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T Nagasaki

Publications and source records attributed to T Nagasaki.

At least 37 records · Page 2Linked to original sources

Relationship between the CYP2D6 genotype and the steady-state plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine.

The relationship between the cytochrome P450 (CYP) 2D6 genotype and the steady-state plasma concentrations (Css) of trazodone and its active metabolite m-chlorophenylpiperazine (mCPP) was studied in 54 depressed Japanese patients receiving trazodone 150 mg at bedtime. By use of allele-specific PCR analysis, the wild type allele, three mutated alleles causing absent enzyme activity (CYP2D6A, CYP2D6B and CYP2D6D) and one mutated allele causing decreased enzyme activity (CYPZD6 Ch) were identified. The means (ranges) of the Css of trazodone, corrected to the median body weight in 17 cases with no mutated allele, 27 cases with one mutated allele and 10 cases with two mutated alleles, were 556 (281-1115), 643 (302-1362) and 671 (234-1418) ng/ml, respectively, while the values of mCPP were 60 (35-121), 65 (33-99) and 58 (38-112) ng/ml, respectively. Neither the Css of trazodone (F = 0.80, P = 0.45) nor that of mCPP (F = 0.49, P = 0.61) significantly differed among the three groups. The present study thus suggests that the CYP2D6 genotype cannot predict the Css of these compounds.

Adult↗

Relationship between single oral dose pharmacokinetics of alprazolam and triazolam.

The relationship between the single oral dose pharmacokinetics of alprazolam and triazolam was studied in 10 healthy male volunteers. Each subject took single oral doses of alprazolam 0.8 mg and triazolam 0.5 mg with at least a 2 week interval between each dose. Blood samplings were performed up to 48 h after alprazolam dosing and up to 12 h after triazolam dosing. Plasma concentrations of both drugs were measured by high-performance liquid chromatography. The means +/- standard deviation of the peak plasma concentration, the total area under the plasma concentration-time curve and the elimination half-life of alprazolam were 11.3 +/- 3.1 ng/ml, 232.4 +/- 59.2 ng/h/ml and 16.5 +/- 4.6 h, respectively, and those of triazolam were 3.2 +/- 1.0 ng/ml, 11.8 +/- 5.2 ng/h/ml and 2.5 +/- 1.1 h, respectively. There was no significant correlation between the two drugs in any pharmacokinetic parameters (r = 0.35, 0.25 and 0.50). The present study thus suggests that the single oral dose pharmacokinetics of alprazolam and triazolam do not correlate well in individuals.

Adult↗

[Changes in symptom and thermography images after lumbar sympathetic ganglion block].

In 35 lower limbs of 22 patients with peripheral circulation disturbance, we evaluated the effects of lumbar sympathetic ganglion block (LSGB) by skin temperature difference (delta T) between the two measured by thermography before and after LSGB. We divided the patients into two groups; ASO group (n = 15): patients with chronic arterial occulusive diseases, and nonASO group (n = 7): those with peripheral circulation disturbance partly due to decrease nervous function. After LSGB, we recognized a significant increase in delta T and remission of ischemic symptoms in all the patients of nonASO group and those in early stage of ASO group. This suggests that in ASO group LSGB should be applied as soon as possible to obtain good outcome, and thermography is useful to evaluate the effects of LSGB in patients with peripheral circulation disturbance of the lower limbs.

Adult↗

Depletion of lysophosphatidic acid triggers a loss of oriented detyrosinated microtubules in motile fibroblasts.

