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S Totsuka

Publications and source records attributed to S Totsuka.

61 records · Page 4Linked to original sources
PubMedDate not supplied

Increase in urinary excretion of 6beta-hydroxycortisol in common marmosets as a marker of hepatic CYP3A induction.

The ratio of urinary 6beta-hydroxycortisol (6beta-OHF) to free cortisol (F), i.e., the 6beta-OHF/F ratio, has been reported to be a specific marker for human CYP3A induction by in vivo studies of human subjects. In the development of drugs, it is quite beneficial to predict human CYP3A induction in preclinical safety studies using urine samples from experimental animals. We examined the 6beta-OHF/F ratio in urine of common marmosets administered with rifampicin, a potent inducer of CYP3A, to evaluate the usefulness of common marmosets for the prediction of CYP3A induction. Rifampicin was orally administered to three groups of four male common marmosets at doses of 0, 10, and 20 mg/kg per day for 4 days. Amounts of 6beta-OHF and F in urine samples were determined by means of high-performance liquid chromatography (HPLC) during the experimental period. One day after the 4th dosing, animals were killed, and P450 contents and P450-catalyzed. 7-alkoxycoumarin O-dealkylase (ACD) activities in the liver were measured. Western blot analysis of liver microsomes was also performed using anti-rat P450 (CYP1A1, 2B1/2, 3A, and 4A) antibodies. The results indicated elevations in the 6beta-OHF/F ratios that were dependent on both the dosing period and dose levels adopted. The ratios on day 4 reached 4.7- and 5.3-fold the pre-administration values in the 10 and 20 mg/kg per day groups, respectively. P450 contents and ACD activities were also elevated in all of the groups. Western blot analysis showed specific increases in the protein which cross-reacts with anti-rat CYP3A antibody in all of the groups. Furthermore, the 6beta-OHF/F ratio was well correlated with the CYP3A contents in liver (r = 0.906). These results indicated that increase in urinary excretion of 6beta-OHF is a specific marker of the induction of hepatic CYP3A in common marmosets just as in humans. Consequently, the present study suggested that human CYP3A induction elicited by chemical agents can be predicted in common marmosets by measuring the urinary excretion of 6beta-OHF.

7-Alkoxycoumarin O-Dealkylase↗
PubMedDate not supplied

Correlation of regional cerebral blood flow with performance on neuropsychological tests in schizophrenic patients.

Regional cerebral blood flow (rCBF) was determined by the 133Xe inhalation technique (Headtome II: ring detection SPECT) in 53 DSM-III schizophrenic patients. The rCBF values were corrected by using end-tidal carbon dioxide concentration values (PECO2). After rCBF measurement, neuropsychological tests--Word Fluency Test, Maze Test and Wisconsin Card Sorting Test--were performed. There were significant correlations between frontal rCBF and scores on each neuropsychological test. In particular, a moderate correlations between the frontal rCBF and the performance on the Wisconsin Card Sorting Test was noted. It seems likely that decrease of rCBF in prefrontal regions at rest reflects a disturbance of frontal lobe function in schizophrenic patients.

Adult↗
PubMedDate not supplied

Frontality, laterality, and cortical-subcortical gradient of cerebral blood flow in schizophrenia: relationship to symptoms and neuropsychological functions.

According to the three hypotheses on the regional brain dysfunction in schizophrenia that have received some support in studies of cerebral blood flow (CBF) and cerebral metabolic rate, we calculated eight CBF measurement indices in 59 schizophrenic patients; frontality, laterality, cortical to subcortical gradients and superior to inferior difference. Four factors were selected from these eight indices, treated by principal component factor analysis (factor 1: cortical to subcortical gradient; factor 2: inferior frontality; factor 3: superior frontality; factor 4: laterality). We investigated their correlations with clinical and demographic characteristics. Factor 1 correlated with duration of illness. Factor 2 related most highly to numbers of perseverative errors on the Wisconsin Card Sorting Test and moderately to anhedonia. Factor 4 related to attentional impairment score of the Scale for the Assessment of Negative Symptoms. The schizophrenia specific symptom score calculated from the Brief Psychiatric Rating Scale did not relate to any of these factors. It seemed that there were various dimensions of neural deficits in schizophrenia, corresponding to various aspects of symptomatology or neuropsychological functions.

Adult↗
PubMedDate not supplied

Distribution, excretion, and metabolism of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) in rats and mice after iv administration.

Distribution, excretion, and metabolism of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitrosourea (ACNU) in healthy rats and mice or tumor-bearing mice were studied with the 14C label in each of two positions of the molecule, the ethylene and pyrimidine moieties. After iv injection of 4 mg/kg of ACNU-14C, radioactivity was distributed widely and disappeared rapidly from the body. The half-life of intact ACNU in rat plasma was about 12 minutes. In both animal species, 72%-95% of the radioactivity was excreted into urine within 24 hours. Early dissociation of renal clearance rate was observed between pyrimidine-14C and ethylene-14C, the former being more rapidly excreted than the latter. Ethylene-14C of ACNU was distributed into tumor tissues of X-5563 plasmacytoma-bearing mice, and a tumor level of radioactivity was observed to be twofold higher than the blood level at 3 hours after injection. The concentrations of several metabolites in plasma and urine were determined. Among these compounds, we found an intramolecular carbamoylating product of ACNU. These results suggest that the isocyanate derived from ACNU does not react with any biologic macromolecules, and that the chloroethyl moiety of ACNU has a very important role in the manifestation of the antitumor activity.

Animals↗