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N Kosaka

Publications and source records attributed to N Kosaka.

At least 19 recordsLinked to original sources
PubMed2001

A potent 1,4-dihydropyridine L-type calcium channel blocker, benidipine, promotes osteoblast differentiation.

During their differentiation, osteoblasts sequentially express type I collagen, alkaline phosphatase (ALP), and osteocalcin, and then undergo mineral deposition. Among dihydropyridine-type calcium channel blockers, only benidipine stimulated ALP activity of osteoblastic cells derived from neonatal mouse calvaria. To identify the molecular target of benidipine and elucidate the mechanism of action of the drug in osteoblasts, the mouse osteoblastic cell line MC3T3-E1 was used. Benidipine prompted ALP activity and ALP transcription induced by ascorbic acid, and mineral deposition by ascorbic acid and b-glycerophosphate. Benidipine, however, did not change collagen accumulation. MC3T3-E1 cells expressed the L-type Ca channel a1C subunit throughout the differentiation process, and Ca influx by potassium ions and Bay K 8644, an agonist, was strongly attenuated by benidipine. Each one of three structurally different classes of Ca channel blockers, nifedipine, verapamil, and diltiazem stimulated ALP activity, although at much higher concentrations of ca. 100 nM than benidipine, 1 pM. These results suggest that benidipine directly exerts its effect on osteoblasts and promotes osteoblast differentiation after the step of collagen accumulation by blocking the L-type Ca channel. Since benidipine blocked Ca influx more potently than the three other Ca channel blockers, the unique and potent osteoblast differentiating ability of benidipine may be due to its high affinity for Ca channel together with its high membrane retaining ability, as has been previously reported.

Alkaline Phosphatase↗
PubMed2001

Quantitative determination of amygdalin epimers by cyclodextrin-modified micellar electrokinetic chromatography.

A new capillary electrophoresis method was developed for the quantitative determination of the amygdalin epimers, amygdalin and neoamygdalin, which are biologically significant constituents in the crude drugs, namely Persicae Semen and Armeniacae Semen. The effects of surfactants, additives and other analytical parameters were studied. As a result, the resolution of two epimers was performed by cyclodextrin-modified micellar electrokinetic chromatography with a buffer containing alpha-cyclodextrin and sodium deoxycholate. By the application of this method, a simple, fast and simultaneous quantitative determinations of amygdalin epimers in the crude drugs (Persicae Semen and Armeniacae Semen) and the Chinese herbal prescriptions (Keishi-bukuryo-gan and Mao-to) were achieved.

Amygdalin↗
PubMed2001

UCS15A, a non-kinase inhibitor of Src signal transduction.

Src tyrosine kinase plays key roles in signal transduction following growth factor stimulation and integrin-mediated cell-substrate adhesion. Since src-signal transduction defects are implicated in a multitude of human diseases, we have sought to develop new ways to identify small molecule inhibitors using a yeast-based, activated-src over-expression system. In the present study, we describe the identification of a unique src-signal transduction inhibitor, UCS15A. UCS15A was found to inhibit the src specific tyrosine phosphorylation of numerous proteins in v-src-transformed cells. Two of these phosphoproteins were identified as bona-fide src substrates, cortactin and Sam68. UCS15A differed from conventional src-inhibitors in that it did not inhibit the tyrosine kinase activity of src. In addition, UCS15A appeared to differ from src-destabilizing agents such as herbimycin and radicicol that destabilize src by interfering with Hsp90. Our studies suggest that UCS15A exerted its src-inhibitory effects by a novel mechanism that involved disruption of protein-protein interactions mediated by src. One of the biological consequences of src-inhibition by UCS15A was its ability to inhibit the bone resorption activity of osteoclasts in vitro. These data suggest that UCS15A may inhibit the bone resorption activity of osteoclasts, not by inhibiting src tyrosine kinase activity, but by disrupting the interaction of proteins associated with src, thereby modulating downstream events in the src signal transduction pathway.

