Biomedical subjects

T Terasaki

Publications and source records attributed to T Terasaki.

At least 73 records · Page 4Linked to original sources

PubMed1997

Distributed model analysis of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine distribution in brain tissue and cerebrospinal fluid.

The restricted distribution of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (DDI) in brain tissue and cerebrospinal fluid (CSF) has been analyzed using the distributed model. The distribution volume of AZT and DDI in brain tissue (V(br)) was found to be 1.07 +/- 0.09 and 0.727 +/- 0.030 ml/g brain, respectively, in an in vitro brain slice uptake study. The pharmacokinetic parameters were obtained by fitting the concentration-time profiles of AZT and DDI in brain tissue and CSF after i.v. or i.c.v. administration taking the value of V(br), the CSF bulk flow rate (2.9 microl/min), and the surface area of the cerebroventricular ependyma (2.0 cm2), using a nonlinear least squares program combined with a fast inverse Laplace transform. The efflux transport clearance (PS(BBB,eff)) across the blood-brain barrier (BBB) and the symmetrical permeability clearance (PS(BBB)) across the BBB for AZT were calculated as 179 and 10.3 microl/min/g brain, respectively. The efflux transport clearance (PS(CSF,eff)) across the blood-cerebrospinal fluid barrier (BCSFB) and the symmetrical permeability clearance (PS(CSF)) across the BCSFB for AZT were calculated as 227 and 28.3 microl/min/ml CSF, respectively. For the distribution of DDI, the PS(BBB,eff) and PS(BBB) were 79.2 and 2.03 microl/min/g brain, respectively, while the PS(CSF,eff) and PS(CSF) for DDI were 196 and 5.88 microl/min/ml CSF, respectively. Based on simulation studies using the fitted parameters, a significant degree of efflux transport across the BBB and BCSFB has been suggested to be responsible for the restricted distribution of AZT and DDI in brain tissue and CSF, respectively.

Animals↗

PubMed1997

Kinetic evidence for active efflux transport across the blood-brain barrier of quinolone antibiotics.

A distributed model has been used to clarify the mechanism of the restricted and differential distribution of the quinolone antibiotics in the rat central nervous system (CNS). The symmetrical permeability clearances across the blood-brain barrier (BBB), PS(BBB), and across the blood-cerebrospinal fluid barrier (BCSFB), PS(CSF), and the active efflux clearances across the BBB, PS(BBB,eff), were obtained from a nonlinear least squares regression analysis combined with the fast inverse Laplace transforming program for in vivo data. The values of PS(BBB,eff) were 10- to 260-fold greater than those of PS(BBB), providing kinetic evidence to support the hypothesis that a significant efflux transport across the BBB is responsible for the limited distribution of quinolones in brain tissue. Moreover, by simulation studies, we could demonstrate the concentration profiles in the brain as a function of the distance from the ependymal surface. However, active efflux transport across the BCSFB has been suggested to have only a slight effect on the apparent elimination from the cerebrospinal fluid. Comparing the apparent brain tissue-to-unbound serum concentration ratio at steady state, it has been suggested that the net flux across the BBB, ie., the ratio of PS(BBB) to the sum of PS(BBB) and PS(BBB,eff), is a determinant for the differential distribution of these quinolones in brain tissue. Such a putative active efflux transport system would play a significant role in decreasing the brain interstitial fluid concentration of quinolones.

4-Quinolones↗

PubMed1997

Kinetic analysis of the disposition of MRK16, an anti-P-glycoprotein monoclonal antibody, in tumors: comparison between in vitro and in vivo disposition.

