Biomedical subjects

A Yoshitake

Publications and source records attributed to A Yoshitake.

At least 37 records · Page 2Linked to original sources

PubMed1997

Cerebral ischemic disorders and cerebral oxygen balance during cardiopulmonary bypass surgery: preoperative evaluation using magnetic resonance imaging and angiography.

We compared the preoperative prevalence of small cerebral infarctions and carotid stenosis to jugular venous oxygen saturation (Sjvo2) during coronary artery bypass grafting (CABG). Sjvo2 served as an indicator of whether cerebral oxygen supply meets demand in patients on cardiopulmonary bypass (CPB). The study population consisted of 121 patients who were either older than 65 yr or had a history of cerebrovascular disease. The patients underwent preoperative cerebral magnetic resonance imaging (MRI) and cervical magnetic resonance angiography (MRA) to detect small cerebral infarctions and carotid artery stenosis. Patients with atherosclerosis of the ascending aorta were identified by intraoperative epiaortic ultrasonography. Liberation of emboli from the aorta in these patients was prevented by modification of the standard operation. From preoperative MRI and MRA, 65 patients (54%) had small cerebral infarctions in the white matter or basal ganglia and nine patients (7%) demonstrated moderate or severe stenosis in the carotid arteries. Thirteen patients (11%) had moderate or severe atheromatous disease of the ascending aorta. The severity of aortic atherosclerosis was significantly correlated with the grade of carotid stenosis (P < 0.05). In patients with small infarctions, Sjvo2 was significantly lower than in patients without infarctions (controls) at initiation of CPB, 30 min after aortic cross-clamping, and during the rewarming period of CPB (P < 0.05). Thus, small cerebral infarctions were not uncommon in elderly patients undergoing CABG. Patients with small cerebral infarctions may be at risk for an imbalance in cerebral oxygen supply and demand during the rewarming period because they are unable to deliver the necessary compensatory blood flow.

Aged↗

PubMed1997

Radial artery diameter decreases with increased femoral to radial arterial pressure gradient during cardiopulmonary bypass.

UNLABELLED: A clinically significant femoral to radial artery pressure gradient sometimes develops during cardiopulmonary bypass (CPB), but the mechanism responsible is not clear. We investigated when the pressure gradient developed and what mechanism could be responsible by comparing mean femoral to mean radial artery pressure and radial artery diameter in 75 male patients undergoing coronary artery bypass grafting. A pressure gradient > or =5 mm Hg (High-P) occurred in 38 patients, and the remaining 37 patients had pressure gradients <5 mm Hg (Low-P) at sternal closure. In High-P group, the pressure gradient was significantly greater (4.8 +/- 3.1 vs 1.0 +/- 3.1 mm Hg; P < 0.001) than in Low-P group, and the ratio of radial artery diameter to the diameter after induction of anesthesia was significantly decreased (0.79 +/- 0.12 vs 0.87 +/- 0.14; P = 0.006) at 5 min after aortic clamping. The pressure gradient and the arterial diameter changes persisted until sternal closure. There was a negative linear correlation between the pressure gradient (deltaP) and the radial artery diameter ratio (D) at sternal closure (D = -15.0deltaP + 16.6, r = 0.39, P < 0.001). In a subgroup of 11 High-P patients, palm temperature was significantly lower (P < 0.05) than that of 11 Low-P patients during and after CPB. We conclude that the femoral to radial artery pressure gradient develops by 5 min after aortic clamping during CPB and persists until sternal closure, and that radial artery constriction could be responsible for the pressure gradient. IMPLICATIONS: A femoral to radial pressure gradient has been observed after cardiopulmonary bypass. Arterial vasodilation and vasoconstriction have been considered as causes for this gradient. We measured radial artery diameter using pulsed Doppler ultrasound and examined radial artery vasodilation versus vasoconstriction as possible mechanisms for the pressure gradient.

Aged↗

PubMed1996

Inhibition of animal acetyl-coenzyme A carboxylase by 2-(p-chlorophenoxy)-2-methylpropionic acid and 2-ethylhexanoic acid.

