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Biomedical subjects

M Ohkubo

Publications and source records attributed to M Ohkubo.

At least 37 records · Page 2Linked to original sources
PubMed1999

Synthesis and biological activities of topoisomerase I inhibitors, 6-N-amino analogues of NB-506.

6-N-Amino analogues of NB-506 [6-N-formylamino-12,13-dihydro-1,11-dihydroxy-13-(beta-D-glucopyranosyl) -5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione] (3b) were synthesized and tested with respect to topoisomerase inhibition, cytotoxicity and anticancer effects. Among them, a 1,3-dihydroxypropane analogue (J-109,404, 5t) showed more than ten times more potent anticancer activity in MKN-45 human stomach cancer cells implanted in mice than NB-506.

Animals↗
PubMed1999

Quantification of cerebral blood flow using technetium-99m ethyl cysteinate dimer and single-photon emission tomography.

The aim of this study was to develop a new method for quantifying regional cerebral blood flow (rCBF) with technetium-99m ethyl cysteinate dimer (ECD) and single-photon emission tomography (SPET). Employing a three-compartment model, we introduced a parameter, regional brain fractionation index (BFI), that reflects rCBF values and is obtained by a single SPET scan at optimum time T (min) after tracer injection and the integral of arterial input. By analysing the dynamic SPET and arterial blood sampling data of 15 subjects, including the results of acetazolamide challenges, with the graphical plot method, optimum time T was determined to be approximately 20 min post injection. Regional BFI values of each subject were calculated from the single SPET data at 20 min and arterial input. The relationship between the values of regional BFI and rCBF obtained by xenon-133 inhalation SPET was analysed by approximation with an exponential function, resulting in good agreement (r = 0.907). In the present method, rCBF values were determined from regional BFI values by using the inverse exponential function as a non-linear regression curve. To validate the method, we applied it to six other subjects, in whom acetazolamide challenges were also performed. In comparing rCBF values thus obtained and those obtained by 133Xe inhalation SPET, we found a good correlation (r = 0.901) with an inclination approximating 1 (= 1.02) and without underestimation of rCBF in the high-flow range. Since the present method does not require dynamic planar imaging or dynamic SPET scanning, it can be applied to any type of SPET scanner and is useful in clinical SPET studies.

Brain↗
PubMed1999

In vivo anti-tumor activity of a novel indolocarbazole compound, J-107088, on murine and human tumors transplanted into mice.

J-107088 (6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13-dihydro-2,10-dihydroxy- 13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo [3,4-c]carbazole-5,7(6H)-dione) is a derivative of NB-506, an indolocarbazole compound previously reported as an anti-tumor agent targeting topoisomerase I. The optimal administration schedule of J-107088 was found to be intermittent injections. The GID75 (75% growth inhibiting total dose) values of J-107088 against LX-1 lung cancer and PC-3 prostate cancer when given by intermittent injection (twice a week for 2 consecutive weeks) were 200 and 15 mg/m2, respectively, whereas the 10% lethal dose (LD10) values of J-107088 against LX-1- and PC-3-bearing mice were 578 and 1200 mg/m2. The ratio of LD10/GID75 indicates the therapeutic window of an anti-tumor agent. Although the ratios of doxorubicin, paclitaxel and cisplatin against PC-3 were <0.3, <0.5 and <0.2, J-107088 showed the widest therapeutic window among the anti-tumor drugs tested. J-107088 was also effective on cells that had acquired resistance related to P-glycoprotein. Furthermore, J-107088 was found to be highly effective in inhibiting proliferation of micro-metastases of tumors to the liver in mice. Therefore, J-107088 is considered to be a promising candidate as an anti-tumor drug for treatment of solid tumors in humans.

Animals↗
PubMed1999

Noninvasive quantification of cerebral blood flow using 99mTc-ECD and SPECT.

