PubMed Health⌕ Search

Biomedical subjects

S Higuchi

Publications and source records attributed to S Higuchi.

At least 109 records · Page 6Linked to original sources
PubMed2000

Metabolism of 26,27-hexafluoro-1 alpha,25-dihydroxyvitamin D3 and 26,27-hexafluoro-1 alpha,23(S)25-trihydroxyvitamin D3 in ROS17/2.8 cells transfected with a plasmid expressing CYP24.

1. To clarify the possibility that the metabolism of 26,27-hexafluoro-1 alpha,25-dihydroxyvitamin D3 [F6-1,25(OH)2D3] to 26,27-hexafluoro-1 alpha,23(S),25-trihydroxyvitamin D3 [F6-1,23,25(OH)3D3 and that of F6-1,23,25(OH)3D3 to 26,27-hexafluoro-23-oxo-1 alpha,25-dihydroxyvitamin D3 [F6-23-oxo-1,25(OH)2D3] are catalysed by 25-hydroxyvitamin D3 24-hydroxylase (CYP24), ROS17/2.8 cells transfected with a plasmid expressing CYP24 [pSVL-CYP24(+)] and a corresponding blank plasmid [pSLV-CYP24R(-)] were used. 2. Incubation of [1 beta-3H]-F6-1,25(OH)2D3 for 2 and 5 days with ROS17/2.8 cells transfected with pSVL-CYP24(+) generated a metabolite that co-migrated with authentic F6-1,23,25(OH)3D3 in both normal phase and reversed-phase HPLC systems. 3. Incubation of [1 beta-3H]-F6-1,23,25(OH)3D3 for 5 days with pSVL-CYP24(+)- transfected ROS 17/2.8 cells generated a metabolite that co-migrated with authentic F6-23-oxo-1,25(OH)2D3. In contrast, the metabolites F6-1,23,25(OH)3D3 or F6-23-oxo-1,25(OH)2D3 were not generated in the cells transfected with pSVL-CYP24R(-). 4. The results indicate that CYP24 catalyses the conversion of F6-1,25(OH)2D3 to F6-1,23,25(OH)3D3 and that of F6-1,23,25(OH)3D3 to F6-23-oxo-1,25(OH)2D3.

Animals↗
PubMed2000

Identification of cytochrome P450 isoform involved in the metabolism of YM992, a novel selective serotonin re-uptake inhibitor, in human liver microsomes.

1. In vitro studies were conducted to identify the hepatic cytochrome P450 isoform involved in the metabolism of YM992, ((S)-2-[[(fluoro-4-indanyl)oxy]methyl]morpholine monohydrochloride), a novel serotonin re-uptake inhibitor, in human liver microsomes. 2. Microsomes prepared from yeast expressing CYP1A1, CYP1A2 and CYP2D6 effectively metabolized YM992. A significant correlation was observed between the rate of YM992 metabolism and 7-ethoxyresorufin O-deethylation, CYP1A1/2 specific activity, in liver microsomes from 16 individual donors (r2 = 0.628, p < 0.001). Alpha-naphtoflavone and isosafrole, CYP1A1/2 inhibitors, suppressed the metabolism of YM992 in human liver microsomes in a concentration-dependent manner. 3. The metabolism of YM992 in human liver microsomes was inhibited by approximately 95% by antibodies which recognize both CYP1A1 and CYP1A2 whereas antibodies specific for CYP1A1 did not show inhibitory effects. 4. The same major metabolites, M6 and M7, were generated from YM992 after incubation with human liver microsomes and recombinant human CYP1A2. 5. These results suggest that the metabolism of YM992 in human liver microsomes is mainly catalysed by CYP1A2, and that YM992 might increase plasma concentration of concomitant drugs metabolized by CYP1A2 due to competitive inhibition.

Benzoflavones↗
PubMed2000

Comparison of receptor-mediated endocytosis kinetics between wild-type t-PA and recombinant pamiteplase in isolated rat hepatocytes and liver cell plasma membranes.

1. Differences in receptor-mediated endocytosis kinetics between pamiteplase, an engineered t-PA, and an unmodified rt-PA were examined using liver cell plasma membranes and isolated rat hepatocytes. 2. Whereas the binding site of pamiteplase on hepatocytes was the same as that of rt-PA, the Kd of pamiteplase was 5.1-7.7 times larger than that of rt-PA, indicating a lower affinity of pamiteplase for the t-PA receptor. 3. ke for pamiteplase measured using parenchymal cells or non-parenchymal cells was slightly smaller than that for rt-PA, whereas kon for pamiteplase were much lower than that of rt-PA, suggesting that the interaction between pamiteplase and the receptor is slower than that of rt-PA because of its structural modification. 4. Therefore, the difference in drug disposition between pamiteplase and rt-PA is mainly due to the difference in the hepatic clearance caused by a change in the interaction rate between the ligand and its cell-surface receptor.

