Biomedical subjects

M Hanano

Publications and source records attributed to M Hanano.

At least 19 recordsLinked to original sources

PubMed2000

Pharmacokinetic/pharmacodynamic relationship of eptazocine, a narcotic-antagonist analgesic, in rats.

The relationship between the pharmacokinetics and the pharmacodynamics of eptazocine, a narcotic-antagonist analgesic, was investigated in rats. The analgesic effect of eptazocine (2.5, 5 and 10 mg/kg) following intravenous (i.v) administration was evaluated by both the Randall-Selitto method and the D'Amour-Smith method. The analgesic effects were determined before and at designed intervals for a period of 120 min after eptazocine administration, and are expressed as area under the effect-time curve (AUC(E)). The plasma concentration of eptazocine was determined by fluorescence HPLC and was analyzed with a two compartment open model using the nonlinear least-squares method. Eptazocine produced a dose-dependent analgesic effect. It was demonstrated that eptazocine has a linear relationship between AUC(E) and the area under the plasma concentration-time curve (AUC) following i.v. administration for three different doses ranging from 2.5 to 10 mg/kg.

Analgesics↗

PubMed1999

Effect of the opioid antagonist naloxone on the regional metabolic rate for glucose in the conscious rat brain.

The effect of naloxone, a potent and specific opioid antagonist, on cerebral glucose utilization was investigated in conscious rat. For quantitative evaluation of the functional activity in brain, the regional cerebral metabolic rate for glucose (rCMRglc) was measured by the double tracer technique, using [14C]2-deoxyglucose and [3H]3-o-methylglucose. Intravenous administration of naloxone significantly increased rCMRglc in the medulla and thalamus at a dose of 1 or 10 mg/kg, and in the cerebral cortex, midbrain and cerebellum at a dose of 10 mg/kg. Our findings strongly suggest that naloxone by itself affects the cerebral functional activity within 10 min of administration.

Animals↗

PubMed1999

Transepithelial transport of organic anions across the choroid plexus: possible involvement of organic anion transporter and multidrug resistance-associated protein.

Transport characteristics of 17beta-estradiol 17beta-D-glucuronide (E217betaG), a dual substrate of the transporters for cellular uptake (organic anion-transporting polypeptide 1 or oatp1) and cellular excretion (multidrug resistance-associated protein 1or MRP1), in the rat choroid plexus were studied in vivo and in vitro. The uptake of E217betaG into isolated choroid plexus was mediated by an energy-dependent system with a Km of 3.4 microM. Together with the previous finding that oatp1 is localized on the apical membrane of choroid plexus, these results suggest that oatp1 is responsible for the uptake of this ligand. After intracerebroventricular administration, elimination of E217betaG from cerebrospinal fluid was probenecid sensitive and much more rapid than that of inulin; less than 2% of the administered E217betaG and 40 to 50% of inulin remained in the cerebrospinal fluid 20 min after intracerebroventricular administration. In addition, the amount of E217betaG associated with choroid plexus at 20 min was negligible, suggesting the presence of an efficient excretion system on the basolateral membrane of choroid plexus. Expression of MRP1 was detected in choroid plexus. Semiquantitative reverse transcription-polymerase chain reaction and Western blot analyses indicated that the expression level of MRP1 in choroid plexus is about four or five times higher than that in the lung, one of the tissues exhibiting high expression of MRP1. Together with the in vivo vectorial transport of E217betaG, these results can be accounted for by assuming that there is basolateral localization of MRP1 in choroid plexus. Combined, oatp1 and MRP1 may synergistically mediate the efficient transcellular transport of E217betaG across choroid plexus.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Change of beta-endorphin concentration in rat brain after administration of indomethacin or carrageenin.