3T3 Cells↗
PubMed2001

Craniofacial abnormalities in Japanese patients with severe obstructive sleep apnoea syndrome.

OBJECTIVE: To clarify that factors besides obesity play an important role in the development of obstructive sleep apnoea syndrome (OSAS) in Japanese patients, we compared craniofacial structures in patients with severe OSAS with those of normal controls. METHODOLOGY: The craniofacial structures of 60 Japanese patients with severe OSAS and 30 normal controls were evaluated using standard cephalometric analysis. Patients were stratified according to body mass index (BMI): non-obese, BMI < 25; moderately obese, BMI = 25-30, severely obese, BMI > 30. RESULTS: The SNA (sella to nasion to subspinale angle) was significantly smaller in the patient groups than in the controls. The SNB (sella to nasion to supramentale angle) and NSBa (cranial base flexure) were significantly smaller in the non-obese and moderately obese patients than in controls. The MP-H (distance from the mandibular plane to the hyoid bone) and the PNS-P (distance from the posterior nasal spine to the tip of the soft palate) were significantly longer in the patient groups than in the controls. The PNS-P was significantly longer in the severely obese patients than in the non-obese patients. CONCLUSIONS: Japanese patients with severe OSAS have enlargement of the soft tissues and palate as well as craniofacial bony structural abnormalities. This is particularly apparent in non-obese patients.

Body Mass Index↗
PubMed2001

Rhein, an active metabolite of diacerein, down-regulates the production of pro-matrix metalloproteinases-1, -3, -9 and -13 and up-regulates the production of tissue inhibitor of metalloproteinase-1 in cultured rabbit articular chondrocytes.

OBJECTIVE: Diacerein has proved to be effective in the treatment of osteoarthritis (OA). However, the precise action mechanism of diacerein on OA is not yet fully understood. Therefore, we investigated the effects of rhein, an active metabolite of diacerein, on the production of promatrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase-1 (TIMP-1) in rabbit articular chondrocytes. DESIGN: Confluent rabbit chondrocytes were treated for 24 or 48 h with rhein, naproxen or dexamethasone in the presence of recombinant human IL-1alpha (rhIL-1alpha). ProMMP-9/progelatinase B in the culture medium was monitored by gelatin zymography, and proMMP-1/procollagenase 1, proMMP-3/prostromelysin 1, proMMP-13/procollagenase 3 and TIMP-1 were analysed by Western blot analysis. The steady-state levels of proMMP mRNAs were examined by Northern blot analysis. Total MMPs activity was also determined using FITC-labeled casein. RESULTS: Rhein suppressed the rhIL-1alpha-induced production of proMMPs-1, -3, -9 and -13 in a dose-dependent manner (0.1-30 microM). The suppressed production of proMMPs-1 and -3 was accompanied by a decrease in the steady-state levels of their mRNAs. Interestingly, rhein increased the production of TIMP-1. These observations were further supported by the fact that rhein decreased the apparent total activity of MMPs in the culture medium. CONCLUSION: We have demonstrated that rhein, an active metabolite of diacerein down-regulates the gene-expression and production of proMMPs and up-regulates the TIMP-1 production. The therapeutic effects of diacerein on OA may be due, at least in part, to the chondroprotective effect of rhein, its active metabolite.

Animals↗
PubMed2001

Optimal continuous positive airway pressure in patients with obstructive sleep apnoea: role of craniofacial structure.