Animals↗
PubMed2000

Determination, pharmacokinetics and protein binding of a novel tissue-type plasminogen activator, pamiteplase in human plasma.

1. An enzyme-linked immunosorbent assay (ELISA) and functional bioassay to determine immunoreactive and bioactive concentrations of pamiteplase, a novel thrombolytic agent, in human plasma were developed. The ELISA and functional bioassay showed satisfactory accuracy and precision within a concentration range of 0.5-25 ng.ml(-1) and of 0.127-16.2 ng.ml(-1) respectively. 2. The pharmacokinetics of pamiteplase in healthy human subjects were evaluated using the ELISA and functional bioassay. Irrespective of the method used, plasma concentrations declined bi-exponentially. Half-lives in the beta phase were 1.25 and 0.78 h, and AUCs were 507.9 and 286.4 ng.h.ml(-1) respectively. Total clearances of pamiteplase decreased to 19 and 31% of those of the wild-type tissue-type plasminogen activator. 3. The protein binding of pamiteplase in human plasma was investigated by gel filtration chromatography. Pamiteplase formed three high molecular weight complexes with alpha2-macroglobulin, C1-esterase inhibitor and alpha2-plasmin inhibitor in human plasma. This complex formation was relatively slow, and was thought to be irreversible and covalently bounded. Furthermore, this protein binding in humans resulted in the termination of biological action.

Adult↗
PubMed2000

Diurnal variation in the P300 component of human cognitive event-related potential.

Diurnal variation in the P300 component of the human cognitive event-related potential (ERP) was examined. The P300 component is considered to be a measure of neuroelectric activity related to cognitive functions such as attention allocation and information processing. Nine diurnally active healthy male subjects whose sleep-wake rhythms were synchronized prior to the experiment were studied. The P300 components oral temperature, heart rate, left- and right-hand grip strength, reaction time, subjectively rated sleepiness, attention level, and fatigue were measured at 08:00, 11:00, 14:00, 17:00, and 20:00. Significant diurnal variations in P300 latency, P300 amplitude, oral temperature, heart rate, left- and right-hand grip strength, subjectively rated sleepiness, and attention level were observed. The P300 latency at 08:00 was significantly longer than at 11:00, 17:00, and 20:00, while the P300 amplitude at 08:00 was significantly greater than at 17:00 and 20:00. The P300 latency was correlated positively with subjectively rated sleepiness and negatively correlated with subjectively rated attention level. These results suggest the existence of diurnal variation in human cognitive functions.

Adult↗
PubMed2000

Circadian rhythm abnormalities of wrist activity of institutionalized dependent elderly persons with dementia.

BACKGROUND: The study objective was to clarify the descriptive characteristics of circadian rhythm abnormalities of wrist activity of the institutionalized elderly with dementia. METHODS: We studied 82 elderly persons with dementia who were institutionalized in a long-term medical care facility. The ambulatory continuous monitoring of their wrist activity was conducted for 7 days at 1-minute intervals. The time series data were analyzed using the double-plotted chronogram, spectral analysis was performed using the fast Fourier transformation and periodogram analysis was performed as well. RESULTS: The frequency of circadian rhythm abnormalities of wrist activity rhythm in elderly persons with dementia was 57.3% (47 out of 82). The abnormalities were classified into four categories: severely impaired circadian rhythm type with no boundary between day and night, free-running rhythm type, decreased circadian amplitude type, and accentuation of ultradian rhythm type. CONCLUSION: This four-category classification system provides a scientific approach for studying the mechanisms of circadian activity rhythm abnormalities of elderly persons with dementia.

Activity Cycles↗
PubMed2000

Epidemiologic investigation of the relative clearance of haloperidol by mixed-effect modeling using routine clinical pharmacokinetic data in Japanese patients.