The kinetics of the disposition of MRK16, an anti-P-glycoprotein monoclonal antibody, was studied in two human colorectal tumor cell lines, HCT-15 and COLO205, whose P-glycoprotein expression is extensive and poor, respectively. In a series of in vitro binding studies, the amount of MRK16 associated with HCT-15 cells at steady state was approximately 40 times greater than that associated with COLO205 cells. In in vivo studies, the disposition of MRK16 was determined in tumor-bearing mice after intravenous administration. The difference in the tumor-to-plasma concentration ratio between the two cell lines was only 2.3-fold at 72 hr after injection. To explain the large difference observed between the in vitro and in vivo results, a series of kinetic simulation studies were performed. By considering the physiological parameters specific for MRK16 (such as permeability-surface area product and the kinetic parameters determined in vitro), the time profiles for the tumor concentration were predicted. The predicted difference in the tumor-to-plasma concentration ratio at 72 hr was calculated to be 2.6-fold, although the permeability-surface area product across the tumor capillary and other physiological parameters were comparable between the two tumor cell lines. The discrepancy between the in vitro and in vivo results was accounted for by the fact that the tumor extracellular fluid concentration at this time point was 13-fold lower in HCT-15 tumors than in COLO205 tumors because of the restricted penetration of MRK16 through the tumor capillaries. This finding suggests that this factor accounts for the in vitro and in vivo difference in the tumor disposition of MRK16.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

P-Glycoprotein mediates the efflux of quinidine across the blood-brain barrier.

Recent studies suggest that P-glycoprotein located on the blood-brain barrier restricts the brain uptake of its substrates. We examined the role of P-glycoprotein on the restricted entry of quinidine to the brain. Quinidine is a well known inhibitor of P-glycoprotein, although it is not yet clarified whether quinidine is the substrate for P-glycoprotein. Kinetic analysis of the uptake of quinidine into the rat brain after intravenous bolus administration revealed that the net uptake clearance is 25.5 microl/min/g brain. Intravenous administration of SDZ PSC 833, a multidrug resistance modifier, enhanced the net uptake clearance of quinidine by 15.7-fold. In contrast, no enhancement by SDZ PSC 833 was observed for the brain uptake of mannitol, a marker for the passive diffusion across the blood-brain barrier. The elimination of [3H] quinidine from the rat brain after microinjection into the cerebral cortex was inhibited by preadministered unlabeled quinidine and verapamil. In addition, the brain-to-plasma concentration ratio of quinidine at 10 min after intravenous administration was 27. 6-fold higher in mdr1a knock-out mice than in control mice. These results suggest that P-glycoprotein mediates the efflux of quinidine across the blood-brain barrier, resulting in its restricted entry to the brain.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Selective brain to blood efflux transport of para-aminohippuric acid across the blood-brain barrier: in vivo evidence by use of the brain efflux index method.

Efflux transport of para-aminohippuric acid (PAH) across the blood-brain barrier (BBB) has been demonstrated by use of the brain efflux index (BEI) method. PAH was eliminated from the ipsilateral cerebrum extensively with an apparent efflux rate constant of 0.0587 (min-1) after microinjection into a cerebral cortex region termed Par2. This efflux transport showed a saturation with the Michaelis constant of approximately 400 microM. No more than 3% dose of PAH and carboxyl-inulin, used as a reference compound showing limited permeability at the BBB, were found in the contralateral cerebrum, cerebellum or cerebrospinal fluid up to 20 min after administration. Under saturated conditions for carrier-mediated efflux of PAH via the blood-cerebrospinal fluid barrier, the BEI value of PAH did not change significantly, which suggested that blood-cerebrospinal fluid barrier was not responsible for the elimination of PAH from the brain after microinjection. No significant metabolism of PAH was demonstrated in the brain for at least 20 min after microinjection, and most of the radioactivity in the ipsilateral and contralateral carotid veins was as the intact form. With the distribution volume of PAH, 0.800 ml/g brain, obtained from the brain slice uptake experiment, the apparent efflux clearance was calculated as 46.9 microl/min/g brain. In addition, the influx clearance of PAH across the BBB determined by the in vivo brain uptake index method was much smaller than the efflux clearance, which demonstrates that BBB transports PAH selectively from the brain to the circulating blood.

Animals↗

PubMed1997

[Cerebral embolism due to lone atrial septal aneurysm].

A 71-year-old man was admitted to our hospital because of headache and left hemiparesis. Brain CT scan showed hemorrhagic infarction of the right frontal lobe. Intravenous digital subtraction angiography revealed no occlusion of cerebral arteries. No arrhythmias were observed by the holter ECG. Transthoracic echocardiography showed no abnormalities. Anticoagulation therapy (heparin and warfarin) was started under the diagnosis of cerebral embolism without definite embolic source and there was no recurrence during following four years. Transesophageal echocardiography showed an atrial septal aneurysm (ASA) without patent foramen ovale. A potential cause of cerebral embolism due to atrial septal aneurysm is paradoxical embolization through an interatrial shunt (patent foramen ovale). It was speculated that ASA was a direct source of thrombus formation in this case (lone ASA). Transesophageal echocardiography should be performed to find atrial septal aneurysm in patients with cryptogenic stroke, especially embolic stroke without definite embolic sources.

