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N Sakamoto

Publications and source records attributed to N Sakamoto.

At least 73 records · Page 4Linked to original sources
PubMed2000

DX-8951f: summary of phase I clinical trials.

Exatecan mesylate (DX-8951f) is a new hexacyclic camptothecin analogue with favorable attributes compared to topotecan and CPT-11, including watersolubility, greater potency against topoisomerase I, lack of esterase-dependent activation, broad antitumor activity, and low cross-resistance against MDR-1 overexpressing tumors. In preclinical studies, the compound demonstrated a favorable toxicology profile with hematologic dose-limiting toxicity and moderate gastrointestinal toxicity, linear pharmacokinetics, P450 hepatic metabolism (CYP3A4 and CYP1A2), and predominately fecal excretion. The results of six U.S. and European phase I clinical trials as well as two Japanese studies are presented including total DX-8951 and lactone DX-8951 pharmacokinetics. The toxicity profile was similar for all schedules of administration. Hematologic toxicity was dose-dependent and reversible. Neutropenia was dose-limiting in minimally pretreated patients, whereas neutropenia and thrombocytopenia were dose-limiting in heavily pretreated patients. Non-hematologic toxicity included moderate gastrointestinal toxicity (nausea, vomiting > diarrhea), transient elevation of hepatic transaminases, asthenia, and alopecia. Two cases of acute pancreatitis not predicted by preclinical toxicology were also observed. Antineoplastic activity was detected in several solid tumor types: non-small cell lung cancer, extrapulmonary small cell cancer, colorectal cancer, hepatocellular cancer, and sarcoma. Antitumor activity was seen in CPT-11 and topotecan-resistant tumors. Pharmacokinetics were linear within the dose range tested. A pharmacokinetic/pharmacodynamic model predictive of DX-8951f-induced neutropenia in individual patients was developed. The daily x5, every 3-week schedule with the drug administered as a 30-minute intravenous infusion was selected for future phase II clinical trials based on its superior antitumor activity.

Animals↗
PubMed2000

Xanthine oxidase contributes to host defense against Burkholderia cepacia in the p47(phox-/-) mouse model of chronic granulomatous disease.

Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase in which phagocytes are defective in generating superoxide and downstream microbicidal reactive oxidants, leading to recurrent life-threatening bacterial and fungal infections. Xanthine oxidase (XO) is another enzyme known to produce superoxide in many tissues. Using the p47(phox-/-) mouse model of CGD, we evaluated the residual antibacterial activity of XO. Clearance of Burkholderia cepacia, a major pathogen in CGD, was reduced in p47(phox-/-) mice compared to that in wild-type mice and was further inhibited in p47(phox-/-) mice by pretreatment with the specific XO inhibitor allopurinol. Hepatic B. cepacia burden was similar in the two genotypes, but allopurinol significantly reduced net hepatic killing and killing efficiency only in p47(phox-/-) mice. Clearance and killing of intravenous Escherichia coli was intact in p47(phox-/-) mice and was unaffected by pretreatment with allopurinol. In CGD, XO may contribute to host defense against a subset of reactive oxidant-sensitive pathogens.

Allopurinol↗
PubMed2000

Changes of HDL subfractions by eicosapentaenoic acid intake and physical load in 20- to 25-year-old men.

The effects of daily eicosapentaenoic acid (EPA) intake and physical activity on high-density lipoprotein (HDL) subfraction, which may be an index of health status, were examined. The HDL subfraction, triglyceride and T-chol levels in the serum of 10 male volunteers aged 20-25 were examined before, immediately after and 1 h after being subjected to a physical load by bicycle ergometer at 90 W for 20 min. Subjects were then given 1.25 g EPA/day for 2 weeks, and the above test was repeated. By EPA intake, the distribution of HDL3b and 3c decreased significantly by 16.8 and 15.3%, respectively, and that of 2b increased significantly by 17.9%. The rate of change of subfraction of the 29th part (2b) of 30 parts in the total range of HDL increased by 67%, and decreased by 47% in 7th part (3c). By physical load, the distribution of HDL2a increased significantly by 15.4%, while 3b tended to decrease. By physical load after EPA intake, the distribution of 2a decreased significantly by 9.7%, and those of 3b and 3c increased significantly by 20.5 and 5.4%, respectively, and that of the 7th part (3c) increased by 37%. Thus, the physical load after EPA intake is effective to prevent arteriosclerosis as increasing the rate of change of HDL3c and as showing the longevity pattern of the HDL subfraction. Concentration of TG in a modal HDL pattern group increased by 95% after EPA intake, but that of a bimodal group did not show any change. HDL-cholesterol level in the bimodal group was higher than that in the modal group, especially after EPA intake. Two type III subjects changed to type IV by the load and the EPA intake, respectively. Thus, it seemed that the transformation from a modal pattern to a bimodal pattern by a certain lifestyle, especially regular physical activity and proper food intake, is a very important trial for the prevention of cerebrovascular diseases.

