Biomedical subjects

Y Sawada

Publications and source records attributed to Y Sawada.

At least 361 records · Page 20Linked to original sources

PubMed1992

Effect of basic drugs on the hepatic uptake of ouabain by sinusoidal plasma membrane vesicles isolated from rat liver.

Although antiarrhythmic drugs are used to treat digitalis-induced cardiac disorders, some of these drugs have been reported to increase the serum digoxin concentration in patients, causing the severe side-effects. We have previously shown that many basic drugs including antiarrhythmic drugs inhibited the hepatic uptake of cardiac glycosides into isolated rat hepatocytes, which could be a cause for the increased serum digoxin concentration. The present study was designed to examine the mechanism of this inhibition using isolated rat sinusoidal plasma membrane vesicles. The effect of nine basic drugs (dipyridamole, nifedipine, verapamil, chlorpromazine, lidocaine, quinidine, ajmaline, disopyramide, and propranolol) on the uptake of ouabain was studied. Quinidine reduced the initial uptake rate of ouabain (30 s) while it did not change the uptake of ouabain in an equilibrium condition (30 min). Other basic drugs, such as verapamil, dipyridamole, and nifedipine also significantly reduced the initial uptake rate of ouabain. These basic drugs had no effect on the membrane fluidity. The inhibitory effects on the vesicular uptake were significantly correlated with the inhibitory effects on ouabain uptake by the isolated rat hepatocytes. These findings may suggest that the mechanism of the inhibition involves the inhibition of the transport process via the sinusoidal plasma membrane.

Animals↗

PubMed1992

Nonlinear pharmacokinetics of hepatobiliary transport of rose bengal in rats after i.v. bolus administration with varying doses.

To investigate the nonlinear kinetics in the hepatobiliary transport of rose bengal (RB), the time profiles of plasma concentration and biliary excretion rate after its i.v. administration at various doses were measured in rats. The total body clearance decreased remarkably with increased dose. The hepatic uptake clearance also showed a similar dose dependency, and saturation of hepatic uptake at least partly accounts for the dose-dependent change in total body clearance. The peak biliary excretion rate approached the transport maximum (approximately 150 nmol min-1 kg-1) with increased dose. To further clarify which process in RB hepatobiliary transport has nonlinearity, we analysed thus obtained data based on a three-compartment model. The hepatic uptake and sequestration rate constants decreased remarkably with increased dose. The initial hepatic uptake rates assessed from the plasma disappearance rate during the early phase fit well to the Michaelis-Menten equation with a saturable and a nonsaturable component. The maximum uptake velocity and Michaelis constant were 4.7 mumol min-1 kg-1 and 360 microM, respectively. That hepatic uptake has a much higher capacity (about 30 fold) than biliary excretion suggests that biliary excretion can be a rate-determining process in the overall hepatobiliary transport of RB. We conclude that the saturation of both hepatic uptake and biliary excretion could be the main causes for the nonlinear pharmacokinetics of hepatobiliary transport of RB.

Animals↗

PubMed1992

Pharmacokinetic profile of glycyrrhizin in healthy volunteers by a new high-performance liquid chromatographic method.

An improved high-performance liquid chromatographic method was developed for the quantification of glycyrrhizin and its metabolites in human plasma. The improved method was selective and made it possible to determine precisely glycyrrhizin at levels as low as 500 ng/mL. The pharmacokinetic behavior of glycyrrhizin and its metabolites after oral and intravenous administration of glycyrrhizin to normal subjects was investigated. After oral administration of glycyrrhizin (100 mg) to three normal subjects, the major metabolite of glycyrrhizin (glycyrrhetic acid) appeared in plasma (less than 200 ng/mL), but glycyrrhizin was not found. On the other hand, glycyrrhizin was found in urine, and the amount excreted was 1.1-2.5% of the dose. This finding suggests that glycyrrhizin is partly absorbed in the intact form from the gastrointestinal tract. The concentration of glycyrrhizin in plasma after intravenous administration of glycyrrhizin (40, 80, and 120 mg) showed biexponential profiles during the 24-h period after administration of each dose. The glycyrrhizin metabolites, glycyrrhetic acid and glycyrrhetic acid-3-O-glucuronide, were not detected in either plasma or urine. The terminal half-life of glycyrrhizin, the apparent volume of the central compartment, the steady-state distribution volume, and the total body clearance in three dosing experiments were 2.7-4.8 h, 37-64 mL/kg, 59-98 mL/kg, and 16-25 mL/kg/h, respectively. Glycyrrhizin was not detected in plasma after oral administration of the usual therapeutic dose of glycyrrhizin, and no dose dependency of the drug was observed in the dose range of 40-120 mg.

