Biomedical subjects

H Harashima

Publications and source records attributed to H Harashima.

At least 73 records · Page 4Linked to original sources

PubMed1992

Non-Michaelis-Menten type hepatic uptake of liposomes in the rat.

The objective of this study was to verify the methodology for measuring uptake clearance of liposomes and to characterize kinetically the saturable hepatic uptake of liposomes-through phagocytosis. The correction of vascular space was important in the evaluation of hepatic uptake. The efflux of liposomes from liver was shown to be negligible, by a repeated dose study, and thus, hepatic clearance can be obtained by the hepatic uptake divided by the area under the blood concentration-time curve (AUC). The determinant parameter which describes the saturability of uptake clearance of liposomes, independent of infusion rate, was investigated, using the data of an in-vivo constant infusion study, where infusion rate-dependent saturable hepatic clearance was observed. The mean blood concentration failed to obtain an infusion rate-independent function. On the other hand, the AUC could explain the saturability of hepatic clearance for every infusion rate by a unique relationship. The hepatic uptake amount could also explain this saturability, independent of infusion rate. These kinetic characteristics are inconsistent with Michaelis-Menten type kinetics, therefore a new model is required to describe the saturable hepatic clearance in the disposition of liposomes.

Animals↗

PubMed1991

Saturable, non-Michaelis-Menten uptake of liposomes by the reticuloendothelial system.

Multilamellar vesicles (300-350 nm) were infused into the rat femoral vein at the rate of 4, 40 and 400 nmol phosphatidycholine min-1 for 6 h using [3H]inulin as an aqueous marker. The time courses of blood concentration of vesicles, normalized for infusion rate, were not superimposable, showing the non-linearity of liposome disposition in the blood circulation. These time courses of blood concentration were well fitted by a single Michaelis-Menten equation. On the other hand, the time courses of tissue content could not be so accommodated. Additionally, the observed relationship between the uptake of liposomes by the liver and their clearance from it and other organs differed essentially from a simulation based on Michaelis-Menten type saturable kinetics. Therefore, it is suggested that there is a time-dependent non-Michaelis-Menten type process in the phagocytosis of macrophages in the reticuloendothelial system.

Animals↗

PubMed1991

Non-linear digital filters for extracting crackles from lung sounds.

A non-linear digital filter system is proposed for automatic extraction of crackles which are discontinuous paroxysmal sounds in lung sounds. This system is composed of two filters: one is a stationary-non-stationary separating filter and the other is a width separating filter. The former separates non-stationary signals from stationary ones, using the prediction error for the input. This filter can roughly separate the crackles as non-stationary signals. The latter, the width-separating filter, performs signal extraction on the basis of the interval between the zero-crossing points of the non-stationary signals, simply realized by logical algebra. This filter extracts a small-width impulsive signal and its succeeding waves; such a waveform is typical of crackles. Crackles can be more precisely extracted from the non-stationary signals by this filter. Both of the filters are realized quite simply. The high performance of this system is shown in processing actual lung sound data.

Humans↗

PubMed1990

Kinetic analysis of the dose-dependent hepatic handling of 1-anilino-8-naphthalene sulfonate in rats.

The dose dependency in the hepatic transport of an anionic fluorescent dye, 1-anilino-8-naphthalene sulfonate (ANS), was investigated by measuring the plasma disappearance and biliary excretion in rats. Bulk of the administered ANS distributed into the liver at 10 min after iv bolus injection. The plasma disappearance curves of ANS were then kinetically analyzed based on a two-compartment model, in which the ligand is eliminated only from the peripheral compartment (liver compartment). The total body clearance (CLtot) decreased with increasing dose of ANS. That is, the values of CLtot were 4.06 and 1.98 ml/min/per kg at the doses of 3 and 100 mumol/kg, respectively. The clearances of the uptake and sequestration processes (CLup and CLseq, respectively) for a total ligand were constant irrespective of dose, while the efflux clearance (CLeff) for a total ligand was increased by twofold with increasing dose. A mechanism for the increase in the CLeff value might be explained by a saturation of the ANS binding to the intracellular proteins. The hepatocellular distribution and the binding of ANS to cytosolic proteins were then determined. ANS mainly distributed to the cytosol fraction, and the unbound fraction in the cytosol increased from approximately 0.04 to 0.09 when the cytosolic concentrations of ANS increased from 40 to 900 microM, respectively. In spite of such increase in the unbound fraction in the cytosol, the CLseq values remained unchanged with increasing dose, suggesting that the saturation of sequestration clearance for unbound ANS might occur. Furthermore, the plasma disappearance curves of ANS at various doses were simultaneously analyzed based on three nonlinear kinetic models: Model I is a model incorporating both saturable intracellular binding and saturable sequestration; Model II is a model incorporating only saturable intracellular binding; Model III is the model incorporating only saturable sequestration. Goodness-of-fit evaluated by AIC value was best for Model I. Taken together, the nonlinearity in the plasma clearance of ANS was confirmed to be attributed to saturation of both its binding to cytosolic proteins and sequestration process.

Anilino Naphthalenesulfonates↗

PubMed1990

Effect of various organic anions on the plasma disappearance of 1-anilino-8-naphthalene sulfonate.

