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Y Sawada

Publications and source records attributed to Y Sawada.

At least 91 records · Page 5Linked to original sources
PubMed2000

Pharmacokinetic analysis of felodipine-grapefruit juice interaction based on an irreversible enzyme inhibition model.

UNLABELLED: Aims Ingestion of grapefruit juice (GFJ) alters the pharmacokinetics of various orally administered drugs. Quantitative evaluation of this GFJ-drug interaction is required for the proper clinical management of patients. Methods Using felodipine as a model drug, we constructed a pharmacokinetic model based on irreversible inhibition of intestinal cytochrome P450 3A4 (CYP3A4) by GFJ. We fitted previously published data [5, 6] for felodipine ER (extended release formulation) to the ratio of CLGI,int before and after grapefruit juice ingestion by nonlinear least-squares regression analysis to estimate the reaction rate constant between GFJ and CYP3A4 (K) and the elimination rate constant of CYP3A4 (k ). RESULTS: The model gave a turnover rate of CYP3A4 of 0.0849 h-1, corresponding to a half-life of 8.16 h, in agreement with reported values. The AUC-time profiles of felodipine ER in the case of different amounts and schedules of GFJ ingestion were simulated using the parameter values estimated from the model. CONCLUSIONS: The modelling leads to the important conclusion that GFJ-felodipine interaction increases with increasing frequency and amount of GFJ ingestion, and that an interval of 2-3 days between GFJ intake and felodipine administration is necessary if GFJ-felodipine interaction is to be avoided.

Adult↗
PubMed2000

Rapid patterning in 2-D cultures of Dictyostelium cells and its relationship to zonal differentiation.

Rapid patterning has been observed in confined 2-D cultures of Dictyostelium discoideum Ax-2 cells as an outer dark zone and a inner light zone. The width of outer zone was usually approximately100 microm, irrespective of the size of cell masses under atmospheric conditions. The width of the outer zone, however, changed depending on external O2 concentrations and reached up to 250 microm at 100% O2. A clear regional difference in tetramethyl rhodamine methyl ester (TMRM) staining was noticed between the outer zone and the inner zone: the inner zone was more strongly stained with TMRM than the outer zone, which faced the air. Using inhibitors of oxidative phosphorylation (dinitrophenol (DNP) or NaN3) and a specific inhibitor of CN-resistant respiration (benzohydroxamic acid (BHAM)), it has been demonstrated that the outer zone is basically formed by the O2 threshold for oxidative phosphorylation, while the inner cells mainly perform cyanide-resistant respiration. When cells around the early mound stage (just before prestalk and prespore differentiation) were cultured as 2-D cell masses, ecmA-expressing cells (pstA cells), ecmB-expressing cells (pstB cells) and D19-expressing cells (prespore; psp cells), arose in a position-dependent manner in the outer zone. In the inner zone, cell motility seemed to be markedly impaired and neither prestalk nor prespore differentiation occurred. In addition, once-differentiated prespore cells were found to dedifferentiate rapidly in the inner zone. The reason for dedifferentiation as well as for failure of cells to differentiate in the inner zone is discussed with reference to O2 radicals.

Animals↗
PubMed2000

Relationship between time after intake of grapefruit juice and the effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy subjects.

A clinical study was performed in eight healthy volunteers to investigate the effect of various timing of grapefruit juice intake on nisoldipine pharmacokinetics and pharmacodynamics, and to validate our pharmacokinetic model. The subjects were given 10 mg oral nisoldipine with water (control), or 5 mg oral nisoldipine with 200 mL grapefruit juice (G0) or with water at 14 (G14), 38 (G38), 72 (G72) or 96 hours (G96) after a 7-day period of thrice-daily intake of grapefruit juice. Grapefruit juice ingestion did not affect heart rate or the effect area during the first 8 hours of heart rate after nisoldipine administration, although significant decreases of systolic and diastolic blood pressure were caused in G0 by coadministration of grapefruit juice with nisoldipine. Headaches were reported by 3, 2, and 1 persons in G0, G14, and G38, respectively, but no subjects in G72 and G96 reported headaches. Compared with the control group, the maximum plasma concentration of nisoldipine was significantly increased after grapefruit juice intake in G0 and G14, and the plasma concentration was significantly increased at each time in G0 to G72. Therefore the effect of grapefruit juice decreased time dependently and lasted for at least 3 days after intake. Furthermore, our model gave predicted values in good agreement with the observed values. It is therefore necessary to withhold grapefruit juice for at least 3 days before administration of the drug to prevent grapefruit juice-nisoldipine interaction.