UNLABELLED: The aim of this study was to develop a simple, noninvasive method for quantifying regional cerebral blood flow (rCBF) using 99mTc-ethyl cysteinate dimer (ECD) by a single SPECT scan and single venous sampling. METHODS: Using a three-compartment model, we introduced the regional brain fractionation index (BFI), Cb(Ts)/integral of 0-Ts Ca(tau)dtau [Ca(t), arterial input; Cb(t), brain activity]. Regional BFI obtained at the optimum time Ts (min) was converted to rCBF using an exponential function, which was obtained by analyzing the relationship between regional BFI and rCBF (= F) obtained by the standard 133Xe inhalation SPECT method. The integral of the concentration of 99mTc-ECD in arterial blood corrected for physical decay [Ca(t)] in BFI was estimated from a single venous blood sample obtained at the optimum time Tv using the regression line obtained by analyzing the relationship between the integral of Ca(t) and venous sample data. The data come from three groups of patients. The first group of patients (n = 16) underwent a complete 99mTc-ECD BFI study with measurement of Ca(t) and dynamic SPECT scanning, as well as a 133Xe inhalation study to measure rCBF The results were used to analyze the relationship between regional BFI and rCBF (obtained with 133Xe) and to determine the optimum time Ts for obtaining BFI. Data from the second group of patients (n = 15) were used to analyze the relationship between the integral of Ca(t) and venous sample data and to determine the optimum time Tv for one-point venous blood sampling. Finally, the third group of patients (8 patients, 10 studies) was used to validate the current method by comparing the results with 133Xe inhalation SPECT. RESULTS: Regional BFI obtained at time Ts = 20 min showed good agreement (r = 0.907; a = 0.552, b = 0.962) with rCBF. The venous sample data obtained at time Tv = 6 min showed a good correlation (r = 0.988) with BFI. In comparing rCBF values thus obtained and those obtained by the 133Xe method, we found a good correlation (r = 0.917, slope = 1.01). CONCLUSION: The proposed method has three advantages: (a) accurate quantification of rCBF without underestimation in the high flow range, (b) simplicity and noninvasiveness and (c) the ability to use any type of SPECT camera for the study.

Administration, Inhalation↗
PubMed1999

A DNA binding indolocarbazole disaccharide derivative remains highly cytotoxic without inhibiting topoisomerase I.

NB-506 is a glucosylated indolocarbazole related to the antibiotic rebeccamycin and is currently under clinical trials as an anticancer drug. This compound is a DNA intercalating agent and a potent topoisomerase I poison. The glucose residue attached to the planar indolocarbazole chromophore plays a significant role in the interaction of the drug with nucleic acids and contributes positively to the stabilization of topoisomerase I-DNA covalent complexes. To investigate further the influence of the carbohydrate moiety, we studied the DNA binding and topoisomerase I inhibition properties of an analogue of NB-506 bearing a disaccharide side chain. Fluorescence and footprinting studies indicate that the replacement of the glucose chain of NB-506 with a maltose residue does not hinder the capacity of the drug to bind to DNA and to recognize GC-rich sequences. The addition of the second sugar residue does not reinforce the interaction with DNA but abolishes the capacity of the drug to inhibit topoisomerase I. Unexpectedly, the disaccharide analogue of NB-506 has totally lost its capacity to stimulate DNA cleavage by topoisomerase I. In addition, like NB-506, the new analogue is not an inhibitor of topoisomerase II. However, despite the absence of topoisomerase poisoning activity, the cytotoxic activity is fully maintained. The maltosyl-indolocarbazole drug proved to be as potent as NB-506 at inhibiting the growth of various human and murine tumour cell lines. The study raises the question as to whether topoisomerase I poisoning is important for the antitumour activity of rebeccamycin analogues.

Animals↗
PubMed1998

T-cell receptor variable gene analysis of renal allograft-infiltrating cells in biopsy specimens using a nonradioisotopic micromethod.