Adult↗
PubMed2000

Hand assisted laparoscopic radical nephrectomy for renal carcinoma using a new abdominal wall sealing device.

PURPOSE: We report our initial experience with a hand assisted laparoscopic radical nephrectomy for patients with renal carcinoma, and compare our results to those of conventional open radical nephrectomy. MATERIALS AND METHODS: The clinical data on 6 consecutive patients who underwent hand assisted laparoscopic radical nephrectomy for stage T1N0M0 renal cell carcinoma were reviewed. We performed hand assisted laparoscopic surgery using the new LAP DISC* abdominal wall sealing device. We compared the results of this procedure with those of conventional open radical nephrectomy in 12 patients with stage T1N0M0 renal cell carcinoma. RESULTS: The hand assisted laparoscopic radical nephrectomy for renal carcinoma was successfully performed without any major or minor complications in all 6 patients. Mean operation time for the laparoscopic group was significantly longer than that for the open surgery group (303 minutes versus 224 minutes, p = 0.0042). However, no significant difference was observed in mean estimated blood loss for the 2 groups (264 ml. in the laparoscopic group versus 341 ml. in the open surgery group). The frequency of parenteral analgesia postoperatively in the laparoscopic group was significantly lower than that in the open surgery group (16.7% versus 75.0%, p = 0.043). In addition, the laparoscopic group seemed to recover more rapidly than the open surgery group. The abdominal wall sealing device was easy to attach to the abdominal wall, and allowed rapid hand removal and reinsertion. CONCLUSIONS: Our preliminary results indicate that a hand assisted laparoscopic radical nephrectomy with the abdominal wall sealing device is an effective and safe surgical procedure, and is less invasive than open radical nephrectomy.

Adult↗
PubMed2000

[The indications for autonomic nerve-sparing surgery in rectal cancer patients].

Although extended lymph node dissection was developed to improve the therapeutic result in advanced rectal cancer in the 1970s, postoperative dysfunction remained problematic. Informed consent of cancer is generalized at present. The balance between complete cure and functional preservation is important. Therefore the autonomic nerve-sparing surgical technique for rectal cancer was introduce din the 1980s. The success of nerve-sparing surgery depends on a thorough knowledge of pelvic anatomy, especially the anatomic relationship between the pelvic plexus and internal intestinal vessels. Further investigation is required to clarify the indications for autonomic nerve-sparing surgery in rectal cancer patients.

Autonomic Nervous System↗
PubMed2000

[CD8-positive diffuse large B-cell lymphoma].

In May, 1998, a 63-year-old woman was admitted for treatment of relapsed malignant lymphoma. In March 1997, a diagnosis of diffuse large B-cell lymphoma(DLBL), clinical stage IIISE A, was made from a biopsy specimen of the tumor in the left buccal mucosa. Six cycles of CHOP regimen were given, and complete remission was achieved. However, relapse of the lymphoma was suspected, and the patient was transferred to our hospital. On admission, a right tosillar mass, 8 mm in diameter, was found, and a biopsy showed DLBL. The immunophenotype of the lymphoma cells was CD3- CD4- CD5- CD8+ CD10- CD19+ CD20+ CD23- CD25+ IgL (lambda)+, and dual staining confirmed that the cells were CD8+ and CD19+. The patient was an HTLV-1 carrier, but monoclonal integration of HTLV-1 proviral DNA into the lymphoma cells was not detected. She was diagnosed as having CD8+ DLBL, clinical stage IA. Because she responded to salvage chemotherapy, autologous peripheral blood stem cell transplantation was performed and complete remission was obtained. To our knowledge, this is the first report of CD8+ DLBL.

CD8 Antigens↗
PubMed2000

[Development of a case of Mycobacterium avium complex disease from right pleural effusion].

