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T Takagi

Publications and source records attributed to T Takagi.

At least 343 records · Page 19Linked to original sources
PubMed1996

Theoretical design of prodrug-enhancer combination based on a skin diffusion model: prediction of permeation of acyclovir prodrugs treated with 1-geranylazacycloheptan-2-one.

PURPOSE: A theoretical design of percutaneous penetration enhancement in which prodrug derivation and enhancer application are combined is proposed based on the skin diffusion model and it is experimentally verified. METHODS: Employing acyclovir as a model drug, the hypothesis was tested by synthesis of its prodrugs and evaluation of their in vitro permeation in the rat skin, with or without a penetration enhancer, 1-geranylazacycloheptan-2-one(GACH). RESULTS: Among five acyclovir prodrugs, those with higher lipophilicities (propionate, butyrate, valerate, and hexanoate prodrugs) showed greater skin penetration than those of hydrophilic prodrugs (acetate), when administered in combination with GACH. Furthermore, the observed enhancement ratios were in good agreement with those predicted by theoretical consideration. CONCLUSIONS: Thus, skin permeation of prodrugs applied with an enhancer can be predicted and optimized by model analysis.

Acyclovir↗
PubMed1996

Combined effect of clinically relevant doses of emitefur, a new 5-fluorouracil derivative, and radiation in murine tumours.

We investigated the combined effect of radiation and clinically relevant doses of emitefur (BOF-A2), a newly developed anti-cancer agent consisting of a masked form of 5-fluorouracil (5-FU) and a potent inhibitor of 5-FU degradation, in two types of murine tumours. In preliminary pharmacokinetic studies, the area under the curve for 5-FU in plasma, after administration of 12.5 mg kg-1 and 25 mg kg-1 emitefur in mice, appeared to be similar to that obtained on the first day and that on the seventh day, respectively, after starting administration of 400-600 mg day-1 in humans. These doses (12.5 and 25 mg kg-1) of emitefur were evaluated either alone or in combination with single (15 Gy), five-fraction (4 Gy each) or ten-fraction (2.8 Gy each) irradiation using a tumour growth delay assay for SCCVII tumours and in combination with four-fraction (5 Gy each) irradiation using an in vivo-in vitro assay for EMT6 tumours. The anti-tumour and radiation-enhancing effects of 12.5 mg kg-1 emitefur were not significant in any except the ten-fraction experiment. On the other hand, multiple doses of 25 mg kg-1 emitefur given either alone or in combination with radiation produced marked effects. The mean tumour growth delay time (the time to double in volume for treated tumours minus that for untreated tumours) was 8.1 days for five administrations of 25 mg kg-1 emitefur. 10.4 days for five fractions of 4 Gy and 22.1 days for five treatments with the combination of the two. Thus, the increase in growth delay afforded by this combination was at least additive. The effect of four fractions of 5 Gy with 25 mg kg-1 emitefur in EMT6 tumours was lower than that of four fractions of 7.5 Gy, but the effect of five fractions of 4 Gy with this dose of emitefur in SCCVII tumours was similar to the effect of five fractions of 6 Gy, and the effect of ten fractions of 2.8 Gy with 25 mg kg-1 emitefur was much higher than that of ten fractions of 4.2 Gy. In conclusion, emitefur given either alone or in combination with radiation appears to have a significant anti-tumour effect even at clinically relevant dose levels, although a threshold dose exists between 12.5 and 25 mg kg-1. Further clinical studies of this compound are warranted.

Animals↗
PubMed1996

Dimerization characteristics of the 94-kDa glucose-regulated protein.

