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Biomedical subjects

M Hanano

Publications and source records attributed to M Hanano.

At least 127 records · Page 7Linked to original sources
PubMed1987

Platelet aggregation induced by cryoprecipitate infusion in platelet-type von Willebrand's disease.

Platelet-type von Willebrand's disease (VWD) is a recently described bleeding disorder characterized by a heightened interaction between platelets and von Willebrand factor (vWF) as the result of an intrinsic platelet-membrane abnormality. Administration of cryoprecipitate into a patient with this disorder was followed by thrombocytopenia in vivo and "spontaneous" platelet aggregation in vitro. However, a prolonged bleeding time was shortened and sufficient haemostasis was achieved without thromboembolic complications. These results provide evidence that human vWF infused with cryoprecipitate directly interacts with platelet-type vWD platelets, causing thrombocytopenia in vivo, and suggest that impaired primary haemostasis is related to the depletion of the high-molecular-weight vWF multimers in the circulating plasma.

Hemostasis↗
PubMed1987

Uptake of propranolol by microvessels isolated from bovine brain.

To study the transport system of propranolol (PL), a basic drug, in the blood-brain barrier, the uptake of PL into isolated bovine brain microvessels was investigated. The uptake of PL was a concentrative one via saturable process (Km = 42.5 microM) that was decreased by hypothermia (Q10 = 2.2), but not by metabolic inhibitors (2,4-dinitrophenol, KCN, ouabain). Although basic drugs such as quinidine and imipramine decreased both the initial rate of uptake and the steady-state cell-to-medium concentration ratio (C/M) of PL, acidic drugs (phenobarbital, salicylic acid) did not affect them. These results suggest that PL is taken up by the endothelial cells of the isolated brain microvessels by facilitated diffusion which is specific for basic drugs and then binds to certain binding sites in the cells.

2,4-Dinitrophenol↗
PubMed1987

Tubulin as a major determinant of tissue distribution of vincristine.

The tissue distribution of vincristine was correlated with the tubulin content in different mouse tissues. The concentration of tubulin in the mouse tissues was determined by estimation of the tissue binding capacities for colchicine. Significant differences in the tubulin concentration were observed among the tissues. The comparison of the apparent tissue-to-plasma partition coefficients (KPapp) of vincristine (taken from the literature) with the tubulin concentration (expressed by the binding capacities for colchicine) showed a good correlation. These results suggest that the in vivo distribution of vincristine is predicted by the tissue tubulin concentration.

Animals↗
PubMed1987

Kinetics of hepatic transport of 4-methylumbelliferone in rats. Analysis by multiple indicator dilution method.

Hepatic elimination of 4-methylumbelliferone (4-MU), which has been used as a model compound for conjugative metabolism, was studied by means of a multiple indicator dilution (MID) method in the isolated perfused rat liver. Using this method, three intrinsic hepatic clearances, CLint,inf, CLint,eff, and CLint,seq, which represent the influx, efflux, and sequestration processes, respectively, were obtained. When the dose was increased from a low dose (50 micrograms/rat liver) to a high dose (3000 micrograms/rat liver), the hepatic availability of 4-MU increased from 0.11 to 0.73. With increasing dose, the CLint,eff value increased approximately two times, while the CLint,seq value decreased to approximately one-third. The remarkable dose dependence of hepatic availability was due to nonlinearity in both CLint,eff and CLint,seq values. However, the CLint,inf value was almost independent of dose. The dose-dependent change in CLint,seq might be explained by the saturation of conjugative metabolism of 4-MU, while the increase in the CLint,eff value with increasing dose might be partly explained by the nonlinear tissue binding of 4-MU, since the tissue unbound fraction determined by an ultrafiltration method using liver homogenate increased approximately 1.5 times at higher concentration of 4-MU compared to that at lower concentrations. In addition, based on a comparison of the individual intrinsic clearances, i.e., CLint,inf, CLint,eff, and CLint,seq, the major determining process of the apparent hepatic intrinsic clearance of 4-MU is thought to be the sequestration process at the high dose. However, at the low dose, the membrane transport process (influx and efflux processes) as well as the sequestration process also determine the apparent hepatic intrinsic clearance.

Animals↗
PubMed1987

Effect of a diffusional barrier to a metabolite across hepatocytes on its kinetics in "enzyme-distributed" models: a computer-aided simulation study.