Aged↗

PubMed1996

Kinetics of quinolone antibiotics in rats: efflux from cerebrospinal fluid to the circulation.

PURPOSE: An active transport system, which pumps quinolone antimicrobial agents (quinolones) from cerebrospinal fluid (CSF) to systemic blood, exists at the choroid plexus, an epithelial tissue that forms the blood-CSF barrier (BCSFB). The present study was carried out to clarify the contribution of this transport system to the disposition of quinolones in the central nervous system. METHOD: Six quinolones were administered intracerebroventricularly to rats and their elimination from the CSF was examined. The inhibitory effect of probenecid and quinolones on the efflux of fleroxacin from the CSF was also examined. Probenecid or two types of quinolone (AM-1155, pefloxacin) were co-administered intracerebroventricularly with fleroxacin. RESULTS: The elimination clearance from the CSF for norfloxacin, AM-1155, fleroxacin, ofloxacin, sparfloxacin and pefloxacin was 14, 22, 21, 20, 47 and 35 microliters/min/rat, respectively. An approximately 3.5-fold difference was thus observed between norfloxacin and sparfloxacin. These values were 4- to 14-fold larger than the [14C]mannitol clearance. Furthermore, the elimination clearance of quinolones from the CSF was 7- to 60-fold larger than the active efflux clearance at the BCSFB estimated from our previous in vitro data. Co-administration of AM-1155, pefloxacin and probenecid did not inhibit the elimination of fleroxacin from the CSF. CONCLUSIONS: The active transport system at the BCSFB plays only a small part in the elimination of quinolones from the CSF. Passive diffusion via the BCSFB and diffusion across the ependymal surface into brain extracellular fluid, followed by efflux across the blood-brain barrier, may be the predominant pathway for quinolone elimination from the CSF.

4-Quinolones↗

PubMed1996

Characterization of the transport properties of a quinolone antibiotic, fleroxacin, in rat choroid plexus.

PURPOSE: It is reported that the cerebrospinal fluid (CSF) to plasma unbound concentration ratio of fleroxacin at steady-state is approximately 0.5 in experimental animals. These results can be accounted for by assuming the presence of an active transport system for the efflux of this compound across the choroid plexus. In the present study, the transport system for fleroxacin was characterized in isolated rat choroid plexus. METHODS: Choroid plexus was isolated from the lateral ventricles of rats. The accumulation of [14C] fleroxacin or [3H] benzylpenicillin by the choroid plexus was examined by the centrifugal filtration method. RESULTS: The accumulation of [14C] fleroxacin by the rat isolated choroid plexus was significantly inhibited by metabolic inhibitors (rotenone, 30 microM and carbonyl cyanide rho-trifluorometh oxyphenylhydrazone (FCCP), 100 microM) and sulfhydryl reagent (p-chloromercuribenzenesulfonic acid (PCMBS), 100 microM). This accumulation was composed of a saturable component (Vmax = 240 pmol.min-1.microliter tissue-1, Km = 664 microM) and non-saturable one (P = 0.424 min-1.microliter tissue-1). Accumulation of fleroxacin was competitively inhibited by benzylpenicillin and probenecid with Ki values of 29 microM and 51 microM, respectively. These values are comparable with the Km of benzylpenicillin transport and the Ki of probenecid for the benzylpenicillin transport at the choroid plexus, respectively. Furthermore, fleroxacin inhibited competitively the accumulation of [3H] benzylpenicillin with a Ki of 384 microM, a value comparable with the Km of [14C] fleroxacin transport. CONCLUSIONS: Fleroxacin and benzylpenicillin showed mutual competitive inhibition, suggesting that both are transported via a common transport system in the choroid plexus and are pumped out from CSF into the circulation.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1996

Sodium and chloride ion-dependent transport of beta-alanine across the blood-brain barrier.