Peroxisome proliferators are generally known as activators of fatty acid beta-oxidation which is one of degradation pathways. However, since it is unknown whether peroxisome proliferators have an effect on biosynthesis of fatty acid or not, we commenced to study if acetyl-CoA carboxylase, the rate-limiting enzyme of fatty acid biosynthesis, is inhibited by 2-(p-chlorophenoxy)-2-methylpropionic acid or 2-ethylhexanoic acid which is a typical peroxisome proliferator. Acetyl-CoA carboxylase(s) from rat, mouse, hamster, rabbit, dog and monkey were completely inhibited by 2-(p-chlorophenoxy)-2-methylpropionic acid or 2-ethylhexanoic acid at the concentration of 10(-3)M. For both compounds, there was not a large species difference in the inhibition. However, there was only several times difference between I50 values for the two compounds. The findings imply that inhibition of acetyl-CoA carboxylase by the chemicals leads to reduction of fatty acid biosynthesis when the chemicals are administered to the animals at high dose levels.

Acetyl-CoA Carboxylase↗

PubMed1995

Species-specific mechanism in rat Leydig cell tumorigenesis by procymidone.

To clarify the mechanism of species difference in the induction of testicular interstitial cell tumor (ICT, Leydig cell tumor) between rats and mice, male Sprague-Dawley rats and ICR mice were fed procymidone at dietary concentrations of 700, 2000 or 6000 ppm and 1000, 5000, or 10,000 ppm, respectively, for 3 months. The Leydig cell functions were evaluated by serum testosterone and luteinizing hormone (LH) levels, testosterone levels in the testis, LH levels in the pituitary, the capacity of the testis to respond to gonadotropin stimulation, i.e., the production of testosterone in vitro, and by the testicular binding of labeled human chorionic gonadotropin (hCG). Measurement of testosterone and LH levels in rat serum, the testis, or the pituitary showed that both hormones were enhanced throughout the 3-month treatment period. The hypergonadotropism was associated with the increase of interstitial cell response to hCG in vitro for up to 3 months. As with rats, both serum and pituitary LH were increased in mice at 4 weeks but not at 13 weeks. However, in contrast to rats, no significant increase in testosterone was observed in mice either in vivo or ex vivo during the course of the study. This suggests a difference between the rat and mouse in the response of the Leydig cell to the LH stimulation associated with procymidone administration. These differences in the response of interstitial cells to procymidone may be the basis for the distinct species responses to procymidone-induced Leydig cell tumorigenesis. The sustained response of the Leydig cells to stimulation in the rat results in chronic hyperplasia and subsequent benign tumor formation, while the attenuated response of Leydig cells in the mouse is associated with neither hyperplasia nor neoplasia.

Administration, Oral↗

PubMed1994

Quantitative determination of F6-1,25(OH)2 vitamin D3 in human serum by gas chromatography/mass spectrometry with high-resolution selected ion monitoring.

A highly sensitive and specific gas chromatographic/mass spectrometric method was developed for the determination of very low levels of F6-1,25(OH)2 vitamin D3, a new fluoro analogue of vitamin D3, to facilitate investigation of its pharmacokinetics in man. Deuterium-labelled F6-1,25(OH)2 vitamin D3 was employed as an internal standard for quantification. The method involves extraction from serum samples, separation by a cartridge column system followed by straight-phase high-performance liquid chromatography, O-trimethylsilylation, and analysis by gas chromatography/mass spectrometry using high-resolution selected ion monitoring. With a quantification limit of 2 pg ml-1 and a requirement for 2 ml of serum, the assay method has sufficient sensitivity, selectivity and precision for the analysis of very low concentrations of the drug.

Calcitriol↗

PubMed1994

Lack of induction of epithelial cell proliferation by sodium saccharin and sodium L-ascorbate in the urinary bladder of NCI-black-Reiter (NBR) male rats.