Although nasal continuous positive airway pressure (CPAP) is effective in improving nocturnal obstructive apnoea, daytime sleepiness and well-being in patients with obstructive sleep apnoea syndrome (OSAS), not all patients tolerate this treatment. Since optimal CPAP titration is essential to maintain compliance, it is important to elucidate the factors that help to determine the optimal pressure. However, the determinants of the optimal CPAP level are controversial. The subjects comprised 27 Japanese male patients with OSAS who underwent standard polysomnography (PSG), pulmonary function tests, arterial blood gas analysis, cephalometry and CPAP titration. Twenty normal controls also underwent cephalometric analysis. The apnoea-hypopnoea index (AHI), mean oxygen saturation (mean SaO2) and the lowest SaO2 during sleep were found to be 54.7+/-22.6, 89.0+/-5.6%, and 69.7+/-9.0%, respectively by PSG. The mean optimal CPAP was 9.6+/-1.8 cmH2O. The cephalometric angles (SNA, SNB and NSBa) were similar to those found in the control subjects. but MP-H, and PNS-P were significantly longer than those in the control subjects as shown by cephalometry. The optimal CPAP was correlated with the mean SaO2 (P<0.0001), neck circumference (P<0.05) and three cephalometric variables (NSBa: P<0.01, MP-H: P<0.05, PNS-P: P<0.05). Multiple, step-wise, regression analysis showed that the mean SaO2 and NSBa were independent variables that best predicted the optimal CPAP. These variables accounted for 57.5% of the total variance (R2=0.575, P<0.001). Optimal CPAP was closely correlated with oxygen desaturation during sleep. However, the craniofacial structure had additional effects such as an independent factor in determining the optimal CPAP level.

Adult↗
PubMed2001

Effect of oxatomide, an antiallergic agent, on QT interval in dogs.

Oxatomide (CAS 60607-34-3, KW-4354) is an effective antiallergic agent for allergic rhinitis, urticaria, pruritus cutaneous, and eczema/dermatitis, etc. Terfenadine (CAS 50679-08-8) and astemizole (CAS 68844-77-9), antiallergic agents, have been reported to induce QT prolongation leading to serious ventricular arrhythmia (torsades de pointes) as cardiovascular adverse effects. The present study was carried out to determine whether oxatomide and terfenadine have effects on QT interval as a single drug or in combination with itraconazole (CAS 84625-61-6), an antifungal agent with a CYP3A4 inhibitory effect, in conscious dogs. Terfenadine alone induced QT prolongation at the dose of 30 mg/kg p.o. When itraconazole was administered at the dose of 100 mg/kg p.o. 1 h before terfenadine administration, terfenadine induced QT prolongation at the dose of 10 mg/kg p.o. On the other hand, oxatomide did not induce QT prolongation either as a single agent at the dose of 30 mg/kg p.o. or in combination with itraconazole at the dose of 10 mg/kg p.o. The results present no evidence that oxatomide has the potential to provoke ventricular arrhythmia.

Animals↗
PubMed2001

[Effect of olopatadine hydrochloride, a novel antiallergic agent, on the QT interval in dogs].

Olopatadine hydrochloride (olopatadine), a novel antiallergic agent, is effective in the treatment of allergic rhinitis, chronic urticaria, eczema and dermatitis. It has been reported that terfenadine and astemizole cause side effects on the circulatory system such as QT prolongation followed by serious ventricular arrhythmias (torsades de pointes). To investigate the possibility of QT prolongation, we used both conscious normal dogs and hypokalemia-anesthetized dogs under two conditions: 1) olopatadine used alone and 2) olopatadine used in combination with itraconazole, the CYP3A4-inhibiting antifungal agent, in the present investigation. The group treated with terfenadine alone (30 mg/kg, p.o.) and the group treated with a combination of terfenadine (10 mg/kg, p.o.) and itraconazole (100 mg/kg, p.o.) had a significantly prolonged QT interval. On the other hand, the group treated with olopatadine alone (30 mg/kg, p.o.) and the group treated with a combination of olopatadine (30 mg/kg, p.o.) and itraconazole (100 mg/kg, p.o.) did not show any significant changes in QT interval. Moreover, olopatadine (1 and 5 mg/kg, i.v.) did not influence the QT interval in hypokalemia-anesthetized dogs. These results suggest that there is very little possibility of QT prolongation as a result of clinically used olopatadine.