Adult↗
PubMed2000

Correlating the severity of paraquat poisoning with specific hemodynamic and oxygen metabolism variables.

OBJECTIVE: To investigate the hemodynamics and oxygen metabolism of patients with varying degrees of severity of paraquat poisoning. DESIGN: Prospective, observational, clinical study. SETTING: Intensive care unit in a university hospital. PATIENTS: Forty-three consecutive patients with paraquat and/or diquat poisoning were classified into three groups by the severity index of paraquat poisoning (SIPP; hr/mg/L). INTERVENTIONS: Standard treatments included specific respiratory management, fluid resuscitation, and aggressive circulatory support. MEASUREMENTS AND MAIN RESULTS: Serum paraquat and diquat levels were measured at arrival, and SIPP was calculated. The cardiac index (CI), left ventricular stroke work index (LVSWI), systemic vascular resistance index (SVRI), oxygen delivery index (DO2I), oxygen consumption index (VO2I), and oxygen extraction ratio (O2ER) were measured at 6, 12, 24, 36, 48, 72, and 96 hrs postadmission. A significant inverse correlation between SIPP and survival time was found in 31 fatal cases (r = .85; p < .001). In the SIPP 10-50 group, CI, DO2I, VO2I, and O2ER were maintained at higher levels than in the SIPP group of <10 (p < .05), whereas SVRI decreased significantly (p < .05). In the SIPP group of >50, CI, LVSWI, SVRI, DO2I, and VO2I decreased, whereas O2ER had a tendency to increase progressively. There was a significant correlation between SVRI and SIPP, O2ER and SIPP, and O2ER and SVRI 24 hrs after admission, respectively (p < .001). CONCLUSIONS: Paraquat poisoning is characterized by high oxygen consumption with high oxygen extraction, with the degree of derangement based on the severity index. The development of a marked imbalance between increased oxygen demand and decreased oxygen supply because of myocardial depression might be a possible cause of death in circulatory failure.

Adolescent↗
PubMed2000

Thallium-201 myocardial SPET in patients with collagen disease.

We analysed stress 201Tl myocardial single photon emission tomography (SPET) in collagen disease patients to evaluate abnormal uptake patterns and their clinical significance in the assessment of the cardiac status of these patients. The main purpose of the study was to evaluate the clinical significance of reverse redistribution. Twenty-two collagen disease patients (13 with progressive systemic sclerosis (PSS) and nine with systemic lupus erythematosus (SLE)) were examined by 201Tl myocardial SPET with exercise (n = 9) or dipyridamole stress (n = 13). For quantitative analysis, each 201Tl SPET polar map was divided into 17 segments, and the 201Tl uptake pattern of each segment was classified into four types. Eighteen (82%) of the patients showed abnormal findings on 201Tl SPET. Of the 374 segments analysed, 295 (79%) were classified as normal, 16 (4%) as reverse redistribution, 49 (13%) as reversible defect and 14 (4%) as fixed defect. Patients were divided into two groups: those with cardiac abnormalities on conventional testing (Group A, n = 10) and those without (Group B, n = 12). The incidences of fixed defect, reversible defect and reverse redistribution were significantly higher (P <0.01, P <0.0005, P <0.05, respectively) in Group A than in Group B. Nine (90%) of the patients in Group A and nine (75%) in Group B showed abnormal findings. No significant difference was found between the PSS and SLE patients in the incidence of the individual uptake patterns. Stress 201Tl myocardial SPET appears to be an effective method of evaluating a wide spectrum of myocardial involvement in collagen disease patients and in assessing their clinical cardiac status. Reverse redistribution is found to be a significant finding in collagen disease patients.

Adolescent↗
PubMed2000

Nasal reconstruction based on aesthetic subunits in Orientals.