The 94-kDa glucose-regulated protein (GRP94) is a member of the 90-kDa heat-shock protein (HSP90) family. In this study, we expressed the barley (Hordeum vulgare L.) GRP94 and the alpha isoform of human HSP90 (HSP90 alpha) in Escherichia coli and compared their dimer-forming abilities. Native polyacrylamide gel electrophoresis revealed that GRP94 (amino acids 69-809) and the full-length form of HSP90 alpha existed in the dimeric state. The C-terminal 326 amino acids of GRP94 or the C-terminal 200 amino acids of HSP90 alpha were sufficient for the dimerization. Limited proteolysis of the C-terminal half of GRP94 with thrombin revealed a 16-kDa fragment, which was derived from the C-terminus of GRP94 through the cleavage of either the Arg710-His711 or the Arg735-Leu736 bond. These cleavage sites were nearly, if not completely, equivalent to the proteolyzed region of HSP90 alpha. Their structural similarity prompted us to investigate, by use of a coexpression system, the possibility that the two proteins form a heterodimeric complex. A two-step affinity chromatography that specifically trapped only the complex revealed that the C-terminal 200 amino acids of HSP90 alpha and the C-terminal 326 amino acids of GRP94 associated with HSP90 alpha and GRP94, respectively. However, the C-terminal 326 amino acids of GRP94 failed to form a complex with HSP90 alpha. In conclusion, these results indicate the similarity of the general dimeric conformation of the two HSP90 family member proteins, but show that the similarity is not sufficient to allow heterodimer formation.

Amino Acid Sequence↗
PubMed1996

Inhibitory effect of a new butadiene derivative on the production of plasminogen activator inhibitor-1 in cultured bovine endothelial cells.

Tissue-type plasminogen activator (t-PA) and its physiological inhibitor, plasminogen activator inhibitor-1 (PAI-1), are known to be synthesized by vascular endothelial cells and to play important roles in regulating the fibrinolytic activity of plasma. We found that a new butadiene derivative, (3E, 4E)-3-benzylidene-4-(3,4,5-trimethoxybenzylidene)pyrrolidine -2,5-dione (T-686), inhibits PAI-1 production without affecting plasminogen activator (PA) synthesis in cultured bovine endothelial cells. T-686 (1-10 microM) dose-dependently decreased the accumulation of PAI-1 in conditioned medium from the treated cells and elevated PA activity in the conditioned medium. Analysis of the conditioned medium by the zymography technique indicated that T-686 decreased the activities of PAI-1 with an M(r) of 55,000 and t-PA/PAI-1 complex with an M(r) of 99,000. Furthermore, T-686 attenuated the augmentation of PAI-1 antigen induced by lipopolysaccharide in the conditioned medium. The decrease of PAI-1 antigen was in parallel with the reduction of the PAI-1 mRNA level (Northern blots). These results suggest that T-686 can promote net fibrinolytic activity through suppression of PAI-1 production without affecting PA elaboration in endothelial cells.

Animals↗
PubMed1996

Tachycitin, a small granular component in horseshoe crab hemocytes, is an antimicrobial protein with chitin-binding activity.

Small granules of horseshoe crab hemocytes contain two known major antimicrobial substances, tachyplesin and big defensin (S5), and at least five protein components (S1 to S6), with unknown functions. In the present study, we examined the biological properties and primary structure of a small granular component S2, named tachycitin. This component was purified from the acid extract of hemocyte debris by two steps of chromatography. The purified tachycitin was a single chain protein with an apparent M(r) = 8,500 on Tricine-SDS-polyacrylamide gel electrophoresis. Ultracentrifugation analysis revealed tachycitin to be present in monomer form in solution. Tachycitin inhibited the growth of both Gram-negative and -positive bacteria, and fungi, with a bacterial agglutinating property. Moreover, tachycitin and big defensin acted synergistically in antimicrobial activities. The amino acid sequence and intrachain disulfide bonds of tachycitin were determined by amino acid and sequence analyses of peptides produced by enzymatic cleavages. The mature tachycitin consisted of 73 amino acid residues containing five disulfide bonds with no N-linked sugar. A cDNA coding for tachycitin was isolated from a hemocyte cDNA library. The open reading frame coded for an NH2-terminal signal sequence followed by the mature peptide and an extension sequence of -Gly-Arg-Lys at the COOH-terminus, which is a putative amidating signal. The COOH-terminal threonine amide released after digestion of tachycitin with lysylendopeptidase was identified. The NH2-terminal 28 residues of tachycitin shows sequence homology to a part of chitin-binding regions found in antifungal chitin-binding peptides, chitin-binding lectins, and chitinases, all of which have been isolated from plants. Tachycitin showed a specific binding to chitin but did not bind with the polysaccharides cellulose, mannan, xylan, and laminarin. Tachycitin may represent a new class of chitin-binding protein family in animals.

