 201Tl at S1, 11.4 +/- 8 for 99Tcm-tetrofosmin at S1 and 9.7 +/-9.8 for 99Tcm-tetrofosmin at S2 (P < 0.01), respectively. The washout rate of 99Tcm-tetrofosmin for the first hour was 15.5 +/- 7.3% and 11.8 +/- 7.7% (P < 0.01), respectively, for the normal and ischaemic segments. The image quality of 201Tl at S1 was almost equivalent to that of 99Tcm-tetrofosmin at S1/S2. The overall sensitivity and specificity for the detection of ischaemia was 94% and 82% for 201Tl at S1, 89% and 86% for 99Tcm-tetrofosmin at S1, and 88% and 95% for 99Tcm-tetrofosmin at S2, respectively. The overall accuracy was 86%, 88% and 92%, respectively. The myocardial viability score was 7.4 +/- 7.1 for 201Tl at S3 and 5.8 +/- 7.0 for 99Tcm-tetrofosmin at S4 (P < 0.01). The results indicate that the diagnostic accuracy of 99Tcm-tetrofosmin for myocardial ischaemia is almost equivalent to that of 201Tl as assessed by dual SPET imaging, and that the optimal imaging time for 99Tcm-tetrofosmin is within 10-35 min (S1) after exercise.

Coronary Disease↗

PubMed1998

Increased use of inhaled corticosteroids and reduced hospitalizations in adult asthmatics: 11 years' experience in a Japanese hospital.

Until recently, inhaled corticosteroids have not been recognized as a first-line drug mainly because of the traditional polypharmaceutical approach to asthma in Japan. To examine the trend more precisely following the introduction of inhaled corticosteroids, we retrospectively analysed the relation between the number of prescriptions for anti-asthma drugs including inhaled corticosteroids and the number of hospitalizations due to asthma exacerbation, near fatal episodes and deaths from asthma for a period of 11 years from 1986 to 1996 at Kobe City General Hospital (KCGH). A marked decline in these actual indices in patients attending KCGH, which shows the improvement in asthma control, started coincidentally with the increased use of inhaled corticosteroid, which was followed by both a discontinuation of the trend for increased use of inhaled beta-agonists and the decreased use of oral anti-asthma agents. There was no significant difference in the mean duration of hospital stays between 1988 and 1996. Although the intensification of patient education is likely to play an important role in enhancing the protective effect of inhaled corticosteroids, we highly suspect that the major contributory factor in the great decline in hospitalizations is the increased use of inhaled corticosteroids.

Administration, Inhalation↗

PubMed1998

IL-1ra versus IL-1 levels in prostatic fluid from prostatitis patients.

Recent papers reported that the balance between the production of IL-1ra and IL-1 probably influences the regulation of host responses, the severity and prolongation of the inflammatory reaction in some diseases. Therefore, in our continuing investigation to clarify the significance of leukocytosis and its prolongation in prostatic fluid from prostatitis patients, we investigated whether low levels of IL-1ra versus IL-1 beta secreted in prostatic fluid were the cause of prolonged prostatitis, especially nonbacterial prostatitis (NBP). As a result of the present study, we concluded that a low level of IL-1ra in relation to that of IL-1 secreted in prostatic fluid is unlikely to cause prolongation of NBP for the following reasons: (1) IL-1 beta was detected in 5 of 10 cases (50.0%), but was slightly elevated in only 2 cases (20.0%) at 14 and 17 pg/ml; (2) the average IL-1ra level was not statistically low compared with that in prostatic fluid from acute bacterial prostatitis (ABP) patients who were cured promptly with antibiotics, and (3) in 5 cases of NBP in which IL-1 beta was detected, the average IL-1ra/IL-1 beta ratio was 118 which was comparable to or even higher than that in 3 ABP and 14 acute bacterial cystitis cases in which IL-1 beta was detected and the ratios were 40 and 88, respectively.

Adult↗

PubMed1998

Detection of activated platelets in urine by double immunofluorescence in children with IgA nephropathy.

The relationship between the activation of platelets (PLT) in urine and renal histological findings in children with IgA nephropathy (IgAN), thin basement membrane disease (TBMD), and minimal-change nephrotic syndrome (MCNS) was examined. The ratio of activated PLT to total PLT (activated and nonactivated PLT) was examined by double immunofluorescence using rhodamine-conjugated P selectin antibody (activated PLT) and fluorescein isothiocyanate conjugated PLT membrane glycoprotein antibody (GPIIb/IIIa, total PLT); the effect of urine on activation on PLT was also investigated. The number of activated PLT and the ratio of activated PLT to total PLT in urinary sediments were significantly higher in children with IgAN with diffuse mesangial proliferation than in those with TBMD or MCNS. PLT were activated by addition of urine in 13 out of 27 children with IgAN, and the activity was higher in the urine of those with active glomerular or interstitial lesions, while the urine of children with TBMD or MCNS had no effect. The presence of activated PLT and the effect of urine on PLT activation may be associated with the active glomerular or interstitial lesions in IgAN.