The effects of various organic anions on the hepatic transport of an anionic fluorescent dye, 1-anilino-8-naphthalene sulfonate (ANS) were investigated by measuring the plasma disappearance-time profiles in rats. Ten min after the i.v. administration of ANS (3 mumol/kg), various organic anions (60 mumol/kg) were injected in a bolus. Sulfobromophthalein (BSP), bromophenol blue (BPB) and rose bengal (RB) induced a transient increase in the plasma concentration of ANS (the so-called 'counter-transport' phenomena). The effect of rose bengal was somewhat different. After the administration of rose bengal, the plasma concentration of ANS decreased rapidly followed by a gradual increase. On the other hand, after the administration of bilirubin and taurocholate, the transient increases in plasma ANS concentrations were minimal. No effect was observed after the administration of phenolsulfophthalein (PSP) or oleate. The effects of these organic anions on the binding of ANS to rat liver cytosols were examined by equilibrium dialysis. Sulfobromophthalein, bromophenol blue and rose bengal, which yielded an in vivo 'counter-transport' phenomena, markedly inhibited ANS binding to cytosolic proteins. On the other hand, the other organic anions examined had very small, if any, inhibitory effect. The ANS binders in the cytosol were then identified by gel filtration. ANS bound mainly to X and Y (ligandin) fractions in the cytosol. Sulfobromophthalein, which is one of the organic anions exhibiting the in vivo 'counter-transport' phenomenon, remarkably inhibited ANS binding to ligandin fraction. It was thus suggested that the in vivo 'counter-transport' phenomena may be also explained by the enhancement of back diffusion due to the displacement of intracellular binding. In conclusion, one should be more cautious in interpreting data obtained from so-called in vivo 'counter-transport' experiments.

Anilino Naphthalenesulfonates↗

PubMed1990

Comparative tissue concentration profiles of fentanyl and alfentanil in humans predicted from tissue/blood partition data obtained in rats.

The steady-state tissue/blood partition coefficients of fentanyl and alfentanil were determined in 13 organs and tissues in the rat. A 6-h infusion of both drugs was used in order to achieve steady-state. Blood and tissue concentrations of drugs were measured by gas-liquid chromatography. The partition coefficients of fentanyl were two- to 30-fold higher than those of alfentanil. These data were then used in a physiologic pharmacokinetic model describing the disposition of the two opioids in humans. The model predicted the plasma pharmacokinetics of these drugs in humans reasonably well. However, simulation beyond 24 h after a bolus administration showed a terminal half-life of 20 h for fentanyl, i.e., an elimination phase that has not yet been described in actual pharmacokinetic studies. In keeping with this, the volume of distribution of fentanyl in the model was also larger than expected. The simulated tissue concentration curves of fentanyl and alfentanil in humans could be used to explain the propensity of fentanyl to give secondary peaks in plasma concentration curves and the difference in effect kinetics between the two opioids. Physiologic pharmacokinetic modeling, based on measured data in small animals, can generate information that is not obtainable by empirical methods in humans.

Alfentanil↗

PubMed1989

Separation of fine crackles from vesicular sounds by a nonlinear digital filter.

Crackles are discontinuous adventitious sounds, and their separation is an important process in the analysis of lung sounds. In order to separate the crackles from vesicular sounds automatically, we used a nonlinear digital filter which was designed to separate nonstationary from stationary signals. We applied this filter to the lung sounds recorded from six patients with pulmonary fibrosis. The separation was satisfactory enough to make this method useful in clinical medicine.

Diagnosis, Computer-Assisted↗

PubMed1989

[A digital filtering system for extracting crackles from lung sounds].

A nonlinear digital filter system is proposed for automatic extraction of crackles which are discontinuous adventitious sounds in lung sounds. This system is composed of two nonlinear digital filters; one is a stationary nonstationary separating filter, and the other is a width-discriminating filter. The former separates nonstationary signals from stationary ones in the lung sounds, using the prediction error to the input lung sound signal. If the prediction error is small enough, the lung sound is considered to be stationary, but if the error is large, a nonstationary signal is considered to occur and the nonstationary part is separated. The latter, the width-discriminating filter, performs signal extraction by considering the signal wave form of the crackles, simply realized by logical algebra. This filter extracts an impulsive signal, which is a small-width wave, and its succeeding waves; such wave form is typical of that of crackles. First, crackles are roughly separated by the stationary-nonstationary separating filter as nonstationary signals, and then are more precisely extracted from the nonstationary output by the width-discriminating filter. Some examples of processing actual lung sound data by this system show its high performance.

Filtration↗

PubMed1988

Kinetic analysis of the positive inotropic action (PIA) of ouabain in isolated perfused rabbit heart. Slow onset of PIA and slow binding to Na+, K+-adenosine triphosphatase.

The positive inotropic action (PIA) of ouabain was analyzed kinetically using isolated perfused rabbit heart. The input function of the ouabain concentration in the perfusate (Ci) into the heart was controlled by changing the volume of the reservoir and the rate of ouabain infusion into the reservoir fixed in front of the heart. The time courses of PIA were measured continuously with different infusion rates. The relationship between Ci and PIA clearly depended on the infusion rate in isolated perfused rabbit heart. The binding kinetics of ouabain to Na+, K+-adenosine triphosphatase (ATPase) in the cardiac homogenate showed two kinds of binding sites. The association rate constant (kappa 1), the dissociation rate constant (kappa-1) and the binding capacity of each site was estimated by the simultaneous fitting method. The occupation curve of the high affinity site corresponded well with the PIA measured in the isolated perfused heart at steady state. These results indicate that ouabain binding to the high affinity site is related to the PIA, and the slow binding process of ouabain to Na+, K+-ATPase may be one of the principal reasons for the infusion-rate dependence of ouabain PIA.

Animals↗

PubMed1988