Animals↗
PubMed2000

Long-term effects nasal continuous positive airway pressure on daytime sleepiness, mood and traffic accidents in patients with obstructive sleep apnoea.

To describe the long-term effects of nasal continuous positive airway pressure (CPAP) on the rate of traffic car accidents, excessive daytime sleepiness (EDS) and mood in patients with obstructive sleep apnoea syndrome (OSAS), we investigated the changes of these parameters before and after nasal CPAP treatment using a questionnaire. Seventy-five male patients who were diagnosed with severe OSAS by polysomnography were evaluated for driving competence, by looking at their driving history for 2 yr, for EDS by the Epwarth Sleepiness Scale (ESS) and for mood by the Self-related Depression Scale (SDS), and then underwent nasal CPAP treatment. After 2 yr of treatment, questionnaires inquiring about the patients' use of CPAP, their ESS, SDS and driving history during treatment were sent to the patients. A total of 47 patients (63%) responded to these questionnaires. Forty-six of the 47 responders had continued to use the nasal CPAP and completed the questionnaire. No traffic car accidents were observed among the 39 routine car users during treatment, while 13 of 39 patients (33%) had had car accidents before treatment. Although near-miss accidents had been reported by 32 of 39 patients (82%) before treatment, only four patients reported near-miss accidents during nasal CPAP treatment. The mean score of ESS was significantly (P<0.01) reduced in 46 patients after nasal CPAP. The mean score of SDS was also decreased (P<0.01) after nasal CPAP in 46 patients. Although 26 of 41 patients had been depressive on SDS before treatment, the mood was improved in 13 patients after nasal CPAP. These results suggest that long-term nasal CPAP treatment reduces the rate of traffic car accidents and improves the EDS and the mood in patients with OSAS.

Accidents, Traffic↗
PubMed2000

[GC-MS determination of l-ephedrine and d-pseudoephedrine in human plasma].

To determine l-ephedrine (E) and d-pseudoephedrine (PE) concentrations in human plasma simultaneously, we used a selected-ion monitoring method with gas chromatography-mass spectrometry (GC-MS) using deuterium-labeled E and PE as internal standards. The E and PE in human plasma were extracted with hexane-ethylacetate (9/1) under alkaline conditions and were easily converted into their heptafluorobutyryl derivatives by treating with heptafluorobutyrylimidazole. The calibration curves of E and PE showed a good linearity in the range from 0.82 to 81.9 ng/ml for E, and from 0.41 to 41.0 ng/ml for PE, respectively. The limit of detection was 0.82 ng/ml for E and 0.41 ng/ml for PE in human plasma, respectively.

Ephedrine↗
PubMed2000

Sensitive detection of mediastinal lymph node metastasis of lung cancer with 11C-choline PET.

UNLABELLED: 11C-choline and FDG are PET tracers used to visualize various malignancies. In this study, we compared their capabilities in detecting mediastinal lymph node metastasis originating from non-small cell lung cancer (NSCLC). METHODS: Twenty-nine patients with biopsy-proven NSCLC were studied with PET. 11C-choline PET and FDG PET were performed from 5 and 40 min, respectively, after injection of 370 MBq tracer. PET data were analyzed in terms of the standardized uptake value (SUV). After the PET study, the patients underwent lung resection and mediastinal lymph node dissection. The resected specimens were examined pathologically, and the PET data were analyzed in reference to the pathologic data. RESULTS: With 11C-choline, the SUV in metastasis was similar to the SUV in the primary tumor, where the similarity of the SUV was 100% allowing for a 40% difference. With FDG, small metastases were invisible on the PET image. The SUV of FDG in metastasis was much smaller than that in the primary tumor, and the similarity of the SUV was only 19% allowing for a 40% difference. When pathologic findings were used as standards, the sensitivities of 11C-choline PET and FDG PET in detecting mediastinal lymph node metastasis were 100% and 75%, respectively. CONCLUSION: 11C-choline PET was very effective in detecting lymph node metastases in the mediastinum originating from NSCLC, with a sensitivity of 100%. 11C-choline PET promises to be useful not only before surgery but also after surgery.