Amino Acid Sequence↗
PubMed1996

Comparison of in vivo efficacy of hypoxic cytotoxin tirapazamine and hypoxic cell radiosensitizer KU-2285 in combination with single and fractionated irradiation.

Development of strategies to eradicate radioresistant hypoxic cells would be of great benefit for clinical radiotherapy. In the present study, the in vivo effects of a promising hypoxic cytotoxin, tirapazamine (3-amino-1,2,4-benzotriazine 1,4-di-N-oxide), were examined in comparison with those of KU-2285, one of the best hypoxic cell radiosensitizers, in combination with both single and fractionated irradiation. The tumor response was assessed by the standard in vivo-in vitro clonogenic assay using SCCVII tumors in C3H mice and EMT-6/KU tumors in Balb/c mice with different characteristics of tumor hypoxia. With single-dose irradiation (18 Gy), both tirapazamine and KU-2285 showed significant enhancement of cell killing in a dose-dependent manner, but tirapazamine was more effective for SCCVII tumors with acutely hypoxic cells, while KU-2285 was more effective for EMT-6/KU tumors predominantly with chronically hypoxic cells. In fractionated irradiation regimens (4 fractions of 5 Gy at 12 h intervals), tirapazamine showed more marked combined effects at 10 and 20 mg/kg than KU2285 at 100-200 mg/kg in both SCCVII and EMT-6/KU tumors. We concluded that the effectiveness of KU-2285 and tirapazamine was correlated with the nature of tumor hypoxia with single-dose irradiation, whereas tirapazamine appeared more potent than KU-2285 with fractionated irradiation. These findings suggest the potential usefulness of tirapazamine in clinical fractionated radiotherapy.

Animals↗
PubMed1996

Use of intravascular ultrasound for in vivo assessment of changes in intimal thickness of angiographically normal saphenous vein grafts one year after aortocoronary bypass surgery.

OBJECTIVE: To use intravascular ultrasound in vivo to evaluate changes in the intimal thickness of angiographically normal saphenous vein grafts one year after implantation. DESIGN: Fifteen saphenous vein grafts in 12 patients were examined one month and 12 months after aortocoronary bypass graft surgery with intravascular ultrasound using a 30 MHz transducer. None of the grafts examined showed any angiographic abnormalities. The intimal thickness and intimal area of the graft in the proximal portion were measured on intravascular ultrasound images obtained one month and 12 months after operation. SETTING: General hospital. PATIENTS: Twelve patients who underwent aortocoronary bypass graft surgery. RESULTS: The ultrasound images showed a thin-walled graft with a thin intima one month after operation (mean (SD)) (0.31 (0.09) mm). The intimal thickness of the graft increased significantly to 0.65 (0.08) mm (P < 0.001) 12 months after operation. The intimal area of the graft was 0.90 (0.80) mm2 one month after operation. 12 months after operation the intimal area had increased significantly to 5.26 (1.38) mm2 (P < 0.001). CONCLUSION: Intravascular ultrasound in vivo showed that one year after implantation angiographically normal saphenous vein grafts had a thicker intima than one month after implantation.

Coronary Artery Bypass↗
PubMed1996

Changes in viscoelasticity of the myocardium during cardioplegic arrest.