Reconstruction based on the aesthetic subunit principle has yielded good aesthetic outcomes in patients with moderate to severe nasal defects caused by trauma or tumor resection. However, the topographic subunits previously proposed are often unsuitable for Orientals. Compared with the nose in white patients, the nose in Orientals is low, lacks nasal muscle, and has a flat glabella; the structural features of the underlying cartilage and bone are not distinctly reflected in outward appearance. The authors devised aesthetic subunits suitable for Orientals, and they used these units to reconstruct various parts of the nose. The major difference between these units and those presented previously is the lack of soft triangles and the addition of the glabella as an independent unit. The authors divided the nose into the following five topographic units: the glabella, the nasal dorsum, the nasal tip, and the two alae. The border of the nasal dorsum unit was extended to above the maxillonasal suture. The basic reconstruction techniques use a V-Y advancement flap from the forehead to reconstruct the glabella, an island flap from the forehead to reconstruct the nasal dorsum and nasal tip, a nasolabial flap to reconstruct an ala, and a malar flap to reconstruct the cheek. A combination of flaps was used when the defect involved more than one unit. This concept was used for nasal reconstruction in 24 patients. In one patient undergoing reconstruction of the nasal dorsum and in one undergoing reconstruction of the nasal tip, the texture of the forearm flap did not match well, which resulted in a slightly unsatisfactory aesthetic outcome. In one patient in whom the glabella, nasal dorsum, and part of the cheek were reconstructed simultaneously, a web was formed at the medial ocular angle, and a secondary operation was subsequently performed using Z-plasty. In one patient undergoing reconstruction with a forehead flap, defatting was required to reduce the bulk of the subcutaneous flap pedicle at the glabella. However, suture lines were placed in the most inconspicuous sites in all patients, and the use of a trapdoor contraction emphasized the three-dimensional appearance of the nose. The use of these aesthetic subunits for reconstruction offers several advantages, particularly in Oriental patients. Because the nasal dorsum is reconstructed together with the side walls, tenting of the nasal dorsum is avoided, which prevents a flat appearance of the nose. A forehead flap is useful in the repair of complex defects. Defects of the alae should be separately reconstructed with a nasolabial flap to enhance the effect of the trapdoor contraction and to highlight the three-dimensional appearance of the nose. Candidates for reconstruction should be selected on the basis of nasal structure. The results suggest that these units can also be used in some white patients.

Adult↗
PubMed2000

Invariant power law distribution of langevin systems with colored multiplicative noise

The random multiplicative process is studied for the case of a colored multiplicative noise with exponentially decreasing autocorrelation function. We observe the power law exponent of probability distribution in a statistically steady state numerically to clarify the effect of finite correlation time. The renormalization procedure is applied to derive the power law exponent theoretically. The power law exponent is inversely proportional to the autocorrelation time of the multiplicative noise.

Journal Article↗
PubMed2000

Learning-induced synchronization of a globally coupled excitable map system.

We propose a pulse-coupled neural network model in which one-dimensional excitable maps connected in a time-delayed network serve as the neural processing units. Although the individual processing unit has simple dynamical properties, the network exhibits collective chaos in the active states. Introducing a Hebbian learning algorithm for synaptic connections enhances the synchronization of excitation timing of the units within a subpopulation. The synchronizing clusters approximately exhibit a power-law size distribution, suggesting a hierarchy of synchronization. After applying a stationary signal to a subpopulation of the units with learning, the network then reproduces the signal. The learnable time range is much longer than the inherent time scale of the processing units, i.e., the synaptic delay time. Also, the network can reproduce periodic signals with time resolution finer than the delay time. Our present network model can be considered as a temporal association device which operates in chaotic states.

Animals↗
PubMed2000

Comparative pharmacodynamic analysis of Q-T interval prolongation induced by the macrolides clarithromycin, roxithromycin, and azithromycin in rats.