The steady-state trough concentrations of haloperidol were studied to clarify the role of the characteristics of Japanese patients in estimating haloperidol dosing regimens by using routine therapeutic drug-monitoring data. Nonlinear mixed-effects modeling (NONMEM) was used to estimate the effect of a variety of developmental and demographic factors on haloperidol clearance values using 270 serum level measurements obtained from 191 patients during their clinical course. The final model describing haloperidol's relative clearance was CL = 0.74 x TBW(0.594) x DOSE(0.326) x 1.32CO1 x 0.867AGE, where CL is clearance (measured in liters per hour), TBW is the total body weight (in kilograms), DOSE is the daily dose of haloperidol (in grams per kilogram per day), CO1 = 1 for concomitant administration of antiepileptic drugs (phenobarbital, phenytoin, or carbamazepine) and CO1 = 0 otherwise, and AGE = 1 for patients aged 55 years or older and AGE = 0 otherwise. Concomitant administration of haloperidol and antiepileptic drugs resulted in a 32% increase in haloperidol clearance. Patients aged 55 years or older showed a 13.3% reduction in clearance values compared with the younger population.

Adolescent↗
PubMed2000

Genetic polymorphism of the CYP2C subfamily and excessive serum phenytoin concentration with central nervous system intoxication.

The authors report on a Japanese adult male patient with a long history of partial seizures that were poorly controlled by conventional doses of phenytoin and other drugs. His treatment was complicated by toxic symptoms and an excessive serum phenytoin concentration, 32.6 microg/mL at a dose of 187.5 mg/day. Polymerase chain reaction-restriction fragment length polymorphism analysis disclosed heterozygosity involving cytochrome P450 subfamilies 2C9 (*1/*3) and 2C19 (*1/*3). Currently, it is generally accepted that the former mutation is responsible for the CYP2C9 poor metabolizer phenotype. Pharmacokinetic parameters were estimated by a kinetic analysis, MULTI, using 17 observed dose-concentration data sets: a lower Vmax (5.6 mg/kg/day) and a higher Km (11.5 microg/mL) were observed. Although phenytoin is metabolized predominantly by CYP2C9 with a minor contribution of CYP2C19, patients with the Leu359 variant should be monitored closely when treated with a moderate to high daily dose of phenytoin.

Adult↗
PubMed2000

Catalytic activity of three variants (Ile, Leu, and Thr) at amino acid residue 359 in human CYP2C9 gene and simultaneous detection using single-strand conformation polymorphism analysis.

This study evaluated the catalytic activity of three variants (Ile, Leu, and Thr) at codon 359 of CYP2C9 enzymes expressed in a yeast cDNA expression system, and then established single-strand conformation polymorphism (PCR-SSCP) analysis for simultaneous detection as a screening method. Diclofenac was used for the in vitro experiment, and its hydroxy metabolite (4'-hydroxydiclofenac) was measured by HPLC. To discuss the in vivo effect of the Thr359 variant on the pharmacokinetics of phenytoin, a case report is presented. The efficiency of the SSCP method was evaluated by analyzing DNA samples from a homozygote for Ile359 and a heterozygote for Leu359 or Thr359. To evaluate the interaction between the P450 level and reductase activity, two batches of the Thr359 variant with a different P450:reductase activity ratio (1:4.0 and 1:1.4) were used. The in vitro study revealed that recombinant Ile359, Leu359, and Thr359 (2 batches) possessed a mean Km of 2.0, 16.5 and (3.8 and 2.9) micromol and Vmax of 12.4, 17.9 and (4.4 and 5.1) nmol/min/nmol P450, respectively. Although the magnitude of the change in catalytic efficiency for the Thr359 variant was close to that of the Leu359 variant, the effect of the two variants on diclofenac 4'-hydroxylation appears to be different because Leu359 variant was associated with a high Km, and Thr359 with a low Vmax. No significant differences in the kinetic data were observed between the two Thr359 enzymes, suggesting that low reductase activity in the Thr359 enzyme was not a major determinant in the present in vitro experiment. Estimated pharmacokinetic parameters of phenytoin obtained by the Bayesian method in an epileptic patient who was a heterozygote carrier for Thr359 variant were: Km = 6.45 microg/mL, Vmax = 5.77 mg/kg/d, and Vmax/Km = 0.89 L/kg/day. The Vmax/Km value in this patient was similar to the population mean value (0.90 L/kg/day) in Japanese heterozygotes for the Leu359 variant. Results for PCR-SSCP were in complete agreement with those obtained using established methods. Thus, the PCR-SSCP approach is useful for identifying these three variants of the CYP2C9 gene.

Adult↗
PubMed2000

Pharmacokinetic interactions among phenobarbital, carbamazepine, and valproic acid in pediatric Japanese patients: clinical considerations on steady-state serum concentration-dose ratios.