We reported earlier that isolated plasma membranes trigger a number of responses comprising contact inhibition of motility, including loss of oriented detyrosinated microtubules (Glu MTs) from the lamella of motile fibroblasts. In this study, we show that the membranes trigger this loss of Glu MTs, not by binding to cells, but by removing an essential component from the medium necessary to maintain oriented Glu MTs. Preincubation of membranes with medium containing serum followed by removal of the membranes by sedimentation rendered the membrane-treated medium capable of triggering the loss of oriented Glu MTs. Membrane activity was inhibited by high concentrations of serum and removal of serum from medium triggered the loss of oriented Glu MTs similar to that triggered by membranes. These results suggest that the membranes trigger the loss of Glu MTs by inactivating factors in serum that are required for the maintenance of oriented Glu MTs. By fractionating serum, we have identified lysophosphatidic acid (LPA) as the principal serum factor that is responsible for supporting oriented Glu MTs. The activity of LPA to maintain oriented Glu MTs upon serum withdrawal was half maximal at 100 nM and no activity was observed with structurally related phospholipids. Serum LPA levels were sufficient to account for the ability of serum to support oriented Glu MTs. Enzymatic degradation of serum LPA strongly reduced the ability of serum to support oriented Glu MTs. That membranes degrade LPA was shown by the ability of membranes to block LPA's ability to maintain oriented Glu MTs, and by direct measurement of the loss of radiolabeled LPA after incubation with membranes in vitro. These results show that isolated plasma membranes trigger the loss of Glu MTs from the lamella of motile cells by degrading serum LPA. Coupled with earlier results showing that membranes trigger a number of contact inhibition responses, our data suggest a new model for contact inhibition of motility in which local degradation of LPA and/or interference with LPA-stimulated signalling pathways initiates a contact inhibition response in colliding cells.

Alkaline Phosphatase↗

Insulinotropic action of human glicentin in dogs.

Glicentin has been demonstrated to be released in response to the intraluminal administration of nutrients, but its biological action remains unknown. To clarify the effect of glicentin on the endocrine function of the pancreas, the present study was performed using an in vivo local circulation system of the canine pancreas. During infusion of 0.5% solution of glucose or arginine, 100 and 400 pmol glicentin and 400 pmol glucagon were administered into the pancreaticoduodenal artery (PA) within 10 minutes at 40-minute intervals successively. During glucose infusion, blood glucose in the femoral artery did not change following administration of 100 pmol glicentin, but slightly increased following 400 pmol glicentin. Plasma insulin (immunoreactive insulin [IRI]) in the pancreaticoduodenal vein (PV) increased significantly only following infusion of 400 pmol glicentin. Plasma glucagon (immunoreactive glucagon [IRG]), measured with a specific antiserum to the C-terminal portion of glucagon, did not change following administration of 100 pmol glicentin, but was slightly elevated following 400 pmol glicentin. Plasma total IRG, measured with a nonspecific antiserum, increased promptly after administration of 100 and 400 pmol glicentin. During arginine infusion, the response of plasma IRI to glicentin was markedly exaggerated both in dosages of 100 and 400 pmol. From the present study it was concluded that human glicentin clearly increases insulin release from the canine pancreas.

Animals↗

Disposition of S-1108, a new oral cephem antibiotic, and metabolic fate of pivalic acid liberated from [pivaloyl-14C]S-1108 in rats and dogs.

[pivaloyl-14C]S-1108, which is 14C labeled at the pivalic acid moiety of the pivaloyloxymethyl side chain of S-1108, was administered orally to rats and dogs, and the disposition of pivalic acid cleft from S-1108 was examined. Besides pivaloylcarnitine and pivaloylglucuronide, pivaloylglycine was identified in dog urine as a metabolite of pivalic acid by thin-layer chromatography and high-performance liquid chromatography analysis. The concentrations in the plasma of rats to which doses of 6.65, 26.6, and 532 mg/kg of body weight were administered showed dose-proportionate levels. The radioactivity was eliminated rapidly, with a half-life of approximately 3 h until 24 h at both the 6.65- and 26.6-mg/kg doses. Free pivalic acid in plasma accounted for more than 80% of the concentration of radioactivity. Radioactivity was distributed throughout the body and was eliminated quickly at a rate similar to that of radioactivity from plasma. Most of the absorbed radioactivity was excreted in the urine, and it was completed within 24 h after administration. In dogs, the half-life of radioactivity in plasma was longer than that in the rats. The ratio of free pivalic acid in plasma was 60 to 70% of the radioactivity in plasma. The concentration of radioactivity in the liver, cortex of the kidney, and skeletal muscle 144 h after oral dosing was more than 10 times higher than the concentration in plasma for all doses. Urinary excretion in dogs was slower than that in rats. The differences in the disposition of pivalic acid between dogs and rats may account for differences in the degree of skeletal muscle disorders. The safety in humans of S-1108 given at 200 mg three times a day is discussed in relation to the metabolic formation of the carnitine conjugate of pivalic acid and the reduction of the carnitine concentration in plasma.