Administration, Oral↗

PubMed1992

The effect of continuous topical application of heparin on flap survival.

To evaluate the beneficial effects of heparin on flap survival area, an experimental study was carried out on dorsal flaps in rats. Topical applications of heparin, released from a silicone gel sheet onto the critical area (which generally necrosed without treatment), resulted in an increase in the flap survival area and rate as compared to controls (p < 0.01). When heparin was applied topically but solely to an area proximal to the critical area however, no increase in the survival area resulted.

Administration, Topical↗

PubMed1992

Patterning in hydra cell aggregates without the sorting of cells from different axial origins.

Aggregates of Hydra cells were studied to find out how the primary centers that form new heads are generated in a system of cells in which the original pattern has been destroyed. Since cells that originate near the heads (apical cells) temporarily maintain a high level of head activation potential during aggregate formation and may contribute to pattern formation, their distribution in the aggregates was investigated. The mutual distances between labeled epithelial cells were followed by vitally staining apical cells with DAPI. The distribution was random during early regeneration stages (3, 6, 24 hr). These results show that epithelial cells originating from apical regions do not sort. That is, dynamic cell movement to generate rudiments of new heads is not necessary for head formation in aggregates. A possible explanation of the mechanism is discussed.

Animals↗

PubMed1992

Effect of a novel class I antiarrhythmic agent, TYB-3823, on the calcium current in single guinea pig ventricular myocytes.

The effect of TYB-3823 on Ca2+ current (ICa) of guinea pig ventricular myocytes was investigated by means of whole-cell patch-clamp technique. TYB-3823 (100-1,000 microM) caused a concentration-dependent decrease in ICa. Furthermore, a reduction of ICa induced by TYB-3823 (1,000 microM) was progressively accentuated by repetitive membrane depolarization, indicating a rate-dependent block of ICa. However, the inhibitory potency on ICa was approximately 1/1000 of a Ca2+ antagonistic agent, verapamil hydrochloride. Considering evidence that 3-30 microM TYB-3823 decreased the maximum upstroke velocity of the action potential of guinea pig ventricular muscles, it is indicated that the drug does not show its Ca2+ antagonistic property in the usual concentration range as a class I antiarrhythmic agent.

Animals↗

PubMed1992

A technique of haemostasis of the extremities after debridement of burn wounds.

A technique used to achieve prompt haemostasis in burned wounds of the extremities is described. After tangential debridement using a tourniquet, thrombin solution (1000 units in 1 ml of saline solution) is applied on the entire wound. Immediately after removing the tourniquet; the wound is tightly wrapped with a thin plastic film and a pressure bandage over the entire wound. The pressure bandage is kept on for approximately 10 min after removing the tourniquet. With this procedure, haemostasis of the capillary oozing can be promptly and completely achieved. Furthermore, arterial and venous haemostasis can also be achieved, with clots present at the arterial and venous haemorrhagic points. As these clots can be removed easily, ligation or electrocoagulation is necessary. This technique is especially useful for haemostasis in a wound of the extremity after tangential excision leading to decreasing blood loss.

Adolescent↗

PubMed1992

Benefits of silicone cream occlusive dressing for treatment of meshed skin grafts.

A side-by-side evaluation of a silicone cream occlusive dressing technique for grafted meshed skin on the extremities of 10 patients is described. The site treated by silicone cream showed less congestion in the interstices of the mesh, less visible diamond pattern, and less hardness of the skin in all patients compared with the control site, which was treated by application of petroleum jelly ointment. The general appearance of the silicone cream-treated site showed better cosmetic results when compared with the control site.

Adolescent↗

PubMed1992

Prevention of dressing slippage under an elastic bandage.

A technique is described to prevent the shift in position of dressing materials by applying a double-sided adhesive tape between the skin and the elastic bandage. This technique also prevents a shift in position of a pressure garment, especially when applied around joints on the extremities.

Adhesives↗

PubMed1992

'Albumin-mediated transport phenomenon' observed for ligands with high membrane permeability. Effect of the unstirred water layer in the Disse's space of rat liver.

In this paper, we offer experimental evidence of the rate-limiting diffusion of ligands through the unstirred water layer (UWL) as an explanation for the so-called albumin-mediated transport phenomenon. The relative membrane permeability of various ligands was first evaluated using isolated rat hepatocytes. Then, the effect of albumin on the uptake of ligands of a wide range of membrane permeabilities was examined using the perfused rat liver. The results were similar to those expected from the UWL model: ligands with high membrane permeability (warfarin, diazepam and taurocholate) clearly exhibited albumin-mediated transport, those with medium membrane permeability (tolbutamide and salicylate) showed less albumin-mediated transport, and ligand with low membrane permeability (cefodizime) did not show albumin-mediated transport. These results were explained by simulation studies of two separate cases based on the UWL model; one assuming the rapid equilibrium of ligand binding with albumin, and the other considering the slow dissociation of ligands from albumin. In light of these findings, we suggest that the rate-limiting diffusion through the UWL plays an important role in the so-called albumin-mediated transport phenomenon.