The characteristics of beta-alanine transport at the blood-brain barrier were studied by using primary cultured bovine brain capillary endothelial cells. Kinetic analysis of the beta-[3H]alanine transport indicated that the transporter for beta-alanine functions with Kt of 25.3 +/- 2.5 microM and Jmax of 6.90 +/- 0.48 nmol/30 min/mg of protein in the brain capillary endothelial cells. Beta-[3H]Alanine uptake is mediated by an active transporter, because metabolic inhibitors (2,4-dinitrophenol and NaN3) and low temperature reduced the uptake significantly. Furthermore, the uptake of beta-[3H]alanine required Na+ and Cl- in the external medium. Stoichiometric analysis of the transport demonstrated that two sodium ions and one chloride ion are associated with one beta-alanine molecule. The Na+ and Cl--dependent uptake of beta-[3H]alanine was stimulated by a valinomycin-induced inside-negative K+-diffusion potential. beta-Amino acids (beta-alanine, taurine, and hypotaurine) inhibited strongly the uptake of beta-[3H]-alanine, whereas alpha- and gamma-amino acids had little or no inhibitory effect. In ATP-depleted cells, the uptake of beta-[3H]alanine was stimulated by preloading of beta-alanine or taurine but not L-leucine. These results show that beta-alanine is taken up by brain capillary endothelial cells, via the secondary active transport mechanism that is common to beta-amino acids.

Amino Acids↗

PubMed1996

Mitochondrial biosynthesis controls the sensitivity of Chinese hamster cells to hydrogen peroxide.

The mechanism of H2O2-resistance of Hpr-4, a variant of Chinese hamster V79 cells, was investigated. The effect of H2O2 on the mitochondria of the parental and Hpr-4 cells was compared. First, both biochemical and ultrastructural results showed that mitochondria in the parental cells were damaged by exposure to H2O2, while those in Hpr-4 cells recovered from the damage. Second, the H2O2-resistance of Hpr-4 cells was reversibly reduced or recovered by the addition or removal of inhibitors of mitochondrial biosynthesis, respectively. Third, the parental cells were auxotrophic to pyruvate after exposure to H2O2. Fourth, H2O2-sensitivity of the parental cells was also enhanced by the inhibition of mitochondrial biosynthesis. From these results, it was concluded that the mitochondria of Hpr-4 cells apparently had a greater resistance to H2O2 than those of the parental cells and that functional mitochondria were involved in the recovery of Chinese hamster V79 cells from H2O2-induced damage.

Adenosine Triphosphate↗

PubMed1996

[Self-test of morning urine with urinary dipsticks for 7 consecutive days for asymptomatic microscopic hematuria].

BACKGROUND: The frequency of hematuria and proteinuria was assessed in terms of the existence of glomerular disorders. METHODS: Fifty-five patients with asymptomatic microscopic hematuria, in whom no urological disorders were recognized, were used in this study. The frequency of hematuria and proteinuria was assessed by self-test of the first voided urine in the morning with urinary dipsticks for 7 consecutive days. Hematuria (proteinuria) was judged positive when reaction for hematuria (proteinuria) on a dipstick was 1+ or more, and negative when reaction was - or +/-. On the basis of self-test, the frequency of hematuria (proteinuria) was classified into 3 types as follows: Type C, positive hematuria (proteinuria) recognized continuously throughout 7 days; Type S, positive and negative hematuria (proteinuria) recognized sporadically; Type N, negative hematuria (proteinuria) recognized throughout 7 days. The results were evaluated in terms of the existence of glomerular disorders, as revealed by renal biopsy. RESULTS: Self-tests were completed successfully in 53 (96%) out of 55 patients at the first attempt. Of these 55 patients 32 (58%) were Type C hematuria, 14 (26%) were Type S hematuria and 9 (16%) were Type N hematuria. The incidence of glomerular disorders was significantly higher in patients with Type C (81%, p < 0.0001) and Type S (71% p < 0.01) hematuria than those with Type N (0%) hematuria. CONCLUSION: The presence of hematuria confirmed by self-test used in the present study was suggestive of glomerular disorders.

Adolescent↗

PubMed1996

Brain efflux index as a novel method of analyzing efflux transport at the blood-brain barrier.

