Biomedical subjects

T Terasaki

Publications and source records attributed to T Terasaki.

At least 19 recordsLinked to original sources

PubMed1999

Differences in the hepatobiliary transport of two quinolone antibiotics, grepafloxacin and lomefloxacin, in the rat.

The biliary excretion of grepafloxacin (GPFX) was compared with that of lomefloxacin (LFLX) in rats. The biliary clearances (Cl(plasma)(bile)) of GPFX was 2.9 times greater than LFLX based on the plasma concentration reached during constant intravenous (i.v.) infusion. The liver-plasma unbound concentration ratio, K(pu), of GPFX (1.7) was also higher than that of LFLX (0.7). The hepatic uptake clearance, assessed from an integration plot analysis, of GPFX was comparable with the hepatic blood flow rate, and 1.5 times that of LFLX, indicating that membrane transport in the uptake process is more efficient for GPFX. This was also supported by the difference between the uptake clearance of GPFX and LFLX in isolated rat hepatocytes. The bile-liver unbound concentration ratio of GPFX and LFLX was approximately 6 and 3, respectively, and the biliary clearance based on the unbound liver concentration of GPFX was 1.8 times that of LFLX. These results suggest that the concentrative transport of GPFX also across the canalicular membrane was more efficient than that of LFLX. Thus, the membrane transport activity via both sinusoidal and canalicular membranes determines the net excretion of each compound.

Animals↗

PubMed1999

A novel stromal cell-dependent B lymphoid stem-like cell line that induces immunoglobulin gene rearrangement.

A stroma-dependent B lymphoid cell line (B31-1) has been established by coculturing sorted stem cells on a novel bone marrow stromal cell line (TBR31-1). B31-1 cells express B220, but do not express other B lymphoid differentiation markers including CD43, heat stable antigen (HSA), or surface immunoglobulin (Ig) M (sIgM), and their Ig heavy chain (IgH) gene loci are germ-line in configuration. The addition of interleukin (IL)-7 or coculture with another stromal cell line, ST2, induces D-J rearrangement of the IgH gene and B lymphocyte differentiation markers. B31-1 cells restore an in vivo repopulation activity to lethally irradiated mice, and the repopulated cells differentiate to HSA+ pre-B cells.Continuous coculture results in two distinct populations, B220(-) c-Kit+ cells and B220(+) c-Kit+ cells; B220(-) c-Kit+ cells are self-renewed and differentiate to B220(+) c-Kit+ cells, while B220(+) c-Kit+ cells produce only B220(+) c-Kit+ cells. Both B220(-) and B220(+) cells similarly express the IgH germ-line transcript (Imu), mRNAs for recombinase (TdT, Rag-1, and Rag-2), and lymphoid-specific transcription factors (Pax-5, EBF, E12/E47, Oct-2, and Ikaros), but the DNA binding activity of Pax-5, EBF, Oct-2, and E2A are low in B220(-) cells and while high in B220(+) cells. These results suggest the existence of at least two active states in the IgH locus before the induction of IgH gene rearrangement during B lymphopoietic development.

Animals↗

PubMed1998

[Cerebral embolism with hemiballism due to putaminal lesion].

A 66-year-old man was admitted to our hospital because of hemiballism of his left extremities. The hemiballism disappeared soon after beginning therapy with haloperidol and chlorpromazine. X-ray CT brain scan on day 3 showed infarction in the right putamen and the right parietal lobe. Cerebral angiography on day 9 was normal. Transesophageal echocardiography revealed no abnormality except for an atrial septal aneurysm. Transcranial color-flow imaging demonstrated high intensity transient signal (HITS) with Valsalva maneuver. Paradoxical embolism was, therefore, thought to have caused the patient's brain infarction. It was speculated that the hemiballism was caused by disinhibition of the cortex resulting from loss of negative feedback in the motor system due to the putaminal lesion. It is necessary to treat hemiballism using an appropriate therapy to prevent exacerbation.

Aged↗

PubMed1998

Efflux of taurocholic acid across the blood-brain barrier: interaction with cyclic peptides.