The effect of a diffusional barrier to a metabolite between the blood and hepatocytes on elimination kinetics of formed and preformed metabolites was predicted under various enzymic distributions in the liver by computer-aided simulation. Sequential metabolism by which the primary metabolite (MI) is generated from the parent drug (D) and further metabolized to the terminal metabolite (MII) by enzymes A and B, respectively, was chosen for the simulation. Moreover, four models of enzyme distribution patterns were defined with regard to the hepatic blood flow path. The extraction ratios for the preformed and formed metabolites (designated as Em and Ep----m, respectively) were simulated by varying both the average intrinsic clearance of enzyme B (CLint,B) and the permeability of hepatocytes for MI (Pm), while keeping the average intrinsic clearance of enzyme A (CLint,A) equal to hepatic blood flow (Q). When a rapid equilibrium of MI between the blood and hepatocytes held, i.e., Pm was large relative to Q, Em was equal to or higher than Ep----m for all models, as previously shown by Pang and Stillwell. By contrast, it was found that when a diffusional barrier for MI existed, i.e., Pm was small relative to Q, Em was equal to or lower than Ep----m. Furthermore, it was observed that the smaller Pm became, the larger the difference between Em and Ep----m became. We further simulated the effect of the intrinsic clearance (CLint,C) for a metabolic pathway, which competes for that by enzyme A, on the Ep----m value. In the model assuming even distribution of all the enzymes along the flow path, irrespective of the CLint,C value, a similar effect of Pm on Ep----m was observed when the Pm value was relatively small (Pm less than Q). By contrast, in the case of uneven enzymic distributions of enzymes A and B, the effect of the CLint,C value on the relationship between Pm and Ep----m occurred to some extent. From these simulations, it was concluded that lower membrane permeability (Pm) both diminishes the entry of preformed metabolite into the hepatocytes and accelerates the removal of intracellularly formed metabolite (through sequential metabolism) by diminishing its efflux, yielding lower Em than Ep----m. When Pm becomes small (Pm less than 1/10Q), these mechanisms for lower Em than Ep----m predominate over other mechanisms such as the presence of a competing metabolic route and uneven distribution of enzymes.

Biotransformation↗
PubMed1987

Tracer disposition kinetics in the determination of local cerebral blood flow by a venous equilibrium model, tube model, and distributed model.

Tracer distribution kinetics in the determination of local cerebral blood flow (LCBF) were examined by using three models, i.e., venous equilibrium, tube, and distributed models. The technique most commonly used for measuring LCBF is the tissue uptake method, which was first developed and applied by Kety (1951). The measurement of LCBF with the 14C-iodoantipyrine (IAP) method is calculated by using an equation derived by Kety based on the Fick's principle and a two-compartment model of blood-tissue exchange and tissue concentration at a single data point (Sakurada et al., 1978). The procedure, in which the tissue is to be in equilibrium with venous blood, will be referred to as the tissue equilibration model. In this article, effects of the concentration gradient of tracer along the length of the capillary (tube model) and the transverse heterogeneity in the capillary transit time (distributed model) on the determination of LCBF were theoretically analyzed for the tissue sampling method. Similarities and differences among these models are explored. The rank order of the LCBF calculated by using arterial blood concentration time courses and the tissue concentration of tracer based on each model were tube model (model II) less than distributed model (model III) less than venous equilibrium model (model I). Data on 14C-IAP kinetics reported by Ohno et al. (1979) were employed. The LCBFs calculated based on model I were 45-260% larger than those in models II or III. To discriminate among three models, we propose to examine the effect of altering the venous infusion time of tracer on the apparent tissue-to-blood concentration ratio (lambda app). A range of the ratio of the predicted lambda app in models II or III to that in model I was from 0.6 to 1.3. In the future, there may be a need to determine which model should be used to calculate the LCBF based on this discriminator and to develop another discriminator by using multiple data points based on positron emission tomography.

Animals↗
PubMed1987

Von Willebrand factor fragment in type IIA von Willebrand's disease: demonstration of two different forms of fragments.

A fast-migrating precipitin peak which showed a reaction of partial immunochemical identity with the major von Willebrand factor (vWf) component was detected by crossed immunoelectrophoresis in agarose gel in plasma but not in platelets from a patient with type IIA von Willebrand's disease (vWD). Another patient undergoing urokinase therapy had a vWf fragment in plasma which was antigenically cross-reactive with the major vWf component. When plasma from both patients was mixed and electrophoresed together in the first dimension, two fast-moving precipitin arcs were demonstrated in the second dimension. These data indicate that two different kinds of vWf fragments can be generated in vivo.