This study aimed to investigate the behavior of an endogenous beta-endorphin (beta-EP) in the brain after subcutaneous (s.c.) injection of carrageenin or intravenous (i.v.) injection of indomethacin (IDM). The carrageenin was injected into rat hind paw subcutaneously in order to evoke only a local nociceptive stimulus. The beta-EP concentration in the brain region was determined by radioimmunoassay at designated sampling times after the injection. It was observed that the beta-EP concentration in the midbrain declined from 2.8+/-0.3 at 1 h to 1.3+/-0.02 ng/mg protein at 9 h. After the s.c. injection of carrageenin, the beta-EP concentrations in the midbrain were found to be closely related to the nociceptive sensitivity which was determined by the Randall-Selitto test. On the other hand, a significant elevation of the beta-EP concentration was observed in the hypothalamus from 3 h until 5 h compared with that of control. IDM was injected into rats at doses of 2.9, 5.8 and 8.6 mg/kg via the femoral vein. After i.v. administration of IDM, the beta-EP increased in the hypothalamus, medulla oblongata, and midbrain, depending on the doses used. The value of hypothalamic beta-EP concentration was two times higher than that of carrageenin. We found that nociceptive stimuli and IDM brought a change in the beta-EP concentration in the brain of rats.

Animals↗

PubMed1997

Kinetic analysis of transcytosis of epidermal growth factor in Madin-Darby canine kidney epithelial cells.

PURPOSE: The aim of this study is to clarify the intracellular fate and a rate limiting step in transcytosis of epidermal growth factor (EGF) in Madin-Darby Canine Kidney (MDCK) epithelial cells. METHODS: The kinetics of transcytosis of 125I-EGF was investigated. To examine the fate of EGF molecules bound to its receptor on the cell surface. 125I-EGF was prebound to the basal surface at 4 degrees C, followed by extensive washing and subsequent incubation at 37 degrees C in EGF-free medium. RESULTS: Saturable transport of 125I-EGF through the cell monolayer could only be observed from the basal to apical side. Most (approximately 90%) of the EGF molecules bound to the surface receptor are internalized with a half-life of 1-3 min, followed by intracellular degradation with a half-life of 20-50 min. The exocytosis of internalized EGF into the apical medium is much slower with a half-life of 130-250 min. Even when 125I-EGF was incubated with MDCK cells at 37 degrees C and washed with acid to remove cell-surface 125I-EGF, intact 125I-EGF appeared in the basal medium with a half life of 160-170 min. CONCLUSIONS: The exocytosis of internalized EGF into the apical medium is a rate limiting step in EGF transcytosis. At least a small amount of internalized EGF is recycled.

Animals↗

PubMed1997

Pharmacokinetics of pentazocine and its occupancy of opioid receptors in rat brain.

In order to assess quantitatively the pharmacodynamic process of pentazocine (PTZ), time courses of its plasma concentration and of the occupation of specific opioid receptors in the brain were investigated after intravenous (i.v.) administration of PTZ to rats. The plasma concentration of PTZ was determined by HPLC and the pharmacokinetic parameters were analyzed using nonlinear least-squares analysis. Measurement of ex vivo receptor occupation was made by comparing the specific [3H]naloxone (opioid receptor antagonist) binding in vitro to the crude P2-synaptosomal fractions between vehicle-treated rats (control) and PTZ-treated rats. Following the i.v. administration of PTZ, the occupancy of specific opioid receptors decreased rapidly until 10 min, depending on the two pharmacological doses (2.5 and 10 mg/kg). The results strongly suggest the fast binding kinetics of PTZ in terms of its association with and dissociation from specific opioid receptor sites in the brain in addition to its fast rate of disappearance from the brain compartment. Furthermore, we demonstrated that the time profile of receptor occupancy correlated well (r = 0.8650) with that of the unbound concentration in plasma until 120 min after the i.v. administration of PTZ to rats.

Analgesics, Opioid↗

PubMed1997

Relationship between pharmacokinetics and the analgesic effect of indomethacin in the rat.

The relationship between the pharmacokinetic properties and the analgesic effect of indomethacin (IDM) was evaluated on a carrageenin-induced inflammation model in the rat. Rats were administered the drug in one of two ways: intravenous (i.v.) IDM bolus or i.v. IDM infusion. The analgesic activity was measured by Randall-Selitto test. No correlation was observed between the analgesic effect and the plasma IDM concentration after i.v. bolus administration of IDM. However, in the case of infusion, IDM produced a dose-dependent analgesic effect. In this paper, we demonstrated that the plasma concentration of IDM maintained by i.v. infusion had a prolonged analgesic effect on the carrageenin-induced inflammation model.