In order to evaluate the arrhythmogenic potency of macrolide antibiotics in a quantitative manner, we analyzed the influence of clarithromycin (CAM), roxithromycin (RXM), and azithromycin (AZM) on Q-T intervals from pharmacokinetic and pharmacodynamic points of view and in comparison with the potency of erythromycin (EM) previously reported by us for rats. Male Sprague-Dawley rats were anesthetized, and CAM (6.6, 21.6, and 43.2 mg/kg of body weight/h), RXM (20 and 40 mg/kg/h), and AZM (40 and 100 mg/kg/h) were intravenously injected for 90 min to obtain the time courses of drug concentrations in plasma and the changes in the Q-T intervals during and after the drug injections. Distinct Q-T interval prolongation of up to 10 ms was observed with CAM at its clinical concentrations. RXM and AZM evoked Q-T interval prolongation at concentrations higher than their clinical ranges. The potencies for Q-T interval prolongation, assessed as the slope of the concentration-response relationship, were 6.09, 0.536, and 0.989 ms. ml/microg for CAM, RXM, and AZM, respectively. There was hysteresis between the change in the Q-T intervals and the time course of the plasma concentration of each drug. The rank order of clinical arrhythmogenicity was estimated to be EM > CAM > RXM > AZM, as assessed from the present results and our previous report for EM. In conclusion, RXM and AZM were estimated to be less potent at provoking arrhythmia than EM and CAM. These results should be useful for making a safer choice of an appropriate agent for patients with electrocardiographic risk factors.

Algorithms↗
PubMed2000

Comparison of blood-brain barrier permeability in mice and rats using in situ brain perfusion technique.

Here we present a method for measuring the permeability coefficient-surface area product (PS) values at the blood-brain barrier in mice, using the in situ brain perfusion technique originally developed for rats by Takasato et al. (Am J Physiol Heart Circ Physiol 247: H484-H493, 1984). Retrograde infusion into the right external carotid artery increased the carotid perfusion pressure in proportion to the perfusion rate. Intravascular volume and cerebral perfusion fluid flow at a perfusion rate of 1.0 ml/min in mice were similar to those in rats. In addition, the contribution of systemic blood to total flow in the hemisphere was small (only 3. 2%). These findings indicated that this perfusion rate is suitable for mice. The PS values of more than 20 different compounds were determined in mice by using the in situ brain perfusion technique, and comparisons were made with data from rats. There was a close relationship (1:1) between the PS values in mice and rats, indicating that brain capillary permeabilities are similar in mice and rats.

Animals↗
PubMed2000

New scheme of the biosynthesis of formononetin involving 2,7,4'-trihydroxyisoflavanone but not daidzein as the methyl acceptor.

Glycyrrhiza echinata cell-free extract produced isoformononetin by the 7-O-transmethylation of daidzein from S-adenosyl-L-methionine (SAM). When the yeast microsome expressing 2-hydroxyisoflavanone synthase was mixed with the cell-free extract and incubated with liquiritigenin and SAM, formononetin emerged. Furthermore, the cell-free extract yielded formononetin on incubation with 2,7,4'-trihydroxyisoflavanone and SAM. We propose a novel pathway of formononetin biosynthesis involving 2,7,4'-trihydroxyisoflavanone as the methyl acceptor.

Cell-Free System↗
PubMed2000

Efficient introduction of macromolecules and oligonucleotides into brain capillary endothelial cells using HVJ-liposomes.

In this study, we examined the feasibility of introducing macromolecules into cultured mouse brain capillary endothelial cells (MBEC4 cells) by utilizing the hemagglutating virus of Japan (HVJ)-liposomes with fusogenic activity. We used fluorescein isothiocyanate dextran (FITC-Dextran) and FITC-labeled oligodeoxynucleotide (FITC-ODN) as models of a macromolecule and an ODN, respectively. Intracellular fluorescence appeared rapidly after the exposure of MBEC4 cells to FITC-Dextran-containing HVJ-liposomes, and remained detectable for at least 3 days. Only a control level of intracellular fluorescence was seen after treatment with FITC-Dextran alone, FITC-Dextran with empty HVJ-liposomes or FITC-Dextran-containing liposomes without fusogenic activity. In the early phase after administration (0-30 min), the introduction of FITC-Dextran into MBEC4 cells by the HVJ-liposome method resulted in a rapid and time-dependent increase of intracellular fluorescence intensity. Moreover, FITC-ODN was also introduced into MBEC4 cells by the HVJ-liposome method, although FITC-ODN alone was not introduced. These results indicate that the HVJ-liposome method is useful for the efficient introduction of macromolecules, including ODN, into brain capillary endothelial cells.