Moist pleurisy in patients with Mycobacterium avium Complex (MAC) is rarer than tuberculosis. We encountered an extremely rare case of MAC disease in a 75-year-old man who initially had only right pleural effusion. Gaffky VII was detected in the pleural effusion, and Mycobacterium avium was identified by culture and PCR. Although administration of antitubercular agents (RFP, INH, EB, and SM) + CAM and thoracic lavage were repeated, the Gaffky persisted strongly. Accordingly, pulmonary decortication and filling of the cavity with an omental flap were performed as surgical treatments. However, fistulas were formed between the remaining empyema cavity and the surgical wounds. Fenestration was also carried out. Postoperatively, centriacinar abnormalities appeared on computed tomography (CT). It has been reported that MAC disease begins with centriacinar abnormalities and the incidence of the lymphatic developmental pattern was low. Tuberculosis (the idiopathic pleuritis type) is considered to be caused this pattern from the primary infection focus. Therefore, the onset of unilateral effusion is extremely rare in patient with MAC disease, suggesting that the lymphatic developmental pattern occurs less frequently in patients with MAC disease. Furthermore, in this case, we speculated that centriacinar abnormalities were the MAC infection foci and could be detected by CT due to surgical invasion.

Aged↗
PubMed1999

A nonpathogenic GAAGGA repeat in the Friedreich gene: implications for pathogenesis.

An individual with late-onset ataxia was found to be heterozygous for an unusual (GAAGGA)65 sequence and a normal GAA repeat in the frataxin gene. No frataxin point mutation was present, excluding a form of Friedreich ataxia. (GAAGGA)65 did not have the inhibitory effect on gene expression in transfected cells shown by pathogenic GAA repeats of similar length. GAA repeats, but not (GAAGGA)65, adopt a triple helical conformation in vitro. We suggest that such a triplex structure is essential for suppression of gene expression.

Aged↗
PubMed1999

Electropharmacological effects of UK-1745, a novel cardiotonic drug, in guinea-pig ventricular myocytes.

Effects of (2RS, 3SR)-2-aminomethyl-2,3,7,8-tetrahydro-2,3,5,8, 8-pentamethyl-6H-furo-[2,3-e] indol-7-one hydrochloride (UK-1745), a novel cardiotonic drug with beta-adrenoceptor blocking property and antiarrhythmic activity, on the action potentials of isolated papillary muscles and the membrane currents of single ventricular myocytes of guinea pigs were examined and compared with those of milrinone using conventional microelectrode and patch-clamp techniques. In papillary muscles, UK-1745 (3-100 microM) produced a mild positive inotropic response and depressed the maximum upstroke velocity of the action potential (V(max)) at 100 microM. Milrinone, a phosphodiesterase III inhibitor, markedly shortened the action potential duration with a significant increase in developed tension. In enzymatically-dissociated ventricular myocytes, UK-1745 failed to increase the L-type Ca(2+) current (I(Ca)) at 10 and 30 microM and rather decreased I(Ca) at 100 microM. The high concentration of UK-1745 slightly inhibited the delayed rectifier K(+) current (I(K)). Although UK-1745 antagonized the isoproterenol-induced increase in I(Ca), it potentiated the histamine-induced increase in I(Ca). On the other hand, milrinone per se significantly increased I(Ca) and markedly enhanced the isoproterenol-induced increase in I(Ca). It can be concluded that UK-1745 is a unique cardiotonic drug possessing beta-adrenoceptor blocking and weak phosphodiesterase-inhibitory actions in addition to direct inhibitory actions on the Na(+), Ca(2+) and K(+) channels with its high concentrations.

Action Potentials↗
PubMed1999

Presence of ganglia within the prostatic capsule: ganglion involvement in prostatic cancer.

BACKGROUND: The presence of ganglia within the prostatic capsule (capsular ganglia) is a poorly understood phenomenon. If cancer invasion into or around ganglia is identified in a needle biopsy specimen, such a finding may be diagnosed as an extraprostatic extension. In this study, the presence of capsular ganglia was clarified. Furthermore, we discuss the significance of these ganglia in prostatic cancer patients. METHODS: The study group comprised a total of 42 patients, who had all undergone a radical prostatectomy for prostate adenocarcinoma with a relatively small volume. After surgery, the step-sectioned radical prostatectomy specimens were histologically evaluated. RESULTS: In 22 of 42 cases, capsular ganglia were recognized. With respect to the distribution of the capsular ganglia, the ganglia were most frequently observed at the posteriolateral aspect of the prostatic base. Morphologically there were no obvious differences between the capsular and periprostatic ganglia. Moreover, in 3 of 5 cases with cancer involvement into the capsular ganglia, such involvement was not predictive of extraprostatic extension. CONCLUSIONS: The presence of capsular ganglia needs to be clarified in prostatic cancer patients. Our findings therefore suggest that cancer involvement either in or around the ganglia should not be immediately interpreted as indicating an extraprostatic extension, if such a finding is recognized in a needle biopsy specimen.