Animals↗

PubMed1997

Differential effects of buprenorphine and pentazocine on the regional cerebral metabolic rate for glucose in the conscious rat.

The effects of buprenorphine (BNP, 10-200 micrograms/kg, i.v.) and pentazocine (PTZ, 2.5-10 mg/kg, i.v.) on the regional cerebral metabolic rate for glucose (rCMRglc) were analyzed in nine anatomically discrete areas of the conscious rat brain by the simultaneous use of [14C]2-deoxyglucose, the glucose analogue that can be phosphorylated in the brain, and [3H]3-O-methylglucose, a nonmetabolizable glucose analogue. Originally, this method was developed by Gjedde and Diemer in the rat and in humans. The rCMRglc was significantly decreased by BNP (100 or 200 micrograms/kg) in most of the brain regions investigated, except the cerebellum. In contrast, PTZ (10 mg/kg) significantly increased rCMRglc in the cerebral cortex and medulla. In the cerebral cortex and medulla, the direction of the effect on rCMRglc was opposite for BNP (22% decrease at the dose of 200 micrograms/kg) and PTZ (22% increase at the dose of 10 mg/kg). These findings strongly suggest that the discrepancies between the marked effects of BNP (a partial mu agonist and kappa antagonist) and PTZ (a mu antagonist and kappa agonist) on rCMRglc reflect the selectivity of agonist action at the different types of opioid receptors, mu and kappa receptors, in the rat brain.

Analgesics, Opioid↗

PubMed1995

Induction of hepatic P-glycoprotein enhances biliary excretion of vincristine in rats.

To clarify the contribution of P-glycoprotein to the biliary excretion of vincristine in rats, the effects of induction of hepatic P-glycoprotein by a phenothiazine treatment on the biliary excretion of [3H]vincristine were investigated. Immunoblot analysis using C219, a monoclonal antibody to P-glycoprotein, demonstrated that the phenothiazine treatment increased the P-glycoprotein level in isolated bile canalicular membrane vesicles approximately 6.5-fold. Transport of [3H]vincristine to canalicular membrane vesicles from the phenothiazine-treated and control rats revealed ATP-dependency, with an overshoot that results from the consumption of medium ATP. The maximum ATP-dependent uptake was increased in canalicular membrane vesicles from the phenothiazine-treated rats approximately 2-fold compared to the control. The biliary excretion of [3H]vincristine was further studied using an indicator dilution method in a single-pass perfused liver. The ratios of the cumulative amount of [3H]vincristine excreted into the bile ot the amount of [3H]vincristine taken up by the liver at 15, 30 and 90 min were significantly increased in the phenothiazine-treated rats by 60, 45 and 25%, respectively, compared to the control rats. Furthermore, the corrected mean residence time of [3H]vincristine in hepatocytes in the phenothiazine-treated rats was reduced to 21 min from that in the control rats (30 min), supporting the contention that the induction of hepatic P-glycoprotein on the bile canalicular membrane function sas a transporter not only in the isolated membrane but also in the more physiological perfused liver system. One must be cautious in the interpretation of the data, however, since phenothiazine can induce other proteins which might affect the behavior of [3H]vincristine.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Effect of perfusate pH on the influx of 5-5'-dimethyl-oxazolidine-2,4-dione and dissociation of epidermal growth factor from the cell-surface receptor: the existence of the proton diffusion barrier in the Disse space.