A brain efflux index method has been developed to characterize an efflux transport system for substrates from the cerebrum to the circulating blood across the blood-brain barrier. The brain efflux index value is defined as the relative amount of test drug effluxed from cerebrum compared with that of a reference compound, [14C]carboxylinulin, which has limited blood-brain barrier permeability. Microinjection of 0.2, 0.5 or 1.0 microliter into the parietal cortex area 2 region was found to be an appropriate procedure for obtaining a high recovery and for restricting the test drug and reference compound to the ipsilateral cerebrum. No significant increase in influx clearance of [14C]carboxylinulin into the brain was observed for the ipsilateral cerebrum after the sham microinjection compared with the contralateral cerebrum, which demonstrated that only limited physical damage is caused. Microinjection of [3H]H2O into the cerebrum devoid of cerebral blood flow yielded no elimination from the brain. Analysis based on a pharmacokinetic model demonstrated that the elimination of a highly permeable compound [3H]H2O from the brain was governed by cerebral blood flow. The apparent elimination rate constant (Kel) of [3H]3-O-methyl-D-glucose from the brain was determined as 0.129 +/- 0.014 (min-1) and was reduced significantly by a preinjection of excess cold 3-O-methyl-D-glucose and phloridzin, whereas no significant elimination was observed for L[3H]glucose. The efflux clearance of 3-O-methyl-D-glucose was calculated from the Kel value and the compound's distribution volume, the value being close to that of the influx clearance. These results demonstrate that the brain efflux index method is a useful technique for analyzing an efflux process from the brain across the blood-brain barrier involving a carrier-mediated transport system.

Animals↗

PubMed1996

[A case report of thoracic aortic and common carotid artery dissecting aneurysm diagnosed by duplex ultrasound examination].

A 61-year-old man was admitted to our hospital because of sudden consciousness disturbance, aphasia and right-side hemiparesis. On admission his blood pressure was 124/74mmHg, and his pulse was a regular rate of 46 beats per minute. Electrocardiogram was normal. Thirty minutes after the onset brain computed tomographic (CT) scan showed no abnormality. Fifty minutes after the onset cervical ultrasound examination with color-coded Doppler demonstrated a subintimal dissection with a false channel of the left common carotid artery. Eighty minutes after the onset thoracic CT scan demonstrated the false lumen in ascending and descending thoracic aortic artery. Cervical CT scan showed a dissection with a false channel of the left common carotid artery. We could diagnose him as cerebral infarction due to thoracic aortic and common carotid artery dissection by means of ultrasound examination within 80 minutes after the onset. He spontaneously and fully recovered three days later. We emphasize the usefulness of noninvasive technique such as cervical ultrasound examination with color-coded Doppler in the diagnosis and follow-up of common carotid artery dissection.

Aortic Dissection↗

PubMed1996

Comparative distribution of quinolone antibiotics in cerebrospinal fluid and brain in rats and dogs.

The distribution of the quinolone antibiotics, norfloxacin (NFLX), AM-1155, fleroxacin (FLRX), ofloxacin, sparfloxacin (SPFX) and pefloxacin (PFLX), in the central nervous system (CNS) was investigated in dogs and rats. In dogs, the steady-state cerebrospinal fluid (CSF) to unbound serum concentration ratio (Kp,uCSF) differed widely ranging from 0.11 (NFLX) to 1.0 (PFLX). About a 10-fold difference between compounds was also observed in the Kp,uCSF in rats; however, these values were 25 to 50% smaller than those in dogs. Similarly, the brain to unbound serum concentration ratio (Kp,uBrain) of quinolones differed widely ranging from 0.15 (NFLX) to 1.5 (SPFX) in dogs and 0.04 (NFLX) to 0.33 (FLRX) in rats. The steady-state concentration ratio between CSF and brain tissue exhibited a 3-fold difference among quinolones (0.5 for PFLX to 1.6 for SPFX) in dogs, whereas, these values were all close to unity in rats. Kp,uBrain and Kp,uCSF all increased as the lipophilicity of the compound increased (except the Kp,uBrain in dogs). We also found that the quinolones inhibited the saturable accumulation of [14C]FLRX (Km 660 microM) by the isolated rat choroid plexus. About a 20-fold difference among the apparent IC50 values for FLRX transport was observed between NFLX (6000 microM) and PFLX (300 microM). The absence of a negative correlation between the affinity of the quinolones for this transport system, which in turn represents the efflux clearance from the CSF, and their in vivo distribution in rat CNS (Kp,uBrain or Kp,uCSF) suggests a minor contribution of this efflux system to the CNS distribution of quinolones.