To evaluate the efficacy of myocardial preservation during open heart surgery, we measured the viscoelasticity of the canine myocardium during cardioplegic arrest. A transfer function method was used for the measurement with a monitoring system consisting of a vibrator, a function generator, accerometers and a signal processor. Six mongrel dogs were put on cardiopulmonary bypass and after measurement of control hemodynamics, they were subjected to cardioplegic arrest at myocardial temperatures ranging from 4 to 32 degrees C. Viscoelasticity was measured at every 15 min and the cardioplegic solution was added every 30 min. After two hr of cardioplegic arrest, the myocardium was reperfused and postischemic hemodynamics were measured after 30 min of non-working beating. Satisfactory myocardial function returned in 3 hearts with the myocardial temperatures below 24 degrees C with myocardial viscoelasticity within the control range. Moderately decreased myocardial contractility was noted in a heart kept at temperature of 27 degrees C and its viscoelasticity remained in the control range of 90 min of ischemia and then began to decrease. In 2 hearts kept at temperatures higher than 29 degrees C, severely depressed myocardial contractility was noted, and viscoelasticity decreased transiently at 45 to 60 min and then returned to control levels. These results suggested usefulness of continuous monitoring of the viscoelasticity in early detection of its degenerative alterations due to impaired myocardial preservation during open heart surgery.

Animals↗
PubMed1996

[Problems encountered with a programmable pressure valve (SOPHY) positioned in the chest wall].

Sixty-eight hydrocephalic patients were treated with a shunt system that incorporated a SOPHY programmable valve. This device is very effective for treating disorders of CSF circulation. However, when the valve is placed on the scalp, it produces artifacts on MR imaging due to its small magnetic rotor, and may cause necrosis of the scalp above it. On the other hand, when it is positioned on the chest, MR artifacts decrease and exchanging the valve devices becomes easier. Therefore, we have positioned the device on the chest. However, some complications were encountered, such as the turning over of the valve in the subcutaneous pocket and the twisting of the shunt tube. Moreover, the shunt tube may stretch due to growth of the neck during development in infantile patients or extension of the neck during exercise. These complications are associated only with subcutaneous placement on the chest, so we conclude that such a valve, if placed on the chest, should be placed in a lower position on the chest, and if MR examination will not be performed in the foreseeable future, we recommend that it be placed on the occipital scalp, especially in infantile patients.

Aged↗
PubMed1996

[Evaluation of left ventricular volume and ejection fraction using three-dimensional transesophageal echocardiography].

Left ventricular (LV) volume and ejection fraction (EF) derived from three-dimensional echocardiography using a multiplane transesophageal probe (3D-TEE) were compared with LV volume and EF obtained from left ventriculography (LVG) in 14 patients (mean age: 61 years). Left ventricular volumes were calculated using a summation of disks algorithm based on multiple reconstructed short-axis cross-sections from 3D data. Left ventricular volume (end-diastole and end-systole) and EF from 3D-TEE were compared with those from LVG using linear regression analysis. Three-dimensional TEE demonstrated excellent correlations with LVG for measuring LV volume (r = 0.97, SEE = 11 ml) and EF (r = 0.95, SEE-4%), respectively. Three-dimensional TEE is useful for the measurement of LV volume and EF in the clinical setting.

Echocardiography, Transesophageal↗
PubMed1996

[Phasic flow velocity characteristics of the right coronary artery in patients with aortic stenosis: a Doppler guide wire study].