The mechanism for the efflux of taurocholic acid (TC) across the blood-brain barrier (BBB) was studied by examining the elimination of [3H]TC after microinjection into the cerebral cortex. The efflux of [3H]TC from the brain was saturable with a Vmax of 15.0 pmol/min/g brain and a Km value of 0.396 nmol/0.2 microl injectate. Efflux was inhibited by cholic acid (CA), a cationic cyclic octapeptide (octreotide; a somatostatin analogue) and an anionic cyclic pentapeptide (BQ-123; an endothelin receptor antagonist), with an IC50 value of 1.09 nmol/0.2 microl injectate, 1.12 nmol/0.2 microl injectate and 0.12 nmol/0.2 microl injectate, respectively. Probenecid (20 nmol/0.2 microl injectate), but not p-aminohippuric acid (10 nmol/0.2 microl injectate), inhibited the brain efflux of [3H]TC. In addition, elimination of [3H]BQ-123 after microinjection was saturable with a Vmax of 20.8 pmol/min/g brain and a Km of 2.92 nmol/0.2 microl injectate; it was also inhibited by TC with an IC50 value of 0.074 nmol/0.2 microl injectate. In contrast, no significant efflux of [14C]octreotide from the brain was observed until 60 min after microinjection. These results suggest that both TC and BQ-123 are transported from the brain to the circulating blood across the blood-brain barrier via specific mechanisms. Although mutual inhibition was observed between TC and BQ-123, kinetic analysis suggested that the two transport systems differ.

Animals↗

PubMed1998

[Etiological studies on 17 cases of retinal artery occlusion and 16 cases of amaurosis fugax].

Here we present etiological studies on 17 patients (12 males, 5 females, mean age 64 +/- 13 years) with central retinal artery occlusion and branch retinal artery occlusion, and 16 patients (8 males, 8 females, mean age 62 +/- 13 years) with amaurosis fugax who were admitted to our hospital between April 1993 and May 1997. In all patients, carotid ultrasonography and cerebral angiography were performed to clarify the extent of carotid artery disease ipsilateral to the retinal artery occlusion and amaurosis fugax. All patients had clinical assessment of cardiac function and electrocardiogram, and most patients had transthoracic echocardiography, and transesophageal echocardiography as they were required. Arterial stenosis over 50% of the diameter, and occlusion of the internal carotid artery ipsilateral to symptomatic eye were more frequent in retinal artery occlusion than in amaurosis fugax. Two patients with retinal artery occlusion had transient atrial fibrillation, and one had patent foramen ovale with atrial septal aneurysm. One patient with amaurosis fugax had transient atrial fibrillation, and another patient had mechanical prosthetic heart valve. Two patients had antiphospholipid antibody, and one had dysfibrinogenemia. We recommended to investigate internal carotid artery in the patients with retinal artery occlusion, because occlusive disease ipsilateral to the symptomatic eye is more frequent and severe in retinal artery occlusion than in the cases of amaurosis fugax.

Aged↗

PubMed1998

[A case of paradoxical brain embolism in a 17-year-old boy].

A 17-year-old healthy high school boy suddenly suffered from consciousness disturbance immediately after a karate match. His neurological findings on admission were consciousness disturbance, motor aphasia, right hemiparesis, and right Babinski reflex. Cerebral angiography showed occlusion of the precentral branch of the left middle cerebral artery, and X-ray CT scan on the second day revealed low density area in its territory. No abnormality was found on transthoracic echocardiography or Holter ECG. Contrast transesophageal echocardiography with Valsalva maneuver was performed twice (the 2nd and the 14th day), and patent foramen ovale (PFO) was found only on the second trial. It was supposed that paradoxical embolism had occurred. Transesophageal echocardiography is necessary for the embolic patients of unknown origin, especially young adults. To find PFO, it is important to repeat contrast transesophageal echocardiography carefully. if it is negative on the first trial.

Adolescent↗

PubMed1998

Modulation of the tumor disposition of vinca alkaloids by PSC 833 in vitro and in vivo.