Adult↗
PubMed1999

Positron emission tomography of esophageal carcinoma using (11)C-choline and (18)F-fluorodeoxyglucose: a novel method of preoperative lymph node staging.

BACKGROUND: Accurate preoperative staging is an important but difficult problem in determining therapy for patients with esophageal carcinoma. Positron emission tomography (PET) is used with [methyl-(11)C]choline ((11)C-choline) and 2-[(18)F]fluoro-2-deoxy-D-glucose ((18)F-FDG) to detect a variety of malignancies. The authors used PET with both of these agents to detect lymph node metastases in patients with esophageal carcinoma. METHODS: Lymph node metastases in 33 patients with biopsy-proven esophageal carcinoma (16 patients with tumors classified as T1 and 17 patients with tumors classified as T2-4) was examined by PET using (11)C-choline and (18)F-FDG, and the accuracy of the results was correlated with pathology findings after surgery. RESULTS: (11)C-choline PET was more effective than (18)F-FDG PET and computed tomography (CT) in detecting very small metastases localized in the mediastinum. It was ineffective, however, in detecting metastases localized in the upper abdomen, because of the normal uptake of (11)C-choline in the liver. (18)F-FDG PET was superior to CT in detecting metastases in the mediastinum and the upper abdomen, whereas (11)C-choline PET was superior to (18)F-FDG PET in detecting metastases in the mediastinum. When (11)C-choline PET and (18)F-FDG PET were used in combination, they were very effective in evaluating the lymph node status in both the mediastinum and the upper abdomen, and detected 85% of the metastatic lymph nodes (n = 46). CONCLUSIONS: In this study, the combination of (11)C-choline PET and (18)F-FDG PET was very effective in evaluating the lymph node status of patients with esophageal carcinoma preoperatively.

Aged↗
PubMed1999

Nasal continuous positive airway pressure changes blood pressure "non-dippers" to "dippers" in patients with obstructive sleep apnea.

To evaluate the circadian pattern of blood pressure (BP) and the effects of nasal continuous positive airway pressure (CPAP) on patients with obstructive sleep apnea (OSA), we examined 24-hour BP in 38 male OSA patients with and without nasal CPAP. We measured the BP at 30-min intervals during daytime (800 to 2200) and nighttime (2200 to 800) hours. A "dipper" was defined as a patient who showed an average reduction of at least 10 mm Hg systolic and 5 mm Hg diastolic between daytime and nighttime values. The subjects were predominantly "non-dipper" (22 of 38 patients, 58%). Daytime hypertension (>160/95 mm Hg) was present in 11 of 38 patients (4 "dippers" and 7 "non-dippers"). After nasal CPAP treatment for 3 days, the average BP decreased significantly during the day and night in all subjects (p<0.05). Fifteen of 22 subjects who were "non-dippers" before treatment reversed to become "dippers." And daytime hypertension was detected in only 5 of these patients during nasal CPAP treatment (4 "dippers" and 1 "non-dipper"). These results showed that the "non-dipper" status was common in patients with OSA, and that nasal CPAP restored the normal circadian "dipper" pattern. We suggest that nasal CPAP may contribute to an improved prognosis in patients with OSA because of a reduction in cardiovascular risk factors in "non-dipper" with severe OSA.

Adult↗
PubMed1999

Effects of nasal continuous positive airway pressure on pulmonary haemodynamics and tissue oxygenation in patients with obstructive sleep apnoea.