The influx clearance (PSinf.MID) of the weak acid 5,5'-dimethyl-oxazolidine-2,4-dione (DMO) was determined by the multiple indicator dilution method with the isolated perfused rat liver under various perfusate pH conditions, ranging from 6.4 to 7.6. Although the pH partition theory predicted an increase in influx clearance of ten times in proportion to the change in the unionized fraction of DMO, there was no measurable change in this value. The effect of medium pH on the steady-state cell/medium concentration ratio (C/M) ratio of DMO was also investigated using isolated hepatocytes. The C/M ratio increased while medium pH decreased, but this change was less marked than predicted by the pH partition theory. Finally the pH dependency of the dissociation rate constant (koff) of epidermal growth factor from its receptor was also investigated using both isolated rat hepatocytes and the perfused rat liver. When the extracellular pH was changed from 6.4 to 5.6, the koff value of isolated hepatocytes increased 44 times, while that of the perfused rat liver increased only 9 times. Therefore, the effect of changing the extracellular pH on pH-dependent dissociation of epidermal growth factor from its cell-surface receptor was less in the perfused liver than in isolated hepatocytes. These findings, in addition to the well-known existence of the Na(+)-H+ exchanger on the sinusoidal membrane and the possible existence of the unstirred water layer in the Disse space, seem to suggest the existence of the proton diffusion barrier in the rat liver, which remains stronger in the perfused liver than in isolated hepatocytes.

Animals↗

PubMed1994

Kinetics of active efflux via choroid plexus of beta-lactam antibiotics from the CSF into the circulation.

To examine the role of the choroid plexus in eliminating organic anions from the cerebrospinal fluid (CSF), a kinetic study was performed both in in vivo and in vitro experiments using [3H]benzylpenicillin (PCG) as a model compound. In vivo, after intracerebroventricular administration, [3H]PCG was eliminated from the CSF much more rapidly than [14C]mannitol. Analysis of the elimination clearance from the CSF revealed that 12 and 24% of the disappearance of [3H]PCG can be accounted for by convective loss at a rate equivalent to CSF turnover, and by diffusional loss across the ependymal surface into the brain extracellular space, respectively. Approximately two-thirds of [3H]PCG elimination was due to a saturable process [Michaelis constant (Km) = 43.0 +/- 17.8 microM, maximum velocity (Vmax) = 619 +/- 286 pmol.min-1 x rat-1]. These kinetic parameters obtained in vivo were comparable to those determined previously in vitro, i.e., [3H]PCG was accumulated by the isolated rat choroid plexus via an active transport mechanism (Km = 58 microM, Vmax = 504 pmol.min-1 x rat-1; H. Suzuki, Y. Sawada, Y. Sugiyama, T. Iga, and H. Hanano, J. Pharmacol. Exp. Ther. 242: 660-665, 1987). Furthermore, other organic anions (probenecid, ampicillin, cefodizime, cefotaxime, and ceftriaxone) reduced the transport of [3H]PCG in a dose-dependent manner both in vivo and in vitro. A good correlation was observed between the log inhibition constant (Ki) values obtained for these ligands in vivo and in vitro (r = 0.94, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Acquired type II protein C deficiency in a long-term hemodialysis patient.

We present a 57-year-old man with end-stage renal failure due to chronic glomerulonephritis, who had been on hemodialysis for 13.5 years and had suffered from recurrent painful swelling of the left leg for 4.7 years. A diagnosis of deep venous thrombosis was made by the phlebography. Coagulation studies showed decreased protein C activity despite a normal protein C antigen level. None of his relatives had decreased protein C activity, and the levels of the other coagulation factors synthesized by the liver were all normal. Accordingly, the patient was diagnosed as having acquired type II protein C deficiency.

Glomerulonephritis↗

PubMed1994

Plasma urokinase-type plasminogen activator in patients with leukemias.

Plasma levels of urokinase-type plasminogen activator (u-PA) were measured with an enzyme-linked immunosorbent assay in patients with leukemias. As compared with healthy subjects (0.73 +/- SD 0.17 ng/ml), plasma u-PA antigen level was markedly elevated in patients with acute promyelocytic leukemia (APL) (1.76 +/- 0.89 ng/ml) at disease onset. Mean u-PA concentrations in patients with other acute nonlymphoblastic leukemia (0.57 +/- 0.51 ng/ml), acute lymphoblastic leukemia (0.77 +/- 0.82 ng/ml) and chronic myelocytic leukemia in blastic crisis (1.30 +/- 1.35 ng/ml) were not significantly elevated, but some of them showed an elevation of plasma u-PA. Plasma u-PA values were correlated with some of the fibrinolytic parameters such as FDP and D-dimer. Plasma u-PA antigen was decreased after the administration of antileukemic drugs in patients with APL. These results suggest that the coagulopathy in patients with various leukemias may in part be associated with u-PA release from the leukemic cells, especially in patients with APL.