BACKGROUND: A sensitive micromethod for T-cell receptor (TCR) analysis is needed for clonality analysis of renal allograft-infiltrating T cells (RAITs) obtained by needle biopsy. METHODS: TCR cDNA was amplified by the anchored polymerase chain reaction and was hybridized with 28 different TCR beta variable (TCRBV) genes fixed on nylon membranes, and the percentage of each TCRBV gene was measured spectrophotometrically. RESULTS: The specificity and linearity of the hybridization technique and the constancy of the TCRBV percentages over a wide range of sample amounts were demonstrated by control experiments. Analysis of RAITs of biopsy specimens from four patients showed broad or skewed TCRBV usage, indicating the presence of polyclonal and oligoclonal RAIT populations, respectively. In one patient who received OKT3 immunosuppressive treatment, the TCRBV skewness was dramatically reduced after the treatment. CONCLUSION: We have established a powerful method for analyzing RAIT clonality, which is especially useful for monitoring RAIT dynamics after immunosuppression therapy.

Acute Disease↗
PubMed1998

Combined angioplasty and valvuloplasty for coexisting coarctation of the aorta and aortic stenosis in an infant.

The patient was a 1-month-old male infant. Echocardiography showed left ventricular hypertrophy with coarctation of the aorta (CoA) and aortic valve stenosis (AVS). Left ventricular systolic function was poor. At catheterization, the gradient of AVS was 25 mmHg and the annulus size of the aortic valve was 7 mm. There was a CoA measuring 2.1 mm in diameter. Balloon valvuloplasty of the CoA was then performed using the same balloon; the pressure gradient decreased to 0 mmHg, and CoA diameter decreased from 2.1 to 5.5 mm.

Angioplasty, Balloon↗
PubMed1998

Transcatheter occlusion of patent ductus arteriosus with a new detachable coil system (DuctOcclud): a multicenter clinical trial.

A multicenter clinical trial of DuctOcclud, a new detachable coil for transcatheter occlusion of patent ductus arteriosus (PDA), was conducted. DuctOcclud was used in 35 patients (12 male and 23 female) for transcatheter occlusion of PDA between January, 1996, and April, 1997. The age of the patients ranged from 0.5 to 27.2 years (median 7.6 years) and weight from 6.3 to 70.0 kg (median 23.0 kg). The smallest diameter of PDA was 2.0+/-0.7 mm (range 1.0-3.3 mm). Pulmonary-systemic flow ratio (Qp/Qs) was 1.3+/-0.3 (range 1.0-2.2). The coils were successfully implanted in 32 (91%) patients. Of 31 patients who were followed 6 months after the procedure, 26 (84%) had no residual shunt and 5 (16%) had trivial residual shunt. One patient had infective endocarditis 1 month after the procedure but recovered completely. There were no incidences of coil embolization, hemolysis, late coil migration, or pulmonary artery stenosis. We conclude that DuctOcclud is a safe and effective device of transcatheter occlusion of PDA.

Adolescent↗
PubMed1998

[Quantification of regional cerebral blood flow at the control state and loaded with diamox using split-dose 99mTc-ECD SPECT and venous blood samples].

The purpose of the study is to develop a simple and less invasive method for quantifying regional cerebral blood flow (rCBF) at pre- and post Diamox test using split-dose 99mTc-ECD and SPECT. By employing a microsphere model, integral of input function was calculated by the one-point venous sampling method previously reported. The study was performed on 5 subjects with cerebrovascular diseases. A split dose of 99mTc-ECD was injected pre- and post Diamox injection, and rCBF was measured by two SPECT scans and single venous samples, respectively. Mean CBF obtained by the present method was 0.47 +/- 0.07 ml/g/min at the control state, and 0.63 +/- 0.12 ml/g/min loaded with Diamox (mean % increase; 35%), showing good agreement with those obtained by the 133Xe-inhalation method. Since the present method does not require arterial blood sampling, dynamic data acquisition and dose corrections, it is simple, less invasive and useful in clinical SPECT studies.

Acetazolamide↗
PubMed1998

[A study on accuracy of rCBF measurements loaded with acetazolamide based on the microsphere model using iodine-123-IMP SPECT].