Adolescent↗

PubMed1998

Power spectral analysis of heart rate variability in a horse with atrial fibrillation.

This study has demonstrated the power spectral analysis of heart rate variability in a horse with atrial fibrillation. A large peak in the high frequency (HF) area of the power spectrum appeared in the horse. Hourly heart rate, the low frequency (LF) power, the HF power, and LF/HF ratio were almost constant during the recording period. The values of HF and LF power in the horse with atrial fibrillation were much larger than those in normal horses. The normalized unit of HF (HF n.u.) was much larger than that of LF (LF n.u.). Furthermore, the LF/HF ratio was very small in the horse. These results suggest that the ventricular rhythm has a respiratory related periodicity in the horse with atrial fibrillation and the predominant parasympathetic activity may modulate the intrinsic behavior of the atrioventricular node during atrial fibrillation.

Animals↗

PubMed1998

[Reproductive and developmental toxicity study of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na (1). Fertility study in rats].

Fertility study of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na), a novel neutrophil elastase inhibitor, was conducted in Sprague-Dawley (SD) rats. ONO-5046.Na was administered intravenously at doses of 18.75, 37.5 and 75 mg/kg/day to male rats from 64 prior to mating, through the mating period and until necropsy, and to female rats from 15 days prior to mating until Day 7 of gestation, in order to examine its effects on fertility and reproductive performance of males and females and the development of their fetuses. There were no changes attributable to ONO-5046.Na in general signs, body weight, food consumption or autopsy findings in males and females. No drug-related changes were observed in estrous cycles, copulation and fertility indices in males and females. Pituitary weight of dams was decreased in each of the ONO-5046.Na treated groups, but no histopathological changes were observed in the pituitary. In the cesarean section findings in dams, ONO-5046.Na had no effects on the number of corpola lutea, the number of live fetuses, the implantation ratio, the resorbed and dead fetus ratio, fetal or placental weight, or the incidences of external, skeletal or visceral anomalies of the fetuses. From these results, it is considered that the NOAEL of ONO-5046.Na is 75 mg/kg/day for general and reproductive toxicity in males and females and for developmental toxicity in their fetuses.

Animals↗

PubMed1998

[Reproductive and developmental toxicity study of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na) (2). Study for effects on pre- and postnatal development in rats, including maternal function].

Prenatal and postnatal toxicity of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na), a novel inhibitor of human neutrophil elastase, was studied in Sprague-Dawley (SD) rats. ONO-5046.Na was injected intravenously at doses of 0, 18.75, 37.5 and 75 mg/kg/day to pregnant rats from day 7 of pregnancy to day 20 after delivery. All pregnant rats were allowed to deliver naturally for postnatal examination of their offspring. No adverse effects on dams were observed in clinical signs, body weight change, food consumption, pregnant, delivery or lactating performances. ONO-5046.Na did not affect the postnatal development of offspring, including birth index, survival index, physical and functional development, motor activity, emotionality, learning ability and reproductive performance. From these results, it is considered that the NOAEL of ONO-5046.Na is 75 mg/kg/day for dams and their offspring.

Animals↗

PubMed1998

[Reproductive and developmental toxicity study of sodium N-[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino] benzoyl] aminoacetate tetrahydrate (ONO-5046.Na) (3). Teratogenicity study in rabbits].

Teratogenicity of sodium N[2-[4-(2,2-dimethylpropionyloxy) phenylsulfonylamino]benzoyl] aminoacetate tetrahydrate (ONO-5046.Na), a novel inhibitor of human neutrophil elastase, was studied. ONO-5046.Na was injected intravenously at doses of 0, 7.5, 15 and 30 mg/kg/day to pregnant Kbl: NZW rabbits from day 6 to day 18 of pregnancy. All female rabbits were sacrificed on day 29 of pregnancy and their fetuses were examined. There were no clinical signs or death attributable to ONO-5046.Na. One dam in the control group and 3 dams in the 30 mg/kg/day group aborted. Body weight gain in the 15 and 20 mg/kg/day groups and food intake in the 30 mg/kg/day group were decreased during the administration period. These changes had recovered by the end of the study. Kidney weight was increased in the 30 mg/kg/day group. There were no effects of ONO-5046.Na in necropsy findings at cesarean section in dams at any dose levels. Developmental toxicity of ONO-5046.Na was not found at any dose levels. From these results, it is considered that the NOAEL of ONO-5046.Na is 7.5 mg/kg/day for pregnant animals and 30 mg/kg/day for fetuses.

Animals↗