Animals↗

PubMed1992

Kinetic analysis of hepatobiliary transport of vincristine in perfused rat liver. Possible roles of P-glycoprotein in biliary excretion of vincristine.

Recent studies using bile canalicular membrane vesicles have suggested that P-glycoprotein may play a role in excreting some anticancer drugs from the liver to the bile. At steady state after a continuous single-pass perfusion of a tracer concentration of [3H]vincristine in the rat liver, the extraction ratio was approximately 0.6, and 70% of the extracted drug was excreted into the bile mostly in unchanged form. The liver/perfusate and bile/liver unbound concentration ratios obtained after correction for intracellular binding and the inside-negative membrane potentials and/or pH difference between the inside and outside of the cells, were approximately 2-3 and 160-280, respectively, suggesting a highly concentrated biliary excretion process. We also examined the effects of verapamil, a P-glycoprotein-related transport inhibitor in cancer cells, on the hepatobiliary transport of [3H]vincristine. Verapamil 50 microM in the perfusate caused a decrease in the biliary excretion rate of [3H]vincristine, whereas [14C]taurocholate (reference compound) remained constant. In contrast, the hepatic uptake rate of [3H]vincristine exhibited minimum reduction, suggesting that verapamil selectively inhibited the biliary excretion of [3H]vincristine at the canalicular membrane. The fact that verapamil had little effect on the initial velocity of [3H]vincristine uptake by isolated hepatocytes also supports the above findings. Since the effect of 150 microM verapamil in the perfusate was not selective for vincristine, the biliary excretion rates of both compounds ([3H]vincristine, [14C]taurocholate) were reduced by this concentration of verapamil. In conclusion, the concentrative excretion of vincristine into the bile and its selective inhibition by a moderate concentration of verapamil provide indirect evidence for the contribution of P-glycoprotein to the biliary excretion of vincristine in a perfused rat liver system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1992

A nasal vestibular flap for reconstruction of the upper lip.

A technique to reconstruct the hair-bearing upper lip by means of a hair-loaded nasal vestibular flap is described. This flap is elevated from the nasal vestibular area, and does not result in nasal deformity. This flap is especially suitable to reconstruct the medial portion of the hair-bearing upper lip in adult males.

Hair↗

PubMed1992

Kinetic modeling of ouabain tissue distribution based on slow and saturable binding to Na,K-ATPase.

The significance of the binding to Na,K-ATPase in the tissue distribution of ouabain was previously documented (Harashima et al., Pharm. Res. 9:474-479, 1992). The purpose of this study was to obtain a kinetic model of ouabain tissue distribution. In most tissues, the ouabain concentration continued to rise after the termination of infusion (5 min), with the peak tissue concentration at approximately 20 min. This delay could not be explained by the rapid equilibrium model (RE model), nor could the kinetics of ouabain be explained by an RE model modified for saturable binding. Since ouabain binding to Na,K-ATPase is slow, the association and dissociation processes were incorporated into a model that can accurately fit the observed time courses of ouabain. The obtained binding parameters corresponded well with the observed values in the in vitro binding experiments, except for muscle. These results quantitatively support the role of the slow and saturable binding of ouabain to Na,K-ATPase in its tissue distribution.

Animals↗

PubMed1992

Significance of binding to Na,K-ATPase in the tissue distribution of ouabain in guinea pigs.

Ouabain binds specifically to Na,K-ATPase on the plasma membrane and therefore serves to measure the tissue concentration of Na,K-ATPase. We examined the role of ouabain binding to Na,K-ATPase in its overall tissue distribution. The tissue-to-plasma concentration ratio (Kp,vivo) was defined in each tissue after intravenous administration of 3H-ouabain in guinea pigs, and specific binding of ouabain to Na,K-ATPase was measured in tissue homogenate to obtain the dissociation constant and binding capacity in each tissue. A predicted tissue-to-plasma concentration ratio (Kp,vitro) was calculated using the obtained binding parameters and the volume of extracellular space in each tissue. The absolute values of Kp,vitro were comparable to those of Kp,vivo, except in brain. Regression analysis showed that the specific binding capacity of Na,K-ATPase in each tissue is the main factor in the tissue variation of Kp,vivo. Therefore, the binding of ouabain to Na,K-ATPase plays a significant role in the tissue distribution of ouabain.