PSC 833, a nonimmunosuppressive cyclosporin, is able to inhibit the efflux of antitumor drugs mediated by P-glycoprotein (P-gp). The purpose of the present study is to compare the effect of PSC 833 on the tumor disposition of [3H]vincristine ([3H]VCR) and [3H]vinblastine ([3H]VBL) in in vitro and in vivo experiments from a pharmacokinetic point of view. In in vitro experiments, the effect of PSC 833 was investigated on the cellular uptake of [3H]VCR and [3H]VBL by HCT-15 and COLO 205, human colorectal tumor cell lines with extensive and minimal expression of P-gp, respectively. PSC 833 (2 microM) increased the cellular uptake of [3H]VCR and [3H]VBL by HCT-15 cells, but not that by COLO 205 cells, 8- and 6-fold, respectively, without affecting the initial influx rates. In addition, 2 microM PSC 833 reduced the efflux of [3H]VCR from HCT-15 cells to a level comparable with that from COLO 205 cells. Furthermore, the effect of PSC 833 on the tumor disposition of intravenously administered [3H]VCR and [3H]VBL was studied in tumor inoculated mice. Infusion of PSC 833 (10 microg/hr/mouse) increased the HCT-15 tumor disposition of [3H]VBL and [3H]VCR in vivo to a level comparable with that observed in vitro. These findings demonstrate that PSC 833 enhances the tumor disposition of vinca alkaloids by inhibition of P-gp-mediated efflux not only in vitro but also in vivo in a solid tumor model.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Efficient delivery of circulating poliovirus to the central nervous system independently of poliovirus receptor.

The transgenic (Tg) mice carrying the human gene for poliovirus receptor (PVR) are susceptible to poliovirus intravenously (i.v.) inoculated as well as intracerebrally or intraspinally inoculated. Thus, i.v.-inoculated poliovirus may invade the central nervous system (CNS) through the blood-brain barrier (BBB). To know the contribution of PVR to tissue distribution and BBB permeability of i.v.-inoculated polioviruses, these dissemination processes were investigated and compared between the Tg mice and non-Tg mice. Distribution profile of i.v.-inoculated poliovirus in various tissues of the Tg mice is similar to that in non-Tg mice. The data suggest that tissue distribution of the virus occurs independently of the transgene for PVR. The amount of poliovirus delivered to the CNS suggested the existence of a specific delivery system of the virus to the CNS. Virus accumulation in the CNS of the Tg mice was measured up to 7.5 hr after the i.v. inoculation. The viruses, regardless of whether the virulent or attenuated strain, seem to accumulate at a constant rate of approximately 0.2 microliter/min/g tissue. Similar phenomena were observed when the viruses were inoculated into non-Tg mice. The rates of the virus accumulation in the CNS are more than 100 times higher than that of albumin, which is considered not to permeate through the BBB via a specific transport system, and only three times lower than that of monoclonal antibody against transferrin receptor (OX-26), which is a potential candidate as a drug delivery vehicle specific to the CNS. These data suggest that polioviruses permeate through the BBB at a fairly high rate, independently of PVR and virus strains.

Animals↗

PubMed1997

Brain-to-blood active transport of beta-alanine across the blood-brain barrier.

A high-affinity antiluminal uptake system for beta-alanine was demonstrated in primary cultured bovine brain capillary endothelial cells (BCEC) for which K(t) is 66.9 microM. beta alanine uptake was energy-, sodium- and chloride ion-dependent. beta-amino acids strongly inhibited the uptake, while alpha- and gamma-amino acids had a little or no inhibitory effect. In ATP-depleted cells, the uptake was stimulated by preloading beta-alanine or taurine but not by L-leucine. These results suggest that beta-alanine is actively transported across the antiluminal membrane of BCECs that is common to beta-amino acids. The system may function for the efflux from the brain to blood.

Amino Acids↗

PubMed1997

Cell density-dependent mitogenic effect and -independent cellular handling of epidermal growth factor in primary cultured rat hepatocytes.