Enzyme-Linked Immunosorbent Assay↗

PubMed1994

Multiple systems for the biliary excretion of organic anions in rats: liquiritigenin conjugates as model compounds.

Liquiritigenin (LG), 2, 3-dihydro-7-hydroxy-2-(4-hydroxyphenyl)-(S)-4H-1-benzopyran-4-1, is metabolized to five kinds of conjugates (glucuronides and sulfates) that are excreted predominantly into the bile (Shimamura et al., 1993). Using LG as a model compound, we studied the multiplicity for the biliary excretion of conjugates in vivo. LG was administered i.v. as a bolus to Sprague-Dawley rats (SD rats) that received i.v. infusions of the inhibitors [glycyrrhizin (GR), dibromosulfophthalein (DBSP) and indocyanine green (ICG)] at their maximal transport rates. The infusion of GR and that of DBSP reduced significantly the biliary excretion of all the conjugates except LG 4',7-O-disulfate (M3), whereas infusion of ICG did not affect the excretion of conjugates. To minimize the effect of the other tissues on the disposition of the conjugates, the apparent biliary excretion clearance (CLbile,app) was calculated. The CLbile,app values of LG 4'-O-glucuronide (M1), LG 7-O-glucuronide (M2), LG 4'-O-glucuronide 7-O-sulfate (M4) and LG 7-O-glucuronide 4'-O-sulfate (M5) were significantly reduced by GR and DBSP infusion, whereas the CLbile, app value of M3 was not affected by these inhibitors. The CLbile, app values of all the conjugates except M2 were not reduced by ICG infusion. In Eisai hyperbilirubinemic rats, which have a hereditary defect in the canalicular transport system for several organic anions, the biliary excretion clearance of M1, M2, M4 and M5 was markedly reduced, whereas that of M3 was comparable with that in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Establishment of a new cell line with the characteristics of a multipotential progenitor from a patient with chronic myelogenous leukemia in early erythroblastic crisis.

A novel cell line (KH88) was established from a patient with chronic myelogenous leukemia in blastic crisis. The leukemic blasts had the features of undifferentiated blasts with basophilic agranular cytoplasm and they were focally positive for acid phosphatase and alpha-naphthyl acetate esterase. CD36, CD33, HLADR, and CD71 were expressed on the surfaces of the blast cells. Most blasts were positive for platelet peroxidase activity, and some of them had granules containing aggregates of ferritin molecules. These findings were compatible with those of 'early' erythroblastic leukemia, this established cell line (KH88) having similar characteristics, and actually producing hemoglobin A and hemoglobin F. Although the KH88 cells were negative for megakaryocytic markers, they were induced to express CD41 by phorbol ester. Further, a few KH88 cells were positive for myeloperoxidase. This cell line was thus revealed to have the capacity to differentiate into three lineages, providing a useful model for studying the differentiation of multipotential stem cells. Moreover, a subline of KH88 had a peculiar chromosome abnormality, del(3)(q21q25); it would be useful to study the significance of this chromosomal abnormality.

Aged↗

PubMed1994

Multiple transport systems for organic anions across the bile canalicular membrane.