With antiepileptic drugs, the marked inter- and intrapatient variability of the concentration-dose ratio makes it difficult to predict serum concentrations from the dose administered per kilogram. The effects of comedication on steady-state serum concentration/dose ratios of antiepileptic drugs were evaluated retrospectively in 669 pediatric patients. To avoid complex pharmacokinetic interactions among multiple antiepileptic drugs, the data on serum concentrations in the current study were collected from patients who were co-administered only one additional antiepileptic drug (phenobarbital-carbamazepine, phenobarbital-valproic acid, or carbamazepine-valproic acid) or who received monotherapy. The concentration/dose ratio for the antiepileptic drugs increased significantly with body weight in children up to 15 years old. Associated therapy with antiepileptic drugs affected the concentration/dose ratio. Therefore, routine monitoring of serum concentrations of the antiepileptic drugs is extremely useful, particularly in children and in patients who require associated antiepileptic medication.

Adolescent↗
PubMed2000

Effects of dosing time and schedule on cisplatin-induced nephrotoxicity in rats.

Renal dysfunction induced by a single injection of cisplatin depends on the timing of the dose. However, the effects of repeated administration of cisplatin on time-dependent toxicity have not been evaluated despite the fact that in clinical practice high doses are repeatedly injected at intervals or low doses are administered daily. We studied chrononephrotoxicity in rats after weekly or daily cisplatin injections. Weekly high doses (5 mg kg(-1)) or daily low doses (1.2 mg kg(-1)) of cisplatin were injected at four time points (3, 9, 15 and 21 h after the light was turned on (HALO)) for 3 weeks. Changes in body weight after weekly cisplatin administration were independent of the timing of the doses. In the group that received daily cisplatin, the loss in body weight in the 3 HALO group was smaller than in animals receiving injections at 15 and 21 HALO (P < 0.05 and 0.001, respectively). The blood urea nitrogen and serum creatinine levels in the control rats showed a significant circadian change (peak at 15 HALO and trough at 9 HALO), but these parameters were markedly elevated in both trials and their circadian variations were disturbed. In conclusion, cisplatin-induced nephrotoxicity was the lowest at 3HALO compared with other time points of both dose regimens.

Animals↗
PubMed2000

Time-dependent nephrotoxicity associated with daily administration of cisplatin in mice.

The chronopharmacokinetics and chronopharmacodynamics of cisplatin were studied in a mouse model to reveal the mechanisms of dosing time-dependent nephrotoxicity induced by daily administration. Chronotoxicity was tested by daily intraperitoneal injections of cisplatin (6mg kg(-1)) for 5 days at four time points (04:00, 10:00, 16:00 and 22:00h) in BALB/c mice (n = 6 in each group). After following the changes in body weight, serum concentrations of blood urea nitrogen (BUN) and creatinine obtained on day 6 were compared. The results showed diurnal variations in cisplatin toxicity, with the 04:00 and 16:00h time points the best and the worst, respectively. We then measured platinum concentrations in blood, liver and kidney and compared the results of the 04:00 and 16:00 h groups (n = 4 in each group). Kidney sensitivity to cisplatin alone, lipopolysaccharide (LPS) alone, cisplatin with LPS and saline (control) were also measured using a tissue culture system (a measurement system of interleukin-6 (IL-6) production) between the 04:00 and the 16:00 h groups (n = 4 in each group). These results showed no significant difference in platinum accumulation between the two groups. IL-6 production was higher in the 16:00 h group than in the 04:00 h group after saline injection alone (P < 0.05). Cisplatin treatment alone did not increase IL-6 production. However, IL-6 levels were markedly augmented by cisplatin with LPS. In conclusion, chrononephrotoxicity induced by daily cisplatin administration does not only depend on cisplatin accumulation, but might also depend on kidney sensitivity to diurnal variations in inflammatory reaction without direct cisplatin toxicity.

Animals↗
PubMed2000

Characterization of microsomal alcohol oxygenase catalyzing the oxidation of 7-hydroxy-delta 8-tetrahydrocannabinol to 7-oxo-delta 8-tetrahydrocannabinol in rat liver.