Electrophoresis, Agar Gel↗
PubMed1987

Heat-treated factor VIII/von Willebrand factor concentrate in platelet-type von Willebrand's disease.

Cryoprecipitate has proved to correct the hemostatic defects in von Willebrand's disease (vWD) and platelet-type vWD. However, recent studies have revealed that transmission of the AIDS retrovirus (HIV) occurs through exposure to blood products including cryoprecipitate. Treatment with heat-treated factor VIII/von Willebrand factor (vWf) concentrates may have certain advantages over treatment with nonheated products, if these preparations are efficacious in these disorders. We found that a commercially available factor VIII/vWf concentrate, Haemate P, contained the high-molecular-weight multimers of vWf and had a ratio of ristocetin cofactor (RCof) to vWf antigen (vWf:Ag) close to unity. In addition, its capacity to directly induce aggregation of platelet-type vWD platelets in vitro was similar to that for cryoprecipitate. When infused into a patient with platelet-type vWD, Haemate P shortened the prolonged bleeding time and caused spontaneous platelet aggregation in vitro with a mild diminution of platelet count. These results indicate that some of the heat-treated factor VIII/vWf concentrates may provide a safer, yet still effective, treatment for platelet-type vWD.

Factor VIII↗
PubMed1987

Pharmacokinetic study of 4-methylumbelliferone in mice.

The pharmacokinetic behavior of 4-methylumbelliferone (4-MU), a compound known to be excreted as conjugated metabolites, was studied in mice and the results were compared with those reported in rats. Plasma half-life of the terminal phase (t1/2,beta) of mice after an intravenous administration of 4-MU was approximately one-twenty fifth of that of rats. Mice showed a dose dependency in both hepatic and extrahepatic clearances, though dose dependent hepatic clearance is reported to be the main route of elimination in rats. In the same dose range (10-25 mg/kg), the hepatic intrinsic clearance per unit body weight of mice was approximately 5 times larger than that of rats. The blood-to-plasma concentration ratio and the unbound volume of distribution of tissues of mice were smaller than those of rats. It was concluded that the shorter t1/2,beta of mice than that of rats may be due to the larger hepatic clearance, the presence of extrahepatic clearance and the smaller volume of distribution.

Animals↗
PubMed1987

Variation in D-glucose uptake along the intestinal tract.

The variation in D-glucose uptake along the intestinal tract was examined by dividing the entire rat small intestine into 10 segments of equal length and by using everted sacs. The superiority of jejunum to ileum in D-glucose uptake, which is generally accepted, was supported by this work. It was attributed mainly to the variation in the maximal transport velocity of the Michaelis-Menten type carrier-mediated transport system with a clear kinetic border in the distal location of the small intestine, between segments 7 and 8. Information obtained in this study is useful for understanding and estimating the absorption process, or the time-course of absorption, of D-glucose as it passes down in the intestinal tract.

Animals↗
PubMed1987

Evaluation of fibrinolytic therapy by measuring cross-linked fibrin derivatives and plasmin-alpha 2-plasmin inhibitor complex in plasma.

Plasma levels of alpha 2-plasmin inhibitor (alpha 2PI), plasmin-alpha 2PI complex and cross-linked fibrin derivatives (XDP) were measured in 8 patients (12 episodes) with thromboembolic disorders on the initial administration of urokinase. In conjunction with a decrease in plasma alpha 2PI activity and antigen, plasmin-alpha 2PI complex increased following urokinase infusion in all cases except one who received a low dose (60,000 units) of urokinase. However, changes in XDP were variable among the patients. Plasma XDP level increased markedly in one, moderately in 4, slightly in one, and remained unchanged in 6 cases (episodes). The increment of plasma XDP correlated (r = 0.804, p = 0.003) with the dose of urokinase administered, but was independent of changes in plasmin-alpha 2PI complex. The plasma XDP elevation was associated with clinical improvement. These results suggest that simultaneous measurements of XDP and plasmin-alpha 2PI complex in plasma would be valuable for the pharmacological or hemostatic assessment of thrombolytic therapy.

Adult↗