AIMS: Mitogenic effect and cellular handling of epidermal growth factor (EGF) were analyzed in primary cultured rat hepatocytes at several cell densities. METHODS/RESULTS: DNA synthesis, assessed by the incorporation of 125I-deoxyuridine, was accelerated by EGF at a low cell density while that stimulated by EGF was relatively low at the highest cell density, suggesting a cell density-dependent regulation of mitogenic response to EGF. An equilibrium binding study of 125I-EGF in the presence of various concentrations of unlabeled EGF at 0 degree C revealed that the dissociation constant (Kd) was 0.47-0.88 nM while the specific binding capacity (n) was 86-96 fmol/mg protein at each cell density. No significant difference was observed in the time profiles of the surface-bound, internalized, and degradation products of 125I-EGF, assessed per mg protein, between different cell densities. Based on a kinetic analysis of the time-profiles, the internalization rate constant and the degradation rate constant were found to be independent of cell density. CONCLUSIONS: These results indicate that the cellular binding and disposition of EGF are not regulated by cell density, and that the cell density-dependence of the mitogenic effect cannot be attributed to differences in the affinity or capacity of the EGF receptor, internalization, or degradation of EGF. We speculate that the cell density-dependent mitogenic response may be accounted for by the difference in other factors such as the signal transduction processes induced by the receptor binding of EGF, or the translocation of a small fraction of the total EGF to hepatocyte nuclei.

Animals↗

PubMed1997

Development and elongation of neurite-like outgrowth on small cell lung cancer cell lines.

One (Lu-134A) of nine human small cell lung cancer cell lines which grow as floating cell aggregates changed its morphology dramatically when cells were cultured on a coverslip coated with polyethylenimine or extracellular matrix of human lung adenocarcinoma cell line PC-9 cells. The Lu-134A cells adhered to the substrate and developed elongated cytoplasmic processes which gradually grew into long neuronal-like processes. These processes developed to a length of more than 10 times the cell body length after 20 days of culture. Addition of dibutyryl cyclic adenosine 3', 5'-monophosphate to the cells on these substrates remarkably promoted the development and elongation of the processes, which grew into a netlike arrangement. The characteristics of these elongated neuronal-like processes were studied using immunocytochemical and electron microscopical methods. The processes reacted intensely with monoclonal antibodies against beta-tubulin and microtubule-associated protein-2. The swelling portions of the distal tips of these processes reacted strongly with polyclonal antibody against synaptophysin. Neurosecretory granules and bundles of microtubules were observed within processes. These findings suggested that this human small cell lung cancer cell line (Lu-134A) differentiated into neuronal cells, and indicated that attachment of cells to a substrate is the key to the development of long neurite-like outgrowths.

Carcinoma, Small Cell↗

PubMed1997

In vivo and in vitro evidence for nonrestricted transport of 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein tetraacetoxymethyl ester at the blood-brain barrier.

2' ,7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein tetraacetoxymethyl ester (BCECF-AM), a fluorescence reagent for the measurement of intracellular pH with a molecular weight of 809 Da, was used to test the hypothesis that the blood-brain barrier (BBB) does not restrict the influx of substrate with a molecular weight greater than 600 Da. Using cultured bovine brain capillary endothelial cells (BCEC), the influx rate of BCECF-AM was found to be 151 +/- 2 microl/min/mg protein and was extrapolated to give 446 +/- 7 microl/min/g brain as a BBB permeability surface area product (PS). No significant saturation was observed for the initial in vitro uptake of BCECF-AM into BCEC at concentrations 0.1, 1.0 and 5.0 microM. The apparent activation energy of the initial uptake of BCECF-AM was found to be 5.09 kcal/mol. These results suggest that BCECF-AM is transported into the BBB by passive diffusion. The in vivo BBB PS value was also found to be 295 +/- 48 microl/min/g brain and 132 +/- 24 microl/min/g brain by the in situ brain perfusion and the carotid artery injection methods, respectively. No significant efflux of BCECF-AM from the brain was observed over a 120 sec washout period, suggesting that BCECF-AM is immediately hydrolyzed to BCECF, a hydrophilic analogue, in the brain after crossing the BBB. The octanol/water partition coefficient of BCECF-AM was found to be 5.66 +/- 0.27. The BBB PS value of BCECF-AM was predicted to be 105 microl/min/g brain, based on the relationship between the BBB PS value and the value of partition coefficient divided by the square root of the molecular weight. These results demonstrate that BCECF-AM transport across the BBB is not restricted despite its large molecular size.

1-Butanol↗

PubMed1997

In vivo evidence for carrier-mediated efflux transport of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine across the blood-brain barrier via a probenecid-sensitive transport system.