The susceptibility to induction of epithelial cell proliferation by three urinary bladder cancer promoters was investigated in NCI-Black-Reiter (NBR) rats, which lack alpha 2u-globulin-synthesizing ability. Six-week-old male NBR and F344 rats were given 5% sodium saccharin (Na-Sac), 5% sodium L-ascorbate (Na-AsA), or 3% uracil in the basal diet for 8 weeks. Administration of uracil evoked a marked cell proliferation response and papillomatosis associated with calculus formation in NBR as well as F344 rats. This result indicates that NBR rats are also susceptible to direct mechanical stimulation. In contrast, both strains of rats given Na-Sac or Na-AsA demonstrated an alkalization of urinary pH and an increase in urinary Na ion concentration, but increase in cell proliferation in the urinary bladder transitional epithelium was only observed in F344 rats. Since previous studies revealed that elevation of urinary pH and Na ion concentration are essential factors for exertion of promotion activity by Na-Sac and Na-AsA, the results of the present investigation suggest that alpha 2u-globulin might also be a necessary component of the mechanisms of their promotion of male rat urinary bladder carcinogenesis.

Animals↗

PubMed1994

11C-labeled 2'-iododiazepam for PET studies of benzodiazepine receptors: synthesis and comparison of biodistribution with its radioiodinated compound.

For PET studies of benzodiazepine receptors, N-11C-methyl-2'-iododiazepam (2'-IDZ) was synthesized by N-methylation of its desmethyl derivative with 11C-methyl iodide, and was subsequently purified by HPLC. The labeling and purification procedures were completed within 45 min after 11C-methyl iodide trapping, and the radiochemical yield (corrected for decay) was approximately 40% based on the initial trapped radioactivity of 11C-methyl iodide. Biodistribution studies in mice demonstrated that 11C-2'-IDZ was rapidly and noticeably accumulated in the brain, and subsequently decreased with time. Accumulation was greater in the cortex than in other brain regions. When compared with 125I-2'-IDZ, the distribution was almost the same until 5 min after injection, but levels were low after 20 min. Metabolic studies indicated that the difference between these two compounds in the time course of brain radioactivity distribution may be due to N-demethylation in vivo.

Animals↗

PubMed1994

Radioiodinated nordiazepam analog for in vivo assessment of benzodiazepine receptors by single photon emission tomography.

2'-Iodo-nordiazepam (2'-IND), a nordiazepam analog iodinated at the 2'-position of the C-5 phenyl ring, was synthesized and evaluated as a potential radiopharmaceutical for investigating brain benzodiazepine receptors by SPECT. [125I]2'-IND was synthesized by the halogen exchange reaction and purified by HPLC. In an in vitro competitive binding study using [3H]diazepam and rat cortical synaptosomol membranes, 2'-IND showed an almost equal affinity for benzodiazepine receptors as diazepam. In a saturation binding study using rat cortical synaptosomal membranes, 2'-IND displayed a Kd of 1.10 nM and a Bmax of 1.87 pmol/mg protein. Biodistribution and metabolism studies in mice showed that [125I]2'-IND exhibited rapid and high accumulation in the brain, and that the cerebral uptake and distribution of this compound occurred in the intact form. Furthermore, the administration of diazepam and flumazenil reduced cortical uptake by approx. 20%, suggesting that the uptake of 2'-IND occurred at least partly in association with benzodiazepine receptors.

Animals↗

PubMed1994

Effect of DDT on hepatic gap junctional intercellular communication in rats.

The effects of in vivo exposure to DDT on hepatic gap junctional intercellular communication (GJIC) and connexin gene/protein expression in Sprague-Dawley rats were examined by in vivo/in vitro dye-transfer assay, immunohistochemical staining, and by Western and Northern blot analyses. In the dose-response study, three dose levels of DDT (5, 25 and 50 mg/kg/day) were administered orally to rats once a day for 2 weeks. The average size of the dye spread after injection of Lucifer Yellow and the area of Cx32 spots per hepatocyte decreased in a dose-dependent manner, but there was no effect on the number of Cx32 spots per hepatocyte. In the time-course study, DDT (50 mg/kg/day) was administered orally once a day for up to 6 weeks. Hepatic GJIC decreased at week 1 but recovered at week 6. The average area of Cx32 spots per hepatocyte gradually decreased at weeks 2 and 4, and remained at the same level at week 6, correlating with the decreased Cx32 protein level in plasma membranes. The average area of Cx26 spots per hepatocyte in the peripheral zones clearly decreased at week 1, but quickly recovered at week 2 and increased at week 6; however, no clear change of the Cx26 protein level in plasma membranes was observed. No changes of Cx32 and Cx26 mRNA levels were observed in DDT groups. These results suggest that DDT, a liver tumor-promoting agent, inhibits hepatic GJIC in vivo dose-dependently in rats and that aberrant Cx32 and Cx26 protein expression and/or localization may be responsible for this effect.