The formation of 7-oxo-delta8-tetrahydrocannabinol (7-oxo-delta8-THC) from 7beta-hydroxy-delta8-THC was found in hepatic microsomes of rats. The activity was stereoselective and about 3-fold higher than that from 7alpha-hydroxy-delta8-THC. The oxidative activity of 7alpha- and 7beta-hydroxy-delta8-THC to 7-oxo-delta8-THC was significantly higher in male than in female, and significantly enhanced by both dexamethasone and phenobarbital, and then inhibited up to about 20% of the control value by antibody against P450GPF-B, presumably a member of the 3A subfamily, a major enzyme responsible for the formation of 7-oxo-delta8-THC in guinea pigs. This antibody also inhibited the formation of 7alpha- and 7beta-hydroxy-delta8-THC, and 7-oxo-delta8-THC from delta8-THC by hepatic microsomes of rats. These results indicate that there is a sex-related difference in the oxidation of 7-hydroxy-delta8-THC to 7-oxo-delta8-THC and the reaction is mainly catalyzed by P450 enzyme(s) belonging to the 3A subfamily as major enzyme(s) of microsomal alcohol oxygenase in rats.

Animals↗
PubMed2000

Evaluation of intracranial pressure by transcranial Doppler ultrasonography in dogs with intracranial hypertension.

Transcranial Doppler ultrasonography (TCD) has been used to confirm changes in cerebral hemodynamics. In this study, we investigated whether the parameters for the basilar artery measured by TCD were correlated with the intracranial and cerebral perfusion pressures in extreme intracranial hypertension. An intracranial hypertension model was produced in seven dogs by inflating a balloon inserted into the epidural space. The resistance index was compared with the corresponding intracranial pressure and cerebral perfusion pressure values during intracranial hypertension. A significant correlation was recognized between the resistance index and cerebral perfusion pressure. Therefore, measurement of the basilar artery by TCD in the dog with intracranial hypertension is useful in estimating the intracranial circulation in cases where the measurement of intracranial pressure is not available or not indicated.

Animals↗
PubMed2000

Purification of bovine urinary beta2-microglobulin and its biochemical characteristics.

In this study, bovine beta2-m was purified from urine by ion-exchange chromatography and gel chromatography, and the characteristics were compared with those of colostral beta2-m by the immunological reactivity, isoelectric points, peptide map, and amino acid sequence. The characteristics of purified urinary beta2-m were consistent with those of the colostral beta2-m. The urinary and colostral beta2-m possessed the same polypeptide chain consisting of 98 amino acids, and its molecular weight is 11.8 kDa. Furthermore, four isoforms of beta2-m were found. The isoelectric points were different from each other.

Amino Acid Sequence↗
PubMed2000

Time-of-day effects of ethanol consumption on EEG topography and cognitive event-related potential in adult males.

Time-of-day effects of ethanol consumption on EEG topography and cognitive event-related potential in adult males were studied. Ethanol (0.5 g/kg) or control drink was orally administered to nine healthy males at 10:00 and 18:00. The alpha 2 amplitude was significantly lower than that of the control at 0.5, 2.5 and 4.5 hours after ethanol consumption in the morning. These effects were observed in the left hemisphere and were only found after consumption in the morning. The subjectively rated attention was significantly lower than that of the control at 0.5 and 2.5 hours after ethanol consumption in the morning and at 0.5 hours after ethanol consumption in the evening. In contrast, the search speed of serial search task and P300 amplitude was significantly lower than that of the control at 2.5 hours after ethanol consumption in the evening. These results demonstrate that effects of ethanol are dependent on time-of-day of consumption. Ethanol consumption significantly lowered the alpha 2 amplitude when consumed in the morning, and lowered P300 amplitude when consumed in the evening.

Adult↗
PubMed2000

Reliability and validity of the questionnaire to determine the biosocial rhythms of daily living in the disabled elderly.

The questionnaire to determine the biosocial rhythms of daily living in the disabled elderly was newly developed. This questionnaire was aimed to evaluate a state of synchronization of biological rhythms in the disabled elderly. Eighteen items of the questionnaire relating to the synchronization of biological rhythms were finally selected by the test-retest method that was conducted for 68 disabled elderly living in a community with a duration of one year. The factor analysis showed that the questionnaire consisted of five factors: outdoor activities, ultradian rhythms, subjective evaluation of health status, social support, and sleep habits. The cumulative contribution rate of five factors was 53.2%. Reliability of the questionnaire was confirmed by a calculation of the Equal-length Spearman-Brown coefficients ranging from 0.60 to 0.80. Regarding the construct validity of the questionnaire, results of factor analysis showed five factors that were consistent with the synchronizers known in chronobiology. The total score of the questionnaire was significantly correlated to Barthel Index score and the competence score, suggesting that it partly reflects the activities of daily living of the disabled elderly. We conclude that a new questionnaire to determine the biosocial rhythm of daily living in the disabled elderly is useful to evaluate the biosocial synchronization of the disabled elderly because of its high reliability and validity.

Activities of Daily Living↗