Adenocarcinoma↗
PubMed1999

Use of bone turnover marker, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), in the assessment and monitoring of bone metastasis in prostate cancer.

BACKGROUND: We investigated whether a new marker of bone turnover, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), could be useful in the assessment of bone metastasis and in monitoring of the response to treatment in patients with prostate cancer with bone metastasis. METHODS: In all, 58 patients with prostate cancer (25 with bone metastasis and 33 without bone metastasis) and 52 patients with benign prostate hypertrophy who were treated between June 1994-August 1997 were included in this study. All patients were newly diagnosed. RESULTS: Serum ICTP levels in patients with prostate cancer with bone metastasis were significantly higher than those in patients with prostate cancer without bone metastasis (P<0.0001) or with benign prostate hypertrophy (P<0.0001). No significant differences were observed in serum ICTP levels between patients with prostate cancer without bone metastasis and those with benign prostate hypertrophy. Serum ICTP levels correlated significantly with Soloway's grading system for bone scans. Serum ICTP levels in patients with bone metastasis showed a significant downward trend in response to hormonal treatment. CONCLUSIONS: The determination of serum ICTP levels is useful in the assessment of bone metastasis and in monitoring the response of bone metastasis to treatment to prostate cancer.

Aged↗
PubMed1999

Localization effects of acetylcholine release from a synaptic vesicle at the neuromuscular junction.

A two-dimensional compartment model devised for the appropriate representation of the transient process of the spontaneous generation of miniature endplate current (MEPC) at the neuromuscular junction is applied for clarifying the biochemical significance of the quantal release mechanism of acetylcholine (ACh), a typical neurotransmitter, in the synaptic chemical transmission process. The simulation analysis with the model demonstrates that the localization of the ACh release due to the fusion of a synaptic vesicle with the presynaptic membrane has significant effects on the amplitude of MEPC and that the stronger effects are caused with the smaller diffusion coefficients of ACh in the cleft. The sharpest and highest response of MEPC is achieved when the release area is about 4 times to the natural release through the narrow pore. On the other hand, the actual localization corresponding to the natural release of ACh makes the amplitude of MEPC higher by a factor about 2.5 compared with that in the most extended release of ACh examined, implying that the natural release mechanism works as an amplifier of the MEPC with the fixed amount of ACh available.

Acetylcholine↗
PubMed1999

Sticky DNA: self-association properties of long GAA.TTC repeats in R.R.Y triplex structures from Friedreich's ataxia.

A novel DNA structure, sticky DNA, is described for lengths of (GAA.TTC)n found in intron 1 of the frataxin gene of Friedreich's ataxia patients. Sticky DNA is formed by the association of two purine.purine.pyrimidine (R.R.Y) triplexes in negatively supercoiled plasmids at neutral pH. An excellent correlation was found between the lengths of (GAA.TTC) (> 59 repeats): first, in FRDA patients, second, required to inhibit transcription in vivo and in vitro, and third, required to adopt the sticky conformation. Fourth, (GAAGGA.TCCTTC)65, also found in intron 1, does not form sticky DNA, inhibit transcription, or associate with the disease. Hence, R.R.Y triplexes and/or sticky DNA may be involved in the etiology of FRDA.

DNA↗
PubMed1999

Low vitamin K intake effects on glucose tolerance in rats.