We studied the accuracy of the method for measuring regional cerebral blood flow (rCBF) loaded with acetazolamide based on the microsphere model using iodine-123-IMP (IMP) SPECT. Two methods were examined, the super-early microsphere method with continuous withdrawal of arterial blood using the SPECT image obtained 5 min after tracer injection and the early microsphere method with one-point arterial sampling using the SPECT image obtained 30 min postinjection. On five subjects, after acetazolamide administration we measured rCBF by the analysis based on the two-compartment model using the data derived from dynamic SPECT scans and the sequential arterial blood sampling after IMP injection. Values of rCBF obtained by both super-early microsphere method and early microsphere method were significantly correlated with those obtained by the two-compartment model analysis (r = 0.982, 0.930, respectively). We conclude that it is possible to use the method based on the microsphere model in measuring rCBF loaded with acetazolamide. The early microsphere method with one-point sampling should be used clinically because of its simplicity and less-invasiveness.

Acetazolamide↗
PubMed1998

[Quantification of cerebral blood flow with 99mTc-ECD SPECT based on a 3-compartment model].

In the present study we developed a method for quantifying regional cerebral blood flow (rCBF) using 99mTc-ECD SPECT based on a 3-compartment model. The dynamic SPECT scanning and sequential sampling of arterial blood were performed on 12 subjects with cerebrovascular diseases and etc. We defined brain fractionation index (BFI) as a parameter of rCBF, which was obtained from a single SPECT data and arterial input. The relationship between the values of BFI and rCBF obtained by the 133Xe inhalation method was analyzed by approximation with exponential function. In this method, rCBF was calculated from the values of BFI using the inverse function of the exponential function as a regression curve. The method was applied seven other patients with cerebrovascular diseases and the values of rCBF were compared with those obtained by the 133Xe inhalation method. We observed a good correlation (r = 0.854), and the inclination was approximately 1. This method can be applied to not only large field SPECT cameras but also conventional SPECT cameras.

Adult↗
PubMed1997

125I-iomazenil binding shows stress- and/or diazepam-induced reductions in mouse brain: supporting data for 123I-iomazenil SPECT study of anxiety disorders.

Effects of repeated swim stress on the binding of 125I-iomazenil were examined in the brains of diazepam-treated and non-treated mice. The mice were orally administered diazepam or vehicle (0.5% ethylene glycol) and subjected to daily swim stress (at 20 degrees C for 10 min) for seven consecutive days. The distribution and the amount of 125I-iomazenil binding were analyzed autoradiographically after in vivo and in vitro binding experiments. Repeated swim stress decreased the in vivo binding in the hippocampus (p < 0.05) and cerebral cortex (p < 0.05) of vehicle-treated mice but caused no significant changes in diazepam-treated mice. Subchronic treatment with diazepam decreased the in vivo binding approximately 50% in all brain regions examined (p < 0.01). The in vitro experiment, however, revealed no significant changes except in the hippocampus, where a small but significant decrease in the binding was observed after subchronic treatment with diazepam (p < 0.01). The stress- or diazepam-induced reductions seem to represent alterations in the in vivo environment related to 125I-iomazenil binding. These results suggest that we can investigate the pathophysiology of stress and anxiety with 123I-iomazenil SPECT. Care must be taken concerning the effects of benzodiazepines.

Animals↗
PubMed1997

Dilation mechanism, causes of restenosis and stenting in balloon coarctation angioplasty.

This review focuses on the individual dilation mechanism, the possible cause of restenosis after balloon angioplasty and the clinical application of a stent in coarctation of the aorta. Balloon angioplasty is still not the first choice of therapy in neonates with native coarctation because of the potential risk of aortic disruption, the high incidence of restenosis and the satisfactory results of surgical coarctectomy. Intravascular ultrasound imaging provides the individual mechanism of aortic dilation by balloon, and this will be a new modality for assessing the relationship between restenosis and aortic luminal morphology after balloon dilation. Although the cause of restenosis after balloon angioplasty remains uncertain, it may be due to a combination of elastic recoil by ductal tissue constriction, intimal hyperplasia and arterial remodelling. A stent could be an effective alternative to conventional balloon angioplasty in native coarctation of the aorta, preventing ductal tissue constriction. However, the problematic relationship between patient growth and relative stenosis of the stent should be clarified before clinical application of a stent for this disease.