Animals↗

PubMed1993

An approach for assaying benzodiazepine receptor binding with radioiodinated ligand: 125I-labeled diazepam derivative.

[125I]2'-Iododiazepam (IDZ) was prepared and its application in a benzodiazepine receptor binding assay was studied. [125I]2'-IDZ binds to the rat cortical membrane with a high affinity (Kd, 0.66 nM). Various benzodiazepines showed competition with [125I]2'-IDZ for the binding sites in the rat cortical membrane, and the specificity of its binding correlated well with that of [3H]diazepam (r = 0.992, p < 0.001). These findings suggested that [125I]2'-IDZ binds to the same sites as [3H]diazepam and indicated that [125I]2'-IDZ can be used in a benzodiazepine receptor assay.

Animals↗

PubMed1993

Effects of procymidone on reproductive organs and serum gonadotropins in male rats.

To investigate the mechanism and toxicological significance of testicular interstitial cell tumors (ICT) observed in a long-term rat study with procymidone, N-(3,5-dichlorophenyl)-1,2-dimethylcyclopropane-1,2-dicarboximi de, male Sprague-Dawley rats were fed procymidone in diets for up to 6 months with a positive control group receiving a single subcutaneous injection of cadmium chloride. Examinations mainly for gonadal functions such as serum testosterone and luteinizing hormone (LH), reproductive organ weight and histopathology presented evidence of the indirect involvement of gonadotropins in the production of ICT in rats. A significant increase in both serum testosterone and LH was observed in the early stage at high dietary concentrations of procymidone without any lesion in gonadal systems in histopathology, whereas administration of cadmium chloride produced the expected substantial increase in serum LH and a concomitant decrease in serum testosterone with a marked damaging effect on gonadal systems. Increases in serum testosterone and LH levels in animals receiving procymidone were reversible. The no-effect level for procymidone on serum testosterone and LH was 300 ppm over six months of treatment. The possible mechanism of ICT production in rats by non-genotoxic procymidone, structurally similar to flutamide, a synthetic non-steroidal antiandrogen, is likely to be derived from its induction of a hypergonadotropism due to the competitive binding to the androgen receptor, preventing the normal effect of testosterone to control the circulating level of LH.

Animals↗

PubMed1993

The affinity of procymidone to androgen receptor in rats and mice.

To clarify the mechanism of gonadotropin imbalances and the differential response of rat and mouse testicular interstitial cells (Leydig cells) to procymidone, N-(3,5-dichlorophenyl)-1,2-dimethylcyclopropane-1,2-dicarboximi de, male Sprague-Dawley rats and ICR mice were fed procymidone in diet for 2 weeks at 0, 700, 2,000 and 6,000 ppm for rats, or 0, 1,000, 5,000 and 10,000 ppm for mice. Testosterone and luteinizing hormone (LH) levels in serum, testis or pituitary and the in vitro binding affinities of procymidone, flutamide and related compounds to the androgen receptor in prostate cytosol of rats and mice were examined. Hypergonadotropism in rats and mice was clearly observed in the same order two weeks after the initiation of treatment with procymidone. Increased levels of testosterone and LH in serum at 6,000 ppm and LH in pituitary at and above 700 ppm in rats were observed. In mice, testosterone levels in serum and testis elevated at 10,000 ppm. LH levels in serum and pituitary elevated significantly as well at around 5,000 to 10,000 ppm. In the competitive binding assay, procymidone showed a significant but lower binding affinity comparing to that of cyproterone acetate, the steroidal androgen receptor antagonist, for the androgen receptor in both rats and mice under the condition that unlabeled dihydrotestosterone (DHT) effectively inhibited the binding of [3H]-DHT to the androgen receptor in both species. The relative binding affinity (RBA) of procymidone was of the same order as that of flutamide, a synthetic non-steroidal antiandrogen structurally similar to procymidone. These results indicate that procymidone is an active antiandrogen and the androgen receptor antagonism is the likely mechanism of action.