Multiplicity for the transport of organic anions across the bile canalicular membrane was studied in vivo and in vitro using dibromosulfophthalein (DBSP), [14C]cefodizime, [3H]leukotriene C4 (LTC4) and indocyanine green (ICG) as model compounds in rats. A high concentration of DBSP in plasma reduced the biliary excretion of cefodizime and leukotriene radioactivity to about 15 and 35% of their control values, respectively, but did not affect the excretion of ICG. A high plasma concentration of ICG reduced the excretion of cefodizime to about 60% of the control value, but exerted minimal effect on the excretion of leukotriene radio-activity and DBSP. In vitro, ATP-dependent uptake of LTC4 into the canalicular membrane vesicles was reduced by DBSP, cefodizime and ICG in a dose-dependent manner, with approximate IC50 values of 0.1 microM, 10 microM, and 1 microM, respectively. The hepatic unbound concentration of DBSP sufficient to reduce the excretion of cefodizime, leukotriene radioactivity and DBSP itself in vivo was calculated to be approximately 10 microM, a concentration which was also sufficient to reduce the transport of LTC4 in vitro. In contrast, the hepatic unbound concentration of ICG that saturated the excretion of ICG in vivo was calculated to be less than 0.1 microM, which was more than ten times smaller than the IC50 of ICG for the transport of LTC4 in vitro. These results suggest the presence of multiple systems for the transport of organic anions across the bile canalicular membrane: one is the predominant transport system for DBSP and cefodizime, which also accepts LTC4 as a substrate; the other is the primary transport system for ICG, which is distinct from that for DBSP, cefodizime and LTC4, although some overlap in the substrate specificity may be observed between the two systems.

Animals↗

PubMed1993

Comparative hepatic transport of desglycylated and cyclic metabolites of rilmazafone in rats: analysis by multiple indicator dilution method.

Rilmazafone (RZ) is an orally active sleep inducer which can be activated to its cyclic form (M1) via the labile desglycylated metabolite (DG). In this scheme, RZ is exclusively metabolized to DG and M1 by aminopeptidases in the small intestine. The concentration of M1 in the systemic plasma after oral administration of RZ has been reported to be higher than that observed after administration of M1, due to the lower hepatic extraction of DG than M1 (Koike et al., Drug Metab. Dispos., 16, 609 (1988)). In the present study, the disposition of DG and M1 in rat liver was investigated, using the multiple indicator dilution method. The hepatic availabilities (F) of DG and M1, assessed from the recovery into the hepatic vein, were 0.16 and 0.07, respectively, which was consistent with the previous in vivo finding that the first-pass elimination of M1 was greater than that of DG. The kinetic analysis based on the distributed model showed that the influx (k'1) and efflux (k'2) rate constants for M1 were larger than those for DG, whereas no significant difference in the sequestration rate constant (k'3) was observed between the two ligands. Based on the concept proposed by Miyauchi et al. (J. Pharmacokinet. Biopharm., 15, 25 (1987)), it was suggested that the determinant factor of the hepatic intrinsic clearance was the influx clearance for both ligands, because the values of k'2 for each ligand were much smaller than the respective k'3 values. It was concluded that the higher plasma concentration of M1 after oral administration of RZ than that observed after administration of M1 is due to the fact that the hepatic uptake of DG is lower than that of M1.

Administration, Oral↗

PubMed1993

Comparison of the hepatic uptake clearances of fifteen drugs with a wide range of membrane permeabilities in isolated rat hepatocytes and perfused rat livers.

The hepatic uptake clearances of 15 ligands with a wide range of permeabilities were determined in rats using two techniques: centrifugal filtration with isolated hepatocytes and the multiple indicator dilution (MID) method with isolated perfused livers. Some of the uptake clearance values were taken from the literature. Uptake clearance values obtained from isolated hepatocytes were extrapolated to that per gram liver (PSinf.cell), assuming that 1 g of liver has 1.3 x 10(8) cells. The values of PSinf.cell varied from approximately 0.1 to 72 (mL/min/g liver). The values of PSinf.cell were similar to those (PSinf.MID) determined by the MID method for ligands with uptake clearances below approximately 1 mL/min/g liver. However, for the ligands with larger uptake clearances, the PSinf.MID values were lower than the PSinf.cell values and appeared to reach an upper limit (approx. 15-20 mL/min/g liver). The PSinf.cell values of 1-propranolol, tetraphenylphosphonium (TPP+), and diazepam were 72, 43, and 22 mL/min/g liver, respectively, whereas their uptake clearances (PSinf.MID) determined by the MID method were 4 to 10 times lower. One of the possible mechanisms for this discrepancy is that an unstirred water layer, which may exist in Disse's space in isolated perfused livers (and probably under in vivo condition), limits the hepatic uptake rate of ligands with extremely high membrane permeabilities.

Animals↗