Animals↗

Characteristics of pterional routes to basilar bifurcation aneurysm.

In an attempt to clarify the characteristics of the pterional routes to the basilar bifurcation aneurysm, 65 consecutive surgical cases were retrospectively analyzed concerning the size of the aneurysm, the height of the aneurysm neck, the length of the clip blades, and the direction of clip application. Clipping was performed through the pterional route in 59 cases consisting of 14 opticocarotid and 45 retrocarotid routes. A subtemporal approach was performed for six low-positioned aneurysms. The opticocarotid approach was undertaken because of the following situations: 1) laterally protruded and/or highly sclerotic internal carotid artery (n = 8); 2) long, redundant A1 segment (n = 3); 3) an associated aneurysm of the internal carotid artery obstructing the retrocarotid space (n = 2); and 4) a short and/or large posterior communicating artery obstructing the retrocarotid space (n = 1). The range in height of the aneurysm neck was narrower in the opticocarotid approach (1-10 mm) than in the retrocarotid approach (-7-15 mm). The direction of clip application on the axial plane was more anteriorly deviated in the opticocarotid approach (41.4 +/- 12.8 degrees from the glabella-inion line) than in the retrocarotid approach (58.8 +/- 11.1 degrees; P = 0.01). The retrocarotid route (n = 45) was further subdivided into the medial or lateral retrocarotid routes, depending on the medial or lateral side to the posterior communicating artery, respectively. The medial retrocarotid approach (n = 9) made it possible to reach relatively high-positioned aneurysms (7.0 +/- 3.9 mm) compared with the lateral retrocarotid approach (4.2 +/- 4.7 mm; n = 29).(ABSTRACT TRUNCATED AT 250 WORDS)

Basilar Artery↗

Low concentrations of nocodazole interfere with fibroblast locomotion without significantly affecting microtubule level: implications for the role of dynamic microtubules in cell locomotion.

The role of microtubules (MTs) in cell locomotion is uncertain: while MTs are not essential for motility of certain cells, MTs are necessary for the directed translocation of large cells such as fibroblasts, endothelial cells and neuronal growth cones. Based on previous studies, we hypothesize that cell locomotion may involve MTs in two possible ways: (1) the rate of cell locomotion is proportional to MT level; or (2) cell locomotion is not proportional to MT level but requires a critical level of MTs to proceed. To test these hypotheses, we measured the rate of locomotion of NRK fibroblasts migrating into an in vitro wound, before and after treatment with different concentrations of nocodazole to generate cells with different levels of MTs. Locomotion of cells was monitored directly using timelapse recording and analyzed with an Image-1 image analysis program. Addition of nocodazole (> or = 50 nM) resulted in a rapid reduction in locomotion to a new rate that was maintained for > 2 hours. We found that addition of as little as 100 nM nocodazole decreased the rate of locomotion by more than 60%; and that 300 nM nocodazole completely stopped cell locomotion. Although 100 nM nocodazole decreased locomotion over 60%, we detected no qualitative change in MT distribution by immunofluorescence. Quantitative analysis of MT fluorescence in immunofluorescently stained preparations showed that 100 nM nocodazole had no detectable effect on MT levels and that 300 nM nocodazole only decreased MT levels to approximately 40% of controls. Quantitative analysis of tubulin polymer levels by cell extraction and western blotting yielded results similar to those obtained by quantification of MT fluorescence. A comparison of the locomotion rate measurements with the MT level measurements indicated that over half of the cell locomotion rate could be blocked by nocodazole without significantly affecting MT levels in the cell; the remaining locomotion rate was reduced proportionally to MT levels. These results do not support the notion that a critical level of MTs is required for cell locomotion and suggest that only a portion (< 50%) of the speed of the cells is proportional to MT levels. Rather, by analogy with studies of MT antagonists on the mitotic spindle, they suggest a third possibility: that low concentrations of nocodazole interfere with MT dynamics and thus, MT dynamics are critical for the maximal speed of cell locomotion. This notion was further supported by analogous effects of taxol and vinblastine on cell locomotion: at concentrations that reportedly cause little change in the level of MTs, taxol and vinblastine also dramatically decreased the rate of locomotion of NRK cells. In summary, our results establish the relationship between microtubule levels and locomotion rate and suggest that dynamic MTs are rate-limiting for fibroblast locomotion.