Algorithms↗

PubMed1992

Correlation between the inhibitory effects of basic drugs on the uptake of cardiac glycosides and taurocholate by isolated rat hepatocytes.

The role of the multispecific bile acid transporter for cardiac glycoside uptake is still controversial. This study was designed to examine the inhibitory effects of basic drugs (verapamil, dipyridamole, nifedipine, chlorpromazine, disopyramide, quinidine, propranolol, and lidocaine) on taurocholate uptake by isolated rat hepatocytes and to compare these effects with inhibition of ouabain uptake. Sodium-dependent taurocholate uptake was significantly reduced, to 50-70% of the control value, by 50 microM verapamil, dipyridamole, and nifedipine. Sodium-independent taurocholate uptake was more extensively inhibited, to 20-40%, by these basic drugs. The inhibition of ouabain uptake correlated better with sodium-independent taurocholate uptake (gamma = 0.918) than with sodium-dependent taurocholate uptake (gamma = 0.714). Taurocholate competitively inhibited ouabain uptake in the absence of sodium. These results indicate that the cardiac glycoside transport system is similar to the sodium-independent taurocholate transport system.

Animals↗

PubMed1992

Renal tubular handling of p-aminohippurate and epidermal growth factor (EGF) in filtering and nonfiltering perfused rat kidneys.

We examined the integrity of renal tubular function in filtering and nonfiltering isolated perfused rat kidneys by using p-amino-3H-hippurate (3H-PAH) and the multiple indicator dilution method with 14C-creatinine as a reference. The influx clearance (PSu,1) of unbound 3H-PAH was 0.37 and 0.38 ml/sec in the filtering and nonfiltering kidneys, respectively. The efflux rate constants were comparable between filtering and nonfiltering kidneys, while the sequestration rate constant in the filtering kidney was approximately three times larger than that in the nonfiltering kidney. These data suggest that the nonfiltering kidney maintains 3H-PAH transporting ability through the antiluminal plasma membrane. The renal handling of epidermal growth factor (EGF) by filtering and nonfiltering kidneys was compared. The ratio of the total uptake of tracer 125I-EGF over 20 min in the nonfiltering kidney to that in the filtering kidney was 0.8. This ratio was reduced to 0.2 when the kidneys were perfused with tracer 125I-EGF plus 20 nM EGF. Furthermore, the total uptake of tracer 125I-EGF in the nonfiltering kidney was reduced 20-fold in the presence of 20 nM unlabeled EGF. These findings suggest that the tubular uptake of tracer 125I-EGF by filtering kidney takes place mainly via the antiluminal plasma membrane and that this uptake is a saturable process.

Animals↗

PubMed1992

Development of nitrate tolerance and usefulness of pulse therapy in a patient with vasospastic angina.

In a 58-year-old man with vasospastic angina, we investigated the relationship between the antianginal effects of isosorbide dinitrate (ISDN) and plasma ISDN concentration. Despite adequate plasma ISDN levels, sustained therapy using ISDN tapes and oral ISDN (transcutaneously 160 mg and orally 100 mg ISDN day-1) failed to exhibit antianginal effects. However, pulse therapy using sublingual short-acting ISDN prevented anginal episodes, although the plasma ISDN levels were less than those of sustained therapy. Nitrate tolerance of the antianginal effects was avoided by creating an abrupt plasma ISDN concentration gradient using sublingual ISDN.

Administration, Oral↗

PubMed1992

Postremission therapy without prednisolone improves survival in adults with acute leukemia.

This prospective randomized clinical trial was to clarify whether postremission therapy without prednisolone (PSL) was more effective than therapy with PSL in improving the 5-year survival of adults with acute leukemia. Thirty consecutive adult patients with newly achieved complete remission were randomized to receive postremission therapy either with or without PSL between September 1985 and September 1988. The patients ranged from 16 to 57 years in age. Patients treated without PSL had a significantly better 5-year survival rate than those receiving PSL according to Kaplan-Meier analysis (53.5% vs 15.3%, p < 0.05). In the group treated without PSL, eight out of 15 patients were alive at 72 months, and seven patients maintained their first complete remission at 72 months. Among patients with acute lymphoblastic leukemia (ALL) who were treated without PSL the median duration of remission was 24 months, and the survival rate at 72 months was 50.0%. On the other hand, the median survival was only 13 months for the 5 patients with ALL treated with PSL. Thus, it is desirable that adults with acute leukemia are treated by postremission therapy without PSL.

Acute Disease↗