Animals↗
PubMed2000

Quantitative prediction of metabolic inhibition of midazolam by erythromycin, diltiazem, and verapamil in rats: implication of concentrative uptake of inhibitors into liver.

To evaluate the degree of drug-drug interaction concerning metabolic inhibition in the liver quantitatively, we tried to predict the plasma concentration increasing ratio (R) of midazolam (MDZ) by erythromycin (EM), diltiazem (DLZ), or verapamil (VER) in rats. MDZ was administered through the portal vein at the steady state of plasma concentration of these inhibitors. The R values in the area under the plasma concentration curve of MDZ in the presence of EM, DLZ, and VER were 2.02, 1.64, and 1.30, respectively. The liver to plasma unbound concentration ratios of EM, DLZ, and VER at the steady state after infusion were 20.8, 1.02, and 3.01, respectively, suggesting concentrative uptake of EM and VER into the liver. The predicted R value in the presence of EM calculated by use of plasma unbound concentration was 1.03, whereas the value calculated with liver unbound concentration was 1.61, which was very close to the observed value. These findings indicated the need to consider the concentrative uptake of inhibitors into the liver for the quantitative prediction of metabolic inhibition. However, the predicted values in the presence of DLZ or VER calculated by use of liver unbound concentration were still underestimated. This result may be due to the metabolic inhibition by the metabolites of both inhibitors. Therefore, when predicting the degree of metabolic inhibition quantitatively, the inhibitory effect by coadministered drugs and the disposition of these metabolites in the liver must also be considered.

Animals↗
PubMed2000

Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P450 3A4.

The presence in orange juice of compounds that specifically inhibit the P-glycoprotein (P-gp) drug efflux transporter, but not the cytochrome P450 (CYP) isozyme CYP3A4, was investigated. The uptake of [(3)H]vinblastine, a substrate of P-gp, by Caco-2 cells was measured. An ethyl acetate extract of orange juice did not affect the initial uptake rate of [(3)H]vinblastine but significantly increased the steady-state uptake, as did cyclosporin A (20 microM), an inhibitor of P-gp. No significant effect on the uptake of 3-O-[(3)H]methylglucose or [(14)C]phenylalanine by Caco-2 cells was found, compared with the control. When the extract was separated on a Cosmosil column, the eluate with 70% methanol showed the most potent ability to increase [(3)H]vinblastine uptake. Additional separation of the 70% methanol eluate on a silica gel column with hexane-acetone (3:1) gave 3,3',4',5,6,7,8-heptamethoxyflavone (HMF) and 4',5,6,7,8-pentamethoxyflavone (tangeretin). HMF, tangeretin, and 3',4',5,6,7,8-hexamethoxyflavone (nobiletin), another methoxyflavone contained in orange juice, all increased the steady-state uptake of [(3)H]vinblastine by Caco-2 cells in a concentration-dependent manner. The order of potency of these compounds at the concentration of 50 microM was tangeretin > HMF > nobiletin. None of these methoxyflavones inhibited 6beta-hydroxylation of testosterone catalyzed by CYP3A4. The ethyl acetate extract of orange juice and these methoxyflavones also increased steady-state [(3)H]vinblastine uptake by LLC-GA5-COL300 cells (a cell line transfected with human MDR1 cDNA). We conclude that these methoxyflavones enhanced vinblastine uptake by specifically inhibiting drug efflux via P-gp. They may have potential as agents for reversing multidrug resistance or for recovering the bioavailability of certain drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Experiential assessment of endoventricular circular patch plasty in patients with depressed left ventricular function due to ischemia.