Animals↗

Effects of adriamycin, an anticancer drug showing testicular toxicity, on fertility in male rats.

Adriamycin (ADR), an anticancer drug,was intravenously administered to Slc:SD male rats at doses of 0, 1 and 2 mg/kg once a week for 4 or 9 weeks before pairing, and the treatment period and parameters suitable for detection of male fertility disorder were examined. No adverse effects were observed on the copulation index, fertility index and spermatozoa, but testicular weights were low in the 1 and 2 mg/kg groups after 4-week treatment. In the 2 mg/kg group after 9-week treatment, 11 of 12 males had died or became moribund, and no successful pregnancies were observed. The males in the 1 and 2 mg/kg groups after 9-week treatment had decreased weights of the genital organs, an extremely decreased number of sperm and low sperm motility as well as a low implantation rate and a decreased number of live fetuses. Microscopically, the numbers of spermatogonia were decreased in the 1 and 2 mg/kg groups after 4-week treatment, whereas the numbers of even spermatozoa were diminished and genital organs showed atrophy after 9-week treatment. These results indicate that 4-week treatment before pairing is sufficient to detect effects of ADR on the testis, especially on spermatogonia, and that microscopic findings and testis weight are appropriate parameters for detection of male fertility disorders.

Animals↗

A quantitative concept of the mechanism of intestinal lymphatic transfer of lipophilic molecules.

The partition of mepitiostane, testosterone, and some structurally related compounds between lymph and blood in rat jejunum (lymph-blood partition ratio; LBPR) was determined, and the quantitative relationship between LBPR and lipophilicity was examined. When the delta Rm values (hydrophobic parameter derived from the mobility) relative to testosterone were < 0.2, their logLBPRs remained approximately constant in the range of -2 to -3. When the delta Rm values of the compounds were > 0.2, a linear correlation (r = 0.986, n = 8) was observed between these values and the logLBPRs. The LBPR, but not the extent of lymphatic absorption, of lipophilic molecules was determined strictly by the superlipophilicity, and for high partitioning into the lymph (> 50% of the absorbed amount), the delta Rm value had to be > 0.50 (5.65 as the logP value). The relationship between LBPR and superlipophilicity could be explained on the basis of the theoretical equations derived from absorption kinetics based on a dynamic partitioning model.

Anabolic Agents↗

Isolated plasma membranes induce the loss of oriented detyrosinated microtubules and other contact inhibition-like responses in migrating NRK cells.

We have previously shown that detyrosinated microtubules (Glu MTs), which are oriented toward the direction of locomotion in motile fibroblasts, disappear from the area adjacent to cell-cell contact soon after a cell-cell collision. To identify cell surface molecules that trigger this phenomenon, we have established a system in which this and other cellular reactions to cell-cell contact can be reproduced by the addition of isolated plasma membranes. Experimental wounds were made in confluent monolayers of NRK cells, and cells at the wound margin were allowed to develop oriented Glu MTs. Test samples were added to these cells and after a 1 hour incubation the distributions of Glu MTs, tyrosinated MTs (Tyr MTs) and microfilaments were determined by immunofluorescence. When plasma membranes isolated from NRK cells were added, oriented Glu MTs disappeared from the leading lamella of target cells and instead a small number of Glu MTs were found clustered around the nucleus. As observed for cell-cell contact, plasma membranes did not significantly affect the distribution of Tyr MTs. We also found that both cell-cell contact and membrane treatment caused the collapse of lamellipodia and loss of associated staining with antiactin antibody. Time-lapse recordings of directed locomotion of NRK cells showed that membranes suppressed the forward movement of cells. The loss of Glu MTs from the leading lamella was the most amenable response for quantification and we used it to examine the biochemical properties of the membrane activity. The ability of membranes to induce the loss of oriented Glu MTs was observed at as low as 4 micrograms/ml of membrane protein and was detectable 10 minutes after membrane addition. The loss of oriented Glu MTs was reversible upon removal of membranes, demonstrating that the membranes were not toxic to the cells. The oriented Glu MT reducing activity could be solubilized from the membranes by detergent, was enriched in a plasma membrane fraction, and was labile to heat and acid treatment. In summary, we have successfully reconstituted a number of responses of contact inhibition using solubilized preparations of membranes. Our preliminary results suggest that there is a specific factor in plasma membranes that is capable of triggering contact inhibition. With the assay we have developed, it should now be possible to dissect contact inhibition of motility at the molecular level.