Animals↗

PubMed1993

Metabolism of N-[4-chloro-2-fluoro-5-[(1-methyl-2- propynl)oxy]phenyl]-3,4,5,6-tetrahydrophthalimide (S-23121) in the rat: I. Identification of a new, sulphonic acid type of conjugate.

1. Several metabolites of 14C-labelled N-[4-chloro-2-fluoro-5-[(1-methyl- 2-propynyl)oxy]phenyl]-3,4,5,6-tetra-hydrophthalimide (S-23121) were identified. 2. The major urinary metabolites were found to be 4-chloro-2-fluoro-5-hydroxyaniline, its sulphate and glucuronide by t.l.c. cochromatography with authentic standards. 3. The major faecal metabolites in addition to the parent compound were six sulphonic acid conjugates having a sulphonic acid group incorporated into the double bond of the 3,4,5,6-tetrahydrophthalimide moiety. These sulphonic acid conjugates have never been reported previously for this type of compound. 4. To confirm the mechanism of biosynthesis of the sulphonic acid conjugates, sodium sulphate, cysteine and glutathione labelled with 35S were administered to the male rat together with unlabelled S-23121. The same faecal metabolites as those detected in faeces of the rat dosed with 14C-labelled S-23121 were similarly found after dosing with any of the 35S-labelled chemicals. Their biosynthesis was most pronounced with 35S-labelled sodium sulphate, implying that the sulphonic acid is incorporated into the double bond after reduction of sulphate to sulphite.

Animals↗

PubMed1993

Metabolism of a tetrahydroaminoacridine derivative (SM-10888) in rat: structural analysis of an N-glucuronide of SM-10888 and an O-glucuronide of hydroxylated SM-10888 by FAB-MS/MS.

1. The metabolism of 9-amino-8-fluoro-1,2,3,4-tetrahydro-2,4-methanoacridine citrate (SM-10888), a cholinesterase inhibitor was studied in rat. 2. The phase I metabolite (designated M3) was isolated from urine and identified as 1-hydroxylated SM-10888 by 1H-n.m.r. and EI-MS. 3. Two glucuronides (designated SMG and M3G) were isolated from bile and urine and their structures examined by FAB-MS/MS and beta-glucuronidase hydrolysis. 4. FAB-mass spectra of SMG and M3G showed molecular ions ([M+H]+) at m/z 405 and 421, respectively. In their daughter spectra, fragment ions of aglycones (SM-10888 and M3), generated by the loss of glucuronic acid (176 amu) were observed. The daughter spectra of these aglycones were essentially similar to those of the corresponding synthetic standards. 5. SMG was hydrolysed non-enzymically at pH 5 as is often the case with N-glucuronides of arylamines. M3G could be hydrolysed by beta-glucuronidase but proved stable at pH 5. 6. From these results, SMG and M3G were concluded to be the N-glucuronide of SM-10888 and the O-glucuronide of M3, respectively.

Aminacrine↗

PubMed1993

Radioiodinated 2'-iododiazepam: a potential imaging agent for SPECT investigations of benzodiazepine receptors.

2'-Iododiazepam (2'-IDZ) is the diazepam analogue iodinated at the 2'-position of C-5 phenyl ring which was synthesized and evaluated as a potential radiopharmaceutical for investigating brain benzodiazepine receptors by SPECT. The 125I-2'-iododiazepam was synthesized by halogen exchange reaction and purified by HPLC. In vitro competitive binding studies with 3H-diazepam, using rat cortical synaptosomal membranes, showed that the affinity of 2'-IDZ for benzodiazepam receptors was higher than that in diazepam and flumazenil (RO15-1788). Biodistribution studies in mice showed that the brain uptake of 2'-iododiazepam was rapid and profound, and in the brain higher accumulation was found in the cortex than in other regions. Furthermore, the cortical uptake was displaced by benzodiazepinergic compounds. In vivo uptake was assessed by autoradiographic studies. Thus, 2'-iododiazepam bound to benzodiazepine receptors in vivo and therefore holds great potential for in vivo benzodiazepine receptor studies.