By analyzing the amount of ligand remaining in the brain after microinjection into the brain cortex, the apparent efflux rate constants (Keff) of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (DDI) across the blood-brain barrier at low concentrations were determined to be 0.0317 +/- 0.0068 min(-1) and 0.0253 +/- 0.0037 min(-1), respectively. At higher concentrations, efflux exhibited saturation. The concentration of unlabeled DDI to inhibit 50% of the saturable efflux of [3H]DDI was found to be 11.3 +/- 5.7 microM, assuming that DDI diffused into the same volume of brain as that of trypan blue after intracerebral administration. The efflux rate of [3H]AZT from the brain was significantly inhibited by DDI, probenecid, p-aminohippuric acid, benzylpenicillin and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, but not by thymidine. Moreover, the efflux rate of [3H]DDI was significantly inhibited by AZT and probenecid, but not by deoxyinosine and inosine. After intracerebroventricular injection, the apparent efflux clearances of [3H]AZT and [3H]DDI from the cerebrospinal fluid were significantly inhibited by the coadministration of probenecid. However, intracerebroventricularly administered probenecid had no effect on the efflux of [3H]AZT and [3H]DDI from the brain after intracerebral microinjection, which suggested that the efflux transport system of the blood-cerebrospinal fluid barrier is not responsible for the elimination of AZT and DDI from the cerebral cortex. These results provide kinetic evidence that AZT and DDI are transported from brain into circulating blood across the blood-brain barrier via a probenecid-sensitive carrier-mediated efflux transport system.

Animals↗

PubMed1997

Carrier-mediated hepatic uptake of the cationic cyclopeptide, octreotide, in rats. Comparison between in vivo and in vitro.

The plasma concentration and biliary excretion profiles of a cationic cyclic octapeptide, octreotide, were compared between control rats and rats given an intravenous infusion of a bile acid, taurocholate (TCA), and an organic anion, dibromosulfophthalein (DBSP). Both TCA and DBSP reduced the plasma elimination and biliary excretion of octreotide after its intravenous bolus administration. Two mechanisms accounting for this phenomenon were considered a priori: decreased hepatic uptake from blood to liver and decreased biliary excretion from liver to bile. The tissue uptake clearance (CLup) of octreotide in plasma and several tissues was determined, and extensive uptake of octreotide (0.20 ml/min/g liver) was observed only in liver. The kinetic analysis indicated that CLup in liver fell to 10% of controls after administration of both TCA and DBSP. To compare CLup between in vivo and in vitro, the initial velocity of octreotide uptake by isolated hepatocytes and primary cultured hepatocytes was measured. The estimated kinetic parameters KM and Vmax were approximately 100 microM and 200 pmol/min/10(6) cells in both systems, respectively. Hepatic uptake clearance estimated from the in vitro data was comparable with that observed in vivo. Biliary excretion of octreotide is reduced in Eisai hyperbilirubinemic rats (EHBRs), which have a heredity defect of multispecific organic anion transporter on the bile canalicular membrane, compared with that of Sprague-Dawley rats. The kinetic analysis demonstrated that the hepatic uptake was reduced in EHBRs. The uptake study using primary cultured hepatocytes suggested that a high level of unidentified endogenous substrate(s) in EHBR plasma may be responsible for the reduction of hepatic uptake of octreotide in EHBRs. In conclusion, we have demonstrated in vivo that carrier-mediated hepatic uptake of octreotide is inhibited by TCA and DBSP and that the CLup obtained in vivo is comparable with the CLup obtained in vitro in isolated hepatocytes and primary cultured hepatocytes.

Animals↗

PubMed1997

[Brain embolism associated with atrial septal aneurysm].

We studied the clinical significance of atrial septal aneurysm on brain embolism. Of two-hundred twenty-eight consecutive ischemic stroke patients, 128 cases were performed transesophageal echocardiography to find cardiac lesions that could be embolic sources. Three cases were diagnosed as having atrial septal aneurysm with right-to-left shunt demonstrated by contrast echocardiography under Valsalva maneuver. These cases were all diagnosed as brain embolism from clinical courses and findings from brain CT scan, and cerebral angiography. Neurosonologic study, 24 hours Holter ECG, and transthoracic echocardiography did not reveal any other embolic sources. Paradoxical embolic mechanism is supposed to have occurred in these cases. Atrial septal aneurysm often coexists with right-to-left shunt and is clinically significant as a finding suggesting paradoxical embolism.