Cell Communication↗

Vascular reconstruction of carotid artery invaded by extensive parotid gland carcinoma.

A 63-year-old male with the left parotid gland carcinoma was operated with the reconstruction of the left carotid artery after the left radical neck dissection. The greater saphenous vein was used for the vein graft between the left common carotid artery and the medial cerebral artery. Postoperatively, a temporary loss of consciousness and a half body paresis of the contralateral side occurred, but they were recovered completely in 12 hours. Postoperative angiography showed a good blood flow in the reconstructed vessel.

Carcinoma↗

Electrocochleography in syphilitic hearing loss.

Syphilitic labyrinthitis presents such symptoms as hearing loss, tinnitus, vertigo and/or dizziness, and is well known as one of the endolymphatic hydropic diseases. In order to elucidate the relationship between syphilitic hydrops and ECochG findings, we performed ECochG in patients with syphilis following our previously reported study of patients with Meniere's disease. Twenty-two patients who have been serologically and clinically diagnosed as having syphilitic labyrinthitis were examined with ECochG between December, 1982 and November, 1991. Of the 27 ears tested with ECochG, 2 showed no response due to severe hearing loss, and increased SP (SP/AP ratio > 0.37) was observed in 14 (56.0%) out of the remaining 25 ears. The SP/AP ratio of patients with syphilitic labyrinthitis was not significantly different from that of the patients with Meniere's disease or delayed endolymphatic hydrops, while it was significantly higher than that of the patients with sudden deafness and other types of sensorineural hearing loss. We conclude that the electrocochleographic features of endolymphatic syphilitic lesions resemble those in Meniere's disease.

Adult↗

Distribution of detyrosinated microtubules in motile NRK fibroblasts is rapidly altered upon cell-cell contact: implications for contact inhibition of locomotion.

Fibroblasts migrating into an experimental wound contain an extensive array of detyrosinated microtubules (Glu MTs) oriented in the direction of migration, whereas nonmotile cells in the interior of a monolayer contain Glu MTs that are primarily coiled around the nucleus. To determine the role of cell-cell contact in the formation of these distinct arrays of Glu MTs, we studied the distribution of Glu MTs by immunofluorescence in NRK fibroblasts that had been fixed at different intervals after they had established contact with other cells. Time-lapse video recordings were made of the contacting cells to provide a record of cellular behavior. In motile cells that became completely surrounded by virtue of contact with other cells, Glu MTs were found mostly coiled around the nucleus. The proportion of cells whose Glu MTs extended to the original leading edge decreased dramatically after the cells had been surrounded for 10 min or more. At earlier times, when the contact was confined to a portion of the cell margin, Glu MTs were absent from the area behind the contact site, yet were still oriented toward the noncontacting and ruffling margins. The contact-induced alteration of Glu MTs was not due to the cessation of forward locomotion of cells per se, since immobilization of cells with cytochalasin D did not cause a dramatic change in Glu MTs. That cell-cell contact also specifies the type of Glu MTs formed in cells was shown by experiments in which MTs were regrown following complete depolymerization with nocodazole. The remodeling of Glu MTs during cell-cell contact may be involved in cellular repolarization during contact inhibition of locomotion and will be a useful marker for further dissecting the molecular events of contact inhibition of motility.

Cell Movement↗

Potentiation of the activity of mouse liver-derived HBGF-1-like growth factor by heparin and dithiothreitol: evidence for the involvement of a plasma factor.

The potentiation of mouse liver derived heparin binding growth factors 1 and 2 (HBGF-1, HBGF-2) activity has been investigated. It was found that both heparin and various sulfhydryl reagents (such as dithiothreitol, DTT) markedly potentiated HBGF-1 activity, but not HBGF-2 activity. Further studies with HBGF-1 indicated that the growth factor would interact with a plasma factor, in a temperature-dependent manner, to become inactive, and that sulfhydryl reagents would reverse this inactivation. Inactivation would not occur either in the presence of heparin or DTT, indicating that heparin and DTT can protect the growth factor from plasma inactivation. When assayed in the absence of plasma, both heparin and DTT were required to reactivate plasma inactivated HBGF-1-ML. A model is presented to explain these data. This model predicts that either DTT or heparin can block the plasma induced inactivation process, but that once inactivation has occurred only sulfhydryl reagents can restore activity. Furthermore, heparin is thought to activate growth factor activity in the absence of plasma by blocking non-productive growth factor binding to the extracellular matrix. The identification of a plasma inactivating factor for mouse liver derived HBGF-1 has important implications for understanding the regulation of extracellular growth factor activity.