This study investigated the characteristics of the phasic flow velocity pattern of the right coronary artery and the relationship to hemodynamic parameters in patients with aortic stenosis. Coronary flow velocities were recorded at the proximal (segment 1) and the distal (segment 4PD) portion of the right coronary artery using a Doppler guide wire (0.014-in, 15 MHz) in 10 patients with aortic stenosis and 8 control subjects with normal coronary arteries. The diastolic to systolic peak velocity ratio at both the proximal and distal portion were significantly greater in patients with aortic stenosis than in control subjects. Systolic flow reversal was not seen in the right coronary artery in control subjects, but it was observed in 5 patients (50%) at the proximal portion and in 10 patients (100%) at the distal portion. Peak velocity of flow reversal at the distal portion showed a significant correlation with mean pressure gradient across the aortic valve (y = -1.3x + 37.3, r = 0.71, p = 0.02). Systolic flow reversal is characteristic in the right coronary artery, especially at the distal portion, in patients with aortic stenosis. This may be related to the pressure difference across the aortic valve through the posterior descending artery.

Aged↗
PubMed1996

FDG-PET evaluation of therapeutic effects on VX2 liver tumor.

UNLABELLED: Transplanted VX2 liver tumor in the rabbit is an experimental liver tumor model in which 18F-2-fluoro-2-deoxy-D-glucose (FDG) accumulates to a 3.5-fold level that surrounds normal liver tissue. In this study, changes in FDG uptake were assessed in this liver tumor model after transcatheter arterial embolization (TAE) and radiotherapy. METHODS: Fifteen rabbits bearing VX2 liver tumors were treated with TAE with gelatin sponges 1 day before the FDG study, and 18 rabbits received local irradiation with electron beams at a dose of 12-36 Gy 1-10 days before the FDG study. In the FDG study, serial arterial blood sampling was performed to determine arterial input (AI), and 1 hr after tracer injection, normal liver tissue and tumor tissue were excised to measure radioactivity. The tumor FDG level per AI and the tumor-to-normal liver ratio were assessed. Dynamic PET images were obtained in 20 of the 46 rabbits. RESULTS: Tumor FDG uptake was significantly decreased 1 day after TAE (from 3.54 to 0.83 in the tumor-to-normal liver ratio) and 5 days after 30 Gy of irradiation (from 3.54 to 1.28). The decrease in tumor FDG uptake was dose-dependent, especially in the relatively low dose range (12-24 Gy). The untreated tumors could be clearly distinguished from the surrounding normal liver tissue, while the embolized tumors or the irradiated tumors were not clearly delineated. Histological analysis showed that the decrease in tumor FDG after treatment agreed well with the decrease in number of viable tumor cells. CONCLUSION: The VX2 liver tumor is an appropriate experimental tumor model for evaluating the change in FDG uptake in various therapeutic modalities. Moreover, the therapeutic effects can be assessed 1 day after TAE and 5 days after irradiation. Further clinical trials for the early evaluation of therapeutic effects on liver tumors using FDG-PET are warranted.

Animals↗
PubMed1996

[Value and limitations of valve resistance in assessing prosthetic aortic valve function: clinical study using dobutamine stress doppler echocardiography].

Hemodynamic resistance may be a useful index for the severity of valvular aortic stenosis, but little is known about the utility of valve resistance in assessing the prosthetic aortic valve function. This study investigated whether valve resistance is useful in assessing prosthetic valve function in 13 patients with normally functioning CarboMedics prosthetic aortic valves. Transvalvular pressure gradient, effective orifice area and valve resistance derived from two-dimensional and Doppler echocardiography were calculated before and after dobutamine infusion. Dobutamine was infused incrementally (3-12 micrograms/kg/min) under echocardiographic imaging. Transvalvular pressure gradient (24 +/- 7-->53 +/- 18 mmHg, p < 0.01) and valve resistance (102 +/- 32-->140 +/- 57 dynes.sec.cm-5, p < 0.01) significantly increased after dobutamine infusion. However, effective orifice area did not increase significantly (1.1 +/- 0.5-->1.2 +/- 0.5 cm2). These findings indicate that transvalvular pressure gradient and valve resistance are flow-dependent and should be treated with caution when assessing prosthetic valve function.

Adult↗
PubMed1996

[Fast two-compartment model analysis with 99mTc-GSA liver scintigraphy].