UNLABELLED: A concept of volume reduction surgery for patients with end-stage dilated cardiomyopathy was introduced to the surgical aspect. We started consequently to employ this operation for patients with ischemic cadiomyopathy. Between October 1997 and April 1999, 14 patients (mean age 64 years; 12 men, 2 women) underwent endoventricular circular patch plasty (EVCPP) in our institute. TECHNIQUE: The left ventricle (LV) is opened by placing an incision parallel to the left anterior descending (LAD) coronary artery. An endocardial purse-string suture is placed circumferentially at the root of the posterior papillary muscle. The remaining opening of the cavity is closed with a circular bovine pericardial patch. The excluded edges of LV free wall and septum are directly closed with felt strips. RESULTS: There were no significant hemodynamic differences in heart rate, cardiac index and pulmonary capillary wedge pressure before and after the operation. Either LV end-diastolic volume index (from 134.8 +/- 30.7 to 77.1 +/- 16.3 ml/m2) or LV end-systolic volume index (from 85.0 +/- 21.8 to 40.0 +/- 12.5 ml/m2) definitely reduced postoperatively, the LV ejection fraction (EF), consequently, significantly improved from 0.31 +/- 0. 09 to 0.48 +/- 0.10 (p=0.0007). In all patients the New York Heart Association (NYHA) functional class improved from 2.8 +/- 0.7 to 1.3 +/- 0.5 after operation. We will aggressively employ this procedure for patients with ischemic cardiomyopathy in consideration of the limitations of the efficacy and the indication of this operation.

Aged↗
PubMed2000

[Successive myocardial fatty acid metabolic imaging in patients with dilated cardiomyopathy: usefulness as a prognostic indicator].

To evaluate the prognostic value of fatty acid metabolic imaging in patients with idiopathic dilated cardiomyopathy (DCM), we performed myocardial imaging with 123I-BMIPP (BMIPP). We studied 23 patients with DCM who were admitted because of congestive heart failure (CHF) and after discharge the stable condition persisted for more than one year. BMIPP imaging was obtained when CHF recovered (first study) and the second study was performed one year after the first study. From BMIPP imaging we calculated % Uptake (percentage of cardiac uptake of isotope to total injected dose) and Defect Score (degree and extent of regional abnormality in BMIPP uptake, DS). In the first study, we performed myocardial imaging with 201T1 to calculate Uptake Ratio of BMIPP (% Uptake of BMIPP divided by % Uptake of 201T1, UR). During the follow up period of 18.2 +/- 9.5 months (4.5-39.6 months) after the second study, cardiac event developed in 8 patients (cardiac death; 4, deterioration of CHF; 4). On univariate analysis, the following indices differed significantly between the event and event-free groups; left ventricular end-systolic dimension, graded DS, UR and % Uptake of 201T1 at the first study, % Uptake of BMIPP and DS at the second study, difference of % Uptake of BMIPP and DS between the first and second study, and newly designed index from graded DS of the first study and its change in the second study (Defect Index, DI). Cox proportional hazard analysis showed that DI (p = 0.0026) and age (p = 0.0262) were independent predictors of cardiac events. In patients with DI > or = 3, the relative risk of cardiac event was 25.0 times greater than that in patients with DI < or = 2. These data suggested that the extent and degree of regional abnormality of BMIPP uptake (DS) and its changes with time were useful for evaluating the prognosis in patients with DCM even though a clinically stable condition is persisting.

Adult↗
PubMed1999

Effect of cyclosporin A or tacrolimus on the function of blood-brain barrier cells.

Recently, it has been reported that continuous treatment with cyclosporin A or tacrolimus induces encephalopathy in transplant patients. The mechanism of immunosuppressant-induced encephalopathy is unclear. We investigated the cytotoxicity to brain capillary endothelial cells and the effect of these two drugs on P-glycoprotein function using mouse brain capillary endothelial (MBEC4) cells. The transcellular transport of [3H]sucrose was significantly increased and the cellular viability, based on 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and trypan blue exclusion test, was decreased by cyclosporin A (approximately 50% at 5 microM; P<0.005), while tacrolimus showed a much smaller effect. These findings indicate that the toxicity of cyclosporin A was greater than that of tacrolimus. The uptake of [3H]vincristine, a substrate of P-glycoprotein, was increased by these two drugs. The expression of P-glycoprotein in MBEC4 cells was reduced, but there was no effect on mdr1b mRNA levels. The decrease in the expression of P-glycoprotein may be due to the inhibition of the turnover of P-glycoprotein, which involves translation. In conclusion, the direct cytotoxic effect on the brain capillary endothelial cells and the inhibition of P-glycoprotein may be partly involved in the occurrence of immunosuppressant-induced encephalopathy.

ATP Binding Cassette Transporter, Subfamily B↗