Animals↗

PubMed1996

Cellular uptake mechanism for oligonucleotides: involvement of endocytosis in the uptake of phosphodiester oligonucleotides by a human colorectal adenocarcinoma cell line, HCT-15.

We used a 20-mer antisense oligonucleotide against human MDR1 mRNA to study the mechanism of uptake of oligonucleotides by a human colorectal adenocarcinoma cell line, HCT-15.5'-end-32P-labeled oligonucleotides were mainly used. The uptake of phosphodiester oligonucleotides (D-oligo) by HCT-15 cells increased with time, but the uptake of phosphorothioate oligonucleotides (S-oligo) showed minimal increases with time. HeLa cells showed a 4-fold greater D-oligo uptake than did HCT-15 cells, and other cell lines exhibited a 25-fold lower uptake than did HCT-15 cells. On the other hand, S-oligo uptake varied only severalfold among the cell lines used. Doligo up-take consisted of a saturable component (Michaelis constant K(m) = 0.16 microM and maximal uptake rate Vmax = 4.8 pmol/min/mg for HCT-15 cells and K(m) = 0.21 microM and Vmax = 35.6 pmol/min/mg for HeLa cells), i.e., the difference between the cell types was mainly in Vmax. The uptake of labeled D-oligo was inhibited by unlabeled S-oligo at a much lower concentration (Ki = 0.01 microM) than by unlabeled D-oligo (K(m) = 0.16 microM), although the uptake rate of D-oligo was greater than that of S-oligo. The D-oligo uptake was highly temperature dependent. Of the sulfhydryl-modifying reagents (p-chloromercuriphenyl-sulfonic acid and p-chloromercuribenzoic acid), only p-chloromercuribenzoic acid inhibited D-oligo uptake, suggesting the involvement of a protein whose sulfhydryl residues inside the cell are critical for D-oligo uptake. Chloroquine and monensin, which are known to alter the intracellular fate of ligands and receptors, did not affect D-oligo uptake, but phenylarsine oxide, an inhibitor of internalization processes, inhibited uptake significantly. Down-regulation and recovery of D-oligo uptake induced by excess unlabeled D-oligo pretreatment occurred, but this was only partial. Studies with a digitonin equilibrium method and confocal microscopy indicated that intracellular localization of D-oligo was mainly in a vesicular compartment. More stable 3'-end-32P-labeled oligonucleotides were also used, to compare their uptake characteristics with those of the 5'-end-labeled oligonucleotides. The uptake characteristics for the two labels were similar in terms of saturability, greater D-oligo uptake, compared with S-oligo, and the inhibitory effect of p-chloromercuribenzoic acid; however, the stable 3'-end label showed greater uptake than the 5'-end label. Our findings suggest that D-oligo uptake by HCT-15 cells is mediated by endocytosis involving binding sites on the plasma membrane.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗

PubMed1996

Study of the repairing process of gastric ulcer using multivariate analysis of bFGF-positive cells, haemodynamics, PAS-positive mucus amount and glandular index in the gastric mucosa.

To investigate pathophysiological diversities in the repairing process of gastric ulcer, distribution density of basic fibroblast growth factor (bFGF)-positive fibroblasts and myofibroblasts and vascular endothelial cells, mucosal haemoglobin content, PAS-positive mucus amount and glandular index were compared in the peripheral region of an open ulcer (the unhealed group; n = 17), the central region of a red scar (the red scar group; n = 32) and the central region of the white scar (white scar group; n = 32). Density of bFGF-positive fibroblasts and myofibroblasts and vascular endothelial cells was highest in the unhealed group, followed by the red scar group, while the white scar group showed a low value close to control. Mucosal haemoglobin content was high in the red scar and unhealed groups. PAS-positive mucus amount in the unhealed and red scar groups showed lower values compared with that in the white scar group. Glandular index in the unhealed group was the lowest, followed by the red scar group, while the white scar group neared control values. Statistically significant correlations were observed between the density of bFGF-positive "fibroblasts and myofibroblasts' and density of bFGF-positive vascular endothelial cells, between the density of bFGF-positive vascular endothelial cells and mucosal haemoglobin content and between the PAS-positive mucus amount and glandular index. Discriminant analysis demonstrated that the unhealed group could be distinguished from the red and white scar groups, based on glandular index, density of bFGF-positive "fibroblasts and myofibroblasts', mucosal haemoglobin content and PAS-positive mucus amount, while the red scar group could be discriminated from the white scar group based on the density of bFGF-positive "fibroblasts and myofibroblasts', density of bFGF-positive vascular endothelial cells, glandular index, haemoglobin content and PAS-positive mucus amount. The white scar group was difficult to discriminate from control. Our present results show that the recovery of glandular formation and mucus production continues throughout the repairing process, whereas the acceleration of angiogenesis and granulation formation is observed only in unhealed ulcers and at the red scar stage.