The use of numerical integration method (N. INT) was evaluated in determining parameters by two-compartment model analysis from liver scintigraphy. Among the 15 subjects, 14 had liver cirrhosis or chronic hepatitis, and one was normal. When using N.INT, the sum of two exponential functions on heart regression curve following intravenous injection of 99mTc-galactosyl human serum albumin (99mTc-GSA) was promptly calculated. The parameters obtained from N.INT, including transfer rate of 99mTc-GSA from extrahepatic blood to liver (k1), dissociation rate from liver to extrahepatic blood (k2), and excretion rate from liver to gallblader (k3), were significantly correlated with those obtained by the nonlinear least square method (NLS). k1/k2 was related with the maximum removal rate of 99mTc-GSA obtained from nonlinear five compartment model analysis (r2 = 0.705, n = 15) and also with the severity score of liver disease as classified by the First Department of Surgery, Mie University Medical School (r2 = 0.686, n = 13). In terms of the time required to obtain these parameters, including the blood retention rate of 99mTc-GSA at 15 min after injection (%ID15), N.INT was faster than the traditional method (NLS).

Aged↗
PubMed1996

Tirapazamine: hypoxic cytotoxicity and interaction with radiation as assessed by the micronucleus assay.

We investigated the cytotoxicity and the interaction with low-dose radiation (1-4Gy) of tirapazamine by the in vitro cytokinesis-block micronucleus (MN) assay. Murine SCCVII and human melanoma (G-361) cells were treated with tirapazamine under aerobic or hypoxic conditions for 1 h and the MN frequency was determined using cytochalasin-B. The cells were also treated with or without tirapazamine or KU-2285 (hypoxic cell sensitiser) under hypoxic conditions and irradiated with or without reaeration of the cell suspensions. A dose-dependent increase of MN frequency was observed by tirapazamine treatment and the hypoxic toxicity ratio was about 130 for SCCVII and 37 for G-361. The radiation dose-response curves of MN frequency suggested that the interaction of tirapazamine with irradiation appeared to be essentially additive in both cell lines. In contrast, the dose-response curve became steeper by KU-2285 treatment. Combined effects of tirapazamine and irradiation on the hypoxic cells were much higher than the radiation effect on aerobic cells at low doses, while the effects of KU-2285 did not exceed that of aerobic irradiation. In conclusion, tirapazamine appeared to be superior to hypoxic radiosensitisers at clinically relevant doses, not because of aerobic radiosensitisation but because of its potent hypoxic cytotoxicity additive to radiation effect.

Animals↗
PubMed1996

The combined antitumour effect of a new 5-fluorouracil derivative, BOF-A2, and radiation in vivo.

We examined the combined effect of radiation and BOF-A2, a newly developed anti-cancer agent consisting of a masked form of 5-fluorouracil (5-FU) and a potent inhibitor of 5-FU degradation in the liver, on murine tumors. Subcutaneous 8-mm-diameter SCCVII tumours grown in the right thigh of C3H/He mice were used. The mice were locally irradiated with single doses of 10-30 Gy or five fractions of 4 Gy for 5 days, alone or in combination with BOF-A2. BOF-A2 at doses of 30, 75 and 150 mg kg-1 was orally administered 2 h before or immediately after single doses of irradiation, while 15 or 30 mg kg-1 of BOF-A2 was given 1 h prior to each fraction of 4 Gy. The effect of BOF-A2 alone was also examined. The antitumour effect was evaluated by a tumour growth delay assay. BOF-A2 alone showed significant tumour growth delay at all doses used in this study. Combination of BOF-A2 and single or fractionated doses of radiation appeared to produce an additive tumour response, which occurred independently of sequence of the two treatments. The combined effect became greater with the dose of radiation and BOF-A2. In conclusion, BOF-A2 and radiation may be efficiently combined.

Animals↗