We investigated the acute effects of nasal continuous positive airway pressure (CPAP) on pulmonary haemodynamics and tissue oxygenation in eight men with obstructive sleep apnoea (OSA) by means of right heart catheterization. They were tested at four dosage levels of nasal CPAP: 0, 5, 10, and 15 cmH2O. Nasal CPAP significantly reduced the cardiac index at the 10 and 15 cmH2O doses. The mean pulmonary artery pressure was significantly elevated with 10 and 15 cmH2O, and pulmonary capillary wedge pressure was significantly increased with 15 cmH2O of nasal CPAP. Pulmonary vascular resistance was significantly increased with 10 cmH2O of nasal CPAP. The 5 cmH2O dose of nasal CPAP did not affect significantly these parameters. Mixed venous oxygen tension was unchanged at any pressure. We conclude that tissue oxygenation was maintained in the OSA patients during administration of nasal CPAP, even though a high CPAP clearly affected pulmonary haemodynamics.

Adult↗
PubMed1999

Multifocal peripheral bronchial carcinoid tumour.

Peripheral bronchial carcinoids sometimes arise as single solid or nodular lesions in the periphery of the lung. We encountered a 74-year-old Japanese male with bronchial carcinoids that were widely disseminated throughout the lung parenchyma. Pulmonary function tests revealed mild airflow obstruction. A metastatic process was ruled out from primary malignancy and a histological examination revealed findings consistent with a peripheral bronchial carcinoid. Based on these findings, we concluded that this patient had a primary multifocal peripheral bronchial carcinoid. An immunohistochemical examination revealed immunoreactivity for chromogranin A and bombesin. The present case appears to be an unusual case of diffuse multifocal peripheral bronchial carcinoid, confirmed by immunohistochemistry.

Aged↗
PubMed1999

[Effects of benidipine hydrochloride (Coniel) on blood pressure, heart rate and plasma norepinephrine concentration in spontaneously hypertensive rats].

We investigated the effects of benidipine hydrochloride (benidipine, Coniel) on blood pressure, heart rate and plasma norepinephrine (NE) concentration in spontaneously hypertensive rats and compared them with those of other calcium channel blockers. Benidipine (2 mg/kg, p.o.) was compared with the equihypotensive doses of nifedipine (5 mg/kg), cilnidipine (6 mg/kg) and amlodipine (3 mg/kg). All the 4 calcium channel blockers exhibited significant antihypertensive effects. Nifedipine and cilinidipine significantly increased heart rate, as compared with that in the control group, whereas benidipine or amlodipine did not significantly affect it. The area under the curves for hypotensive effect and tachycardic effect for 10 hr after the drug administration were compared among the 4 compounds. As a result, the tachycardic effect of benidipine was significantly lower than those of nifedipine, cilnidipine and amlodipine, while the hypotensive effects were similar among the 4 compounds. Nifedipine and amlodipine, significantly increased plasma NE concentration, cilnidipine tended to increase it. In contrast, benidipine did not significantly affect plasma NE concentration. These results suggest that the effects of benidipine on plasma NE concentration and heart rate are less prominent than those of the other calcium channel blockers.

Amlodipine↗
PubMed1998

alpha-Tocopherol protects PC12 cells from hyperoxia-induced apoptosis.

A rat clonal pheochromocytoma cell line (PC12) was cultured under normoxic (21% O2) and hyperoxic (50% O2) conditions. PC12 cells underwent apoptotic cell death when they were cultured in charcoal-stripped medium in a high-oxygen atmosphere. Vitamin E homologs, alpha-tocopherol (alphaT), beta-tocopherol (betaT), gamma-tocopherol (gammaT), and delta-tocopherol (deltaT), were added to the culture medium to study their biological activities. AlphaT was more effective than gammaT and deltaT in preventing hyperoxia-induced cell death. Addition of exogenous alphaT to charcoal-treated medium prevented lactate dehydrogenase (LDH) leakage from PC12 cells and also inhibited the apoptosis, which was accompanied by DNA fragmentation. Additional alphaT was rapidly concentrated in PC12 cells, suggesting that it exerts antioxidant effects. Our data show that PC12 cell death under high-oxygen conditions is due to apoptosis and that, among the vitamin E homologs, alphaT most effectively prevents hyperoxic apoptosis.

Animals↗