Angioplasty, Balloon↗
PubMed1997

A case simultaneously presenting with a rare portal collateral pathway and left gastric venous anomaly.

We had the opportunity to dissect an autopsy case who had developed a rare portal collateral pathway due to increased portal pressure resulting from liver cirrhosis and simultaneous abnormal left gastric venous distribution. The portal collateral pathway consisted of a well-developed communicating branch located between the left renal vein and the left gastric vein. The left gastric vein did not merge into the portal vein, but directly entered the liver after bifurcating near the hepatic hilum. One branch had an anastomosis to the left branch of portal vein in the liver and the other distributed in the hepatic quadrate lobe. We considered this aberrant left gastric vein to be a congenital residue of the embryological left portal vein. The present case is the third Japanese case to have been described minutely in the literature, following the two cases reported by Miyaki et al. (1987). Persistence of the umbilical vein and the absence of the celiac trunk were also observed.

Aged↗
PubMed1997

A comparative study of simple methods to measure regional cerebral blood flow using iodine-123-IMP SPECT.

UNLABELLED: The aim of this study was to compare the accuracy and reliability of simple methods of quantifying regional cerebral blood flow (rCBF) with 123I-labeled N-isopropyl-p-iodoamphetamine (IMP) and SPECT and to determine which method was best. METHODS: Four methods were examined: (a) the microsphere method with continuous withdrawal of arterial blood, which was based on a microsphere model using the SPECT image obtained 5 min after tracer injection, (b) the microsphere method with one-point sampling, which was the same as the first method except that one-point sampling was used instead of continuous withdrawal, (c) the modified microsphere method with one-point sampling, which was the same as the second method except that a later SPECT image (30-min postinjection) with correction was used and (d) a table look-up method based on a two-compartment model with one-point arterial blood sampling and two SPECT scans obtained 40- and 180-min postinjection. The accuracy of these methods was validated by comparing the rCBF values with those obtained by nonlinear least squares fitting analysis based on the two-compartment model in 15 subjects. RESULTS: Regional cerebral blood flow values obtained by the first method correlated most closely with those obtained by nonlinear least squares fitting analysis (error, 6.8%). The second method estimated rCBF with a mean error of 10.4%. The third method estimated rCBF with a mean error of 13.1%, even though it tended to slightly overestimate rCBF. The fourth method was inclined to underestimate rCBF with a mean error of 17.1%, and it greatly overestimated regional distribution volume. CONCLUSION: The first method was the most accurate and reliable. For less invasiveness, the first method should be combined with one-point sampling instead of continuous withdrawal, which was used in the second method. When using a delayed SPECT image with a conventional SPECT scanner, the third method was considered to be superior to the fourth method.

Adult↗
PubMed1997

[A comparative study of the quality of SPECT images obtained by 123I-IMP, 99mTc-HMPAO and 99mTc-ECD].

The purpose of this study was to comparatively evaluate the quality of SPECT images for the mapping of rCBF using three tracers, 123I-IMP, 99mTc-HMPAO and 99mTc-ECD. We performed three SPECT studies on seven patients with various cerebral diseases under the same conditions. An effect of Lassen's correction on SPECT images obtained by HMPAO was also evaluated. The same irregular regions of interest were placed on the four transaxial SPECT images. To quantitatively evaluate the pattern of tracer uptake and image contrast, the uptake ratio, regional count/mean count of the cerebrum, and its coefficient variations (CV) were defined, respectively. The order of the value of CV was HMPAO with correction > IMP > ECD > HMPAO without correction. HMPAO with correction showed the best image contrast, but HMPAO without correction was the worst. Uptake ratios of ECD and HMPAO with correction were decreased in the brain stem and thalamus in comparison with those of IMP. Both uptake ratios of ECD and HMPAO without correction were increased in the occipital cortex. IMP provides high quality SPECT images. Images obtained by HMPAO should be modified by Lassen's correction to increase image contrast. ECD or HMPAO should not be used to evaluate patients with spinocerebellar degeneration.

Aged↗