Aged↗

PubMed1997

[A case of vertebral artery dissection with lateral inferior pontine syndrome and lateral medullary syndrome].

A 55-years-old woman had left neck pain and headache, dizziness, left Horner's sign, left abducens palsy, diplopia, left peripheral facial palsy, left loss of hearing, left tinnitus, left paralysis of vocal cord and soft palate, dysphagia, left limb ataxia, truncal ataxia, disturbance of temperature and pain sensation over Th10 on the right involving the right face. Left vertebral angiography revealed tapering occlusion of the left vertebral artery. Right vertebral angiography showed normal angiogram of the basilar artery and bilateral anterior inferior cerebellar arteries. MRI disclosed infarcts in the left lateral inferior pons, left lateral medulla, and cerebellum of territories in the anterior inferior cerebellar artery and posterior inferior cerebellar artery. T2 weighted image showed septum (intimal flap) in the left vertebral artery. This is the very rare case of lateral inferior pontine syndrome and lateral medullary syndrome due to the vertebral artery dissection.

Aortic Dissection↗

PubMed1997

Carrier-mediated hepatic uptake of quinolone antibiotics in the rat.

The systemic clearance of many quinolone antibiotics is mainly via metabolism and urinary excretion; by contrast, biliary excretion is a major route of elimination for a new quinolone grepafloxacin (GPFX). Accordingly, we studied the hepatic uptake of GPFX because it is the first step in the drug's hepatobiliary transport. The hepatic uptake of GPFX in vivo after i.v. administration was found to approach the hepatic blood flow, suggesting the existence of an effective hepatic uptake mechanism. To clarify this transport mechanism, GPFX uptake by isolated rat hepatocytes was examined and found to consist of a saturable component (Km 173 microM, Vmax 6.96 nmol/min/mg) and a nonspecific diffusion component. The inhibition of GPFX uptake by ATP-depletors and a lack of effect after replacing Na+ with choline demonstrated that the uptake was an Na+-independent carrier-mediated active process. This uptake was inhibited by other quinolones and for lomefloxacin this was competitive in nature. Mutual inhibition studies were undertaken to investigate whether the transporter for GPFX might be the same as other transporters so far identified. GPFX inhibited the uptake of taurocholic acid, pravastatin (organic anion), cimetidine (organic cation) and ouabain (neutral steroid). However, GPFX uptake was not inhibited by these compounds. Confirmation that GPFX uptake is blood flow limited was obtained by extrapolation of the in vitro data based on mathematical modeling. In conclusion, the effective hepatic uptake of quinolone antibiotics are via carrier-mediated active transport, which is distinct from that involved in the transport of bile acids, organic anions, organic cations or neutral steroids.

Animals↗

PubMed1997

Quantitative brain microdialysis study on the mechanism of quinolones distribution in the central nervous system.

Brain interstitial fluid (ISF) concentrations, which regulate the toxicodynamic effect of quinolone antimicrobial agents (quinolones) in the central nervous system, have been determined for norfloxacin, ofloxacin, fleroxacin, and pefloxacin using a quantitative brain microdialysis technique. Steady-state brain ISF concentrations of the quinolones were 7-30 times lower than the unbound serum concentrations due to restricted distribution in the brain. Cerebrospinal fluid concentrations of the quinolones were approximately twice as high as the brain ISF concentrations, except for norfloxacin. Thus, it seems that an active efflux transport system across the blood-brain barrier is responsible for maintaining brain ISF concentrations lower than unbound serum concentrations at steady-state. A good correlation was observed for norfloxacin, ofloxacin, fleroxacin, and pefloxacin between brain ISF concentrations and total brain concentrations. Moreover, a relatively small difference was observed among the quinolones for the in vitro brain slice-to-medium concentration ratio, compared with an 11-fold difference in the in vivo brain-to-unbound serum concentration ratio after intravenous infusion. These results indicate that the different quinolones studied all exhibit similar apparent binding and/or uptake by brain parenchyma, with an average brain ISF-to-total brain concentration ratio of 0.688.

4-Quinolones↗