Animals↗

PubMed1992

Differences in alpha 2u-globulins increased in male rat kidneys following treatment with several alpha 2u-globulin accumulating agents: cystein protease(s) play(s) an important role in production of kidney-type-alpha 2u-globulin.

Effects of alpha 2u-globulin accumulating agents on alpha 2u-globulins in rat kidneys were examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting analysis. Treatment of male animals with decalin (150 mg/kg), 2,2,4-trimethylpentane (50 mg/kg), isophorone (150 mg/kg), d-limonene (150 mg/kg) or 1,4-dichlorobenzene (150 mg/kg) by gavage for 14 consecutive days in each case resulted in a marked intensification of a protein band corresponding to kidney-type-alpha 2u-globulin, with a molecular mass calculated to be approximately 16 kDa. However, intraperitoneal treatment with leupeptin and E-64 (two times 0.07 mmol/kg, for each), well known cystein protease inhibitors, while only slightly increasing this kidney-type-alpha 2u-globulin band, caused the intensification of a approximately 19-kDa molecular mass protein band which was revealed to be a native-type-alpha 2u-globulin by SDS-PAGE and immunoblotting. These results indicated that at least two types of alpha 2u-globulin can be increased in male rat kidney by chemical treatment. Moreover, cystein protease(s) appear(s) to play an important role in the degradation of alpha 2u-globulin and particularly in the conversion of native-type-alpha 2u-globulin to kidney-type-alpha 2u-globulin in rat kidneys.

Alpha-Globulins↗

PubMed1992

Preparation of 123I-labeled 2'-iodospiperone and imaging of D2 dopamine receptors in the human brain using SPECT.

[123I]2'-ISP was readily prepared using a radioiodine exchange reaction with a radiochemical yield of approx. 50% after HPLC purification. The radiochemical purity of the product was more than 98% and the specific activity was 5.55-11.1 GBq/mumol. Biodistribution studies performed in mice indicated that injection of [123I]2'-ISP with albumin produced a higher gastric uptake and a lower brain uptake than injection of the radioligand in a weakly acidic solution. In addition, toxicity tests performed in mice demonstrated that acute toxic effects would be very unlikely to be encountered if 2'-ISP was used for diagnostic purposes. A preliminary imaging study with [123I]2'-ISP in a healthy human volunteer showed its specific uptake by the basal ganglia, a region of the brain known to have a high density of D2 dopamine receptors.

Animals↗

PubMed1992

Evaluation of N-alkyl derivatives of radioiodinated spiperone as radioligands for in vivo dopamine D2 receptor studies: effects of lipophilicity and receptor affinity on the in vivo biodistribution.

A series of radioiodinated spiperone (2'-ISP) derivatives bearing amide N-alkyl substituents (N-methyl-2'-ISP, N-ethyl-2'-ISP, and N-propyl-2'-ISP) were synthesized and evaluated as potential singlet photon emission computed tomographic radiopharmaceuticals for visualizing dopaminergic receptors. The lipophilicity of these ligands (i.e., the partition coefficient for octanol-phosphate buffer) increased as the chain length increased. Investigation of blood-brain barrier permeability in rats showed a parabolic relationship between the brain uptake index and the partition coefficient. In vitro competitive binding studies showed that the relative affinity for the dopamine D2 receptor was in the order of N-propyl-2'-ISP greater than 2'-ISP greater than N-methyl-2'-ISP approximately N-ethyl-2'-ISP. In vivo biodistribution studies showed that the initial brain uptake correlated fairly well with the brain uptake index and that the kinetics of the radioactivity specifically bound to the striatum were strongly influenced by the dopamine receptor binding affinity of the compounds. Thus, the in vivo behavior of these N-alkylated 2'-ISP derivatives involved a complex interplay between receptor affinity, lipophilicity, and blood-brain barrier permeability.

Animals↗