To investigate the effects of vitamin K (VK) on pancreatic function, intravenous glucose tolerance tests were performed in rats fed with and without low VK diet (including less than 20% required vitamin K1). Plasma glucose and immuno-reactive insulin (IRI) were determined. It was found that at 0 min., plasma glucose and IRI levels in low VK group were slightly less than in the control (glucose, 204.5 +/- 21.7 vs. 229 +/- 19.6 mg/dl, IRI, 6.6 +/- 1.3 vs. 9.3 +/- 1.8 ng/ml mean +/- SEM). At 3 min. after glucose administration, plasma glucose was higher (391.8 +/- 25.6 vs. 371.8 +/- 18.7 mg/dl) and IRI, lower (11.8 +/- 2.1 vs. 18.2 +/- 3.6 ng/ml) in the low VK group. The disappearance rate of plasma glucose in the low VK group at 5-10 min. was significantly less than in the control (6.7 +/- 2.2 vs. 11.9 +/- 1.8 mg/dl/min.). Incremental IRI area at 0 to 5 min. in the low VK group is less than in the control (15.2 +/- 4.4 vs. 25.0 +/- 9.1 ng/ml/min.), but at 5-60 min. and 0-60 min., it was found to be significantly higher compared to the control (210.3 +/- 55.2 vs. 32.5 +/- 47.1 ng/ml/min. at 5-60 min.). Dietary low VK intake would thus appear to induce a tendency of poor early insulin response, and late hyperinsulinemia to the glucose load in rats.

Animals↗
PubMed1999

Surgical excision of a metastatic adrenal lesion in a patient with prostatic cancer.

BACKGROUND: A 64-year-old Japanese man with stage D2 prostatic cancer, after having responded dramatically to androgen ablation, demonstrated a solitary adrenal metastasis without disease progression to any other site. METHODS: A surgical excision of the lesion and adjuvant systemic chemotherapy was performed. RESULTS/CONCLUSIONS: The patient has since remained alive without any evidence of recurrence 21 months after surgery.

Adenocarcinoma↗
PubMed1999

Effect of aldose reductase inhibitors on glucose-induced changes in sorbitol and myo-inositol metabolism in human neutrophils.

AIM: To investigate the influence of glucose and the efficacy of two different aldose reductase (AR) inhibitors, epalrestat and SNK-860, on the polyol pathway and myo-inositol metabolism in human neutrophils. METHODS: We incubated neutrophils with various concentrations of glucose and AR inhibitors. The neutrophils from healthy volunteers were incubated in the media containing 5-40 mmol/l glucose with or without an AR inhibitor. The sorbitol and myo-inositol contents, and myo-inositol uptake were measured by high performance liquid chromatography and radio isotope technique with 2-[3H]-myo-inositol. RESULTS: After 2 h incubation, the sorbitol content increased with rising extracellular glucose concentrations, while the myo-inositol content decreased. Both AR inhibitors reduced the sorbitol content in neutrophils exposed to 40 mmol/l glucose medium. A 70% fall in the myo-inositol content in neutrophils exposed to 40mmol/glucose medium was attenuated approximately 40% by the addition of AR inhibitors. myo-Inositol uptake into neutrophils was inhibited by high glucose. AR inhibitors significantly ameliorated the decrease in myo-inositol uptake, but did not completely normalize it. CONCLUSIONS: Our present in vitro studies showed that the glucose-induced metabolic alterations in human neutrophils were similar to those in tissues prone to diabetic complications, and that AR inhibitors effectively corrected glucose-induced imbalances of the polyol pathway and myo-inositol uptake in neutrophils. In addition, our study suggests that glucose-induced metabolic alterations may result in the neutrophil dysfunction and that an AR inhibitor may be capable ameliorating it.

Adult↗
PubMed1999

Characteristics of intracardiac potentials at successful ablation sites in concealed Wolff-Parkinson-White syndrome.

The authors investigated bipolar electrograms recorded from the catheter tip at the actual successful ablation sites in 22 consecutive patients with concealed Wolff-Parkinson-White syndrome to clarify the characteristics of the potentials indicating the optimal site for catheter ablation. In all patients the retrograde transaortic approach to their left-sided accessory pathways, and a temperature-controlled (60 degrees C) energy delivery, were performed. The authors assumed that a shorter dissociation time (time from energy delivery to ventriculoatrial conduction dissociation) indicated more accurate catheter mapping. A significant negative correlation (r = 0.527, p < 0.05) between the AV ratio (ratio of the amplitudes of the atrial to ventricular potentials) recorded at the ablation catheter tip and the dissociation time was observed. When the AV ratio and the dissociation time were compared among the groups classified according to the corresponding Npeak (the number of positive potential peaks in the electrogram obtained from the ablation catheter tip during right ventricular apical pacing) value, they differed significantly (p < 0.05 and p < 0.01, respectively), ie, a higher AV ratio and a shorter dissociation time related to a multipeak electrogram from the ablation catheter tip. The authors conclude that the atrial insertion site of the accessory pathway, exhibiting a multipeak complex electrogram that may represent nonuniform anisotropic characteristics, is an adequate ablation site.

Action Potentials↗