Animals↗

Kinetic studies on stereospecific recognition by the thromboxane A2/prostaglandin H2 receptor of the antagonist, S-145.

1. The mechanism for the stereospecific recognition of the antagonist S-145 by the thromboxane A2 (TXA2)/prostaglandin H2 (PGH2) receptor was examined by ligand-binding techniques in rat vascular smooth muscle cells (VSMCs) and in human platelet membranes. 2. Scatchard analysis revealed the existence of a single class of binding sites with the same maximum number for both [3H]-(+)-S-145 and [3H]-(-)-S-145 in both cell types. The dissociation constants (Kd) for the binding of the (+)-isomer in rat VSMCs and human platelet membranes were, respectively, 0.40 +/- 0.03 and 0.20 +/- 0.02 nM, each value being lower than that for the (-)-isomer (3.57 +/- 0.74 and 2.87 +/- 0.08 nM, respectively). 3. The rank orders of potency (Ki) for a series of TXA2/PGH2 ligands at inhibiting [3H]-(+)-S-145 binding were highly correlated with those determined for [3H]-(-)-S-145 binding in both cell preparations. 4. Kinetic analysis of the binding of both radioligands revealed a much lower dissociation rate constant (k-1) and a slightly greater association rate constant (k1) for the (+)-isomer compared to those for the (-)-isomer. 5. These results suggest that it is at the stage of dissociation from the TXA2/PGH2 receptor that the stereochemistry of the optical isomers of S-145 confers their difference in affinity for these receptors in rat VSMCs and human platelet membranes.

Animals↗

Otoneurological findings in inner ear syphilis.

Eighty-one ears in 48 patients who had had ear syphilis for the past ten years were studied and otoneurological examinations reviewed. Twenty-five of 48 cases complained of vertigo, 13 of giddiness and/or unsteadiness, and 10 cases denied dizziness. Approximately one half of the patients had abnormal findings on primary equilibrium examinations, such as Mann's test and stepping test. Spontaneous nystagmus and positional nystagmus were frequently seen on electronystagmographic examinations. Many patients showed abnormal responses to the bithermal caloric test and pendular rotation (VOR) test. Moreover, 5 of 8 patients had positive furosemide VOR tests. On transtympanic electrocochleography, 13 of 22 ears demonstrated a dominant -SP response. Eleven of 26 ears had positive findings on an intravenously administered glycerol test. In conclusion, some cases of inner ear syphilis show the characteristic findings of endolymphatic hydrops.

Adult↗

Liver contains heparin-binding growth factors as the major growth factor for cultured fibroblasts.

The presence of heparin-binding growth factors in liver was investigated by measuring the DNA synthesis stimulatory activity of liver extracts using quiescent fibroblasts as target cells. It was found that cytosolic fractions of mouse, rat and human liver, as well as isolated rat hepatocytes, contain a large amount of growth stimulatory activity. Most liver cytosolic activity is due to heparin-binding growth factors, because greater than 90% of the activity bound to a heparin affinity column in the presence of 0.8 mol/L NaCl, and was quantitatively eluted with 2 mol/L NaCl. Purification of these factors from both mouse and rat liver indicated the presence of both heparin-binding growth factor-1 and 2 in liver extracts. The level of the heparin-binding growth factors, as estimated from the biological activity, is approximately 1 microgram/gm mouse liver and 0.1 microgram/gm rat and human liver. Heparin-binding growth factor-1-like factors were 10 times as abundant as heparin-binding growth factor-2-like factors. These data indicate that the cytosolic fractions of mouse, rat and human liver contain heparin-binding growth factors as the primary growth factor for fibroblasts, and heparin binding growth factor-1-like molecules account for most of the cytosolic activity in both mouse and rat liver.

Animals↗