Biopsy↗

PubMed1996

Mechanism of the tissue distribution and biliary excretion of the cyclic peptide octreotide.

The hepatobiliary transport and tissue distribution of the cationic cyclooctapeptide octreotide were studies at steady state after its infusion, at various rates, in rats. After an increase in steady-state plasma concentration, marked decrease in the tissue to plasma concentration ratio was observed only in pancreas, the target organ of octreotide. A marked decrease in the biliary excretion clearance, defined with respect to the concentration in the liver, was also observed, suggesting that a transport carrier was involved in the biliary excretion. The plasma elimination and biliary excretion profiles of octreotide were determined in Eisai hyperbilirubinemic rats (EHBR), which have an hereditary defect of the active transport carrier for organic anions in bile canalicular membranes. Although biliary excretion of octreotide was significantly reduced in EHBR, compared with normal Sprague-Dawley rats, no difference was observed in biliary excretion clearance, defined with respect to the concentration in the liver, between Sprague-Dawley rats and EHBR. On the other hand, the liver to plasma concentration ratio in EHBR fell to half that in Sprague-Dawley rats. These results suggest that the decreased biliary excretion of octreotide in EHBR is due not to reduced biliary excretion ability but to reduced hepatic uptake of octreotide. We studied in vitro transport using bile canalicular membrane vesicles. A significant increase in the transport of octreotide by bile canalicular membrane vesicles was observed in the presence of ATP, and the estimated kinetic parameters K(m) and Vmax were 6.5 microM and 370 pmol/min/mg of protein, respectively. Similar ATP-dependent uptake was observed in bile canalicular membrane vesicles prepared from EHBR. We concluded that the biliary excretion of octreotide is by ATP-dependent primary active transport and that the carrier system for octreotide differs from the so-called "canalicular multispecific organic anion transporter," which is absent in EHBR.

Animals↗

PubMed1995

Na(+)- and Cl(-)-dependent transport of taurine at the blood-brain barrier.

The characteristics of carrier-mediated transport of taurine at the blood-brain barrier (BBB) were studied by using primary cultured bovine brain capillary endothelial cells (BCECs), in situ brain perfusion and brain capillary depletion methods in rats. The uptake of [3H]taurine by cultured cells showed that the active transporter functions on both the luminal and antiluminal membranes of BCECs. The kinetic parameters for the saturable transport of taurine were estimated to be: for the luminal uptake, the Michaelis constant, Kt, was 12.1 +/- 0.5 microM, and the maximum uptake rate, Jmax, was 4.32 +/- 0.05 nmol/30 min/mg protein; for the antiluminal uptake, Kt was 13.6 +/- 2.4 microM and Jmax was 2.81 +/- 0.22 nmol/30 min/mg protein. The luminal and antiluminal uptakes of [3H]taurine were each dependent on both Na+ Cl-. Stoichiometric analyses suggest that two Na+ and one Cl- are associated with the luminal uptake of one taurine molecule. beta-Amino acids such as beta-alanine and hypotaurine strongly inhibited the uptake of [3H]taurine, whereas alpha- and gamma-amino acids had little or no effect. Furthermore, by in situ brain perfusion and in vivo brain capillary depletion methods, the carrier-mediated transport found by in vitro experiments was confirmed to function for the translocation of the taurine molecule from the vascular space into the brain. From these results, it was concluded that a Na+ and Cl- gradient-dependent transport (uptake) system for taurine exists in both the luminal and the antiluminal membranes of BCECs.

Amino Acids↗