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Biomedical subjects

S Nagashima

Publications and source records attributed to S Nagashima.

At least 55 records · Page 3Linked to original sources
PubMed1997

Cardiac and hemodynamic effects of TZC-5665, a novel pyridazinone derivative, and its metabolite in humans and dogs.

1. TZC-5665 is a novel pyridazinone derivative with vasodilatory and beta-adrenergic blocking activities and type III phosphodiesterase inhibitory action. 2. In healthy volunteers, TZC-5665 was rapidly absorbed and immediately metabolized. Its main metabolite, M-2, remained at a higher concentration in plasma. Orally administered TZC-5665 reduced end-diastolic left ventricular volume (20.16 ml) and exhibited a tendency to increase ejection fraction (0.04). 3. In dogs, M-2 dose-dependently increased cardiac contractility and reduced both preload and afterload. These effects appeared more potent in the failed heart than in the normal heart. At the same dose (30 micrograms/kg), the effects of M-2 seem to be more potent than those of milrinone. 4. We concluded that TZC-5665 is a useful medication for treating patients with chronic congestive heart failure (CHF) because of the positive inotropic and vasodilating effects due to its active metabolite in addition to its own beta-adrenergic blocking actions.

Adult↗
PubMed1997

Alveolar bone loss in rats infected with a strain of Prevotella intermedia and Fusobacterium nucleatum isolated from a child with prepubertal periodontitis.

Prevotella intermedia and fusobacterium nucleatum are associated with various forms of periodontal disease. The purpose of the present study was to infect the clinical isolates of these periodontopathic bacteria and to induce a significant loss of alveolar bone in specific pathogen-free (SPF) rats in the absence of ligatures. P. intermedia YKD8 and F. nucleatum YKZ5 were isolated from a prepubertal periodontitis patient, while P. gingivalis MWB13 was from a patient with juvenile periodontitis. At first, SPF Sprague-Dawley rats (70 days of age, male) were infected with A. viscosus Ny1R and subsequently superinfected with P. gingivalis MWB13, P. intermedia YKD8, or F. nucleatum YKZ5, respectively. The control group was infected with A. viscosus Ny1R alone. All rats were killed and periodontal bone levels were assessed morphometrically 135 days after the first infection with A. viscosus. P. intermedia YKD8 was recovered frequently from rats, with serum antibody levels remaining highly elevated throughout the experiment. Significant loss of alveolar bone was found in rats infected with P. intermedia YKD8, the virulence of which was equivalent to that of P. gingivalis MWB13. F. nucleatum YKZ5 also induced alveolar bone loss, but not significantly when compared with rats infected with A. viscosus Ny1R alone.

Aggregatibacter actinomycetemcomitans↗
PubMed1997

Bronchial artery aneurysm as a cause of atelectasis.

A 54-year-old nonsmoker female developed atelectasis of the anterior basal segment of the right lower lobe. A non-pulsating endobronchial tumor was observed bronchoscopically obstructing the right basal bronchus. The tumor was confirmed on arteriography to be a saccular aneurysm of the right bronchial artery. The aneurysm was treated with bronchial artery embolization. Bronchial artery aneurysm, without a predisposing disease, is quite rare, but should be considered as an etiological factor of atelectasis.

Aneurysm↗
PubMed1997

Comparison of the results of bilateral total knee arthroplasty with and without patellar replacement for rheumatoid arthritis. A follow-up note.

Simultaneous bilateral total knee arthroplasty was performed in twenty-six patients who had rheumatoid arthritis, and a patellar replacement was performed concurrently in one randomly selected knee in each patient. A lateral retinacular release was performed in all knees. The patients were followed for at least six years (mean, 6.6 years; range, 6.0 to 7.5 years), and the postoperative status of the patients was evaluated with the knee score of The Hospital for Special Surgery. Pain on standing and on ascending or descending stairs as well as tenderness of the patellofemoral joint also were assessed. The over-all score and the individual scores for pain, function, range of motion, muscle strength, flexion contracture, and instability were not significantly different between the knees that had had a patellar replacement and those that had not. However, pain on standing and on ascending or descending stairs as well as tenderness of the patellofemoral joint were only noted in knees that had not had a patellar replacement. These findings suggest that, in order to diminish pain on standing and on using stairs, replacement of the patella during total knee arthroplasty is preferable for patients who have rheumatoid arthritis.

Adult↗
PubMed1996

Nonsecretory apoptotic killing by human NK cells.

We defined a novel constitutive mechanism of cell-mediated cytotoxicity, utilized by nonactivated human peripheral blood NK cells against a variety of tumor cell targets resistant to secretory (i.e., perforin/granzyme-mediated) NK cell killing. Untreated NK cells rapidly induced membrane damage and necrosis in K562 target cells (as determined by 51Cr release assay and confirmed by transmission electron microscopy; TEM), in the absence of DNA fragmentation and apoptosis (as assessed by [3H]thymidine release assay and TEM). Chelation of extracellular Ca2+ or paraformaldehyde fixation completely abrogated NK cell secretory activity and necrotic killing. In contrast, NK cells with either normal or impaired secretion consistently exhibited cytotoxicity against a wide variety of solid tumor cell lines in 1-h [3H]thymidine release, but not in 4-h 51Cr release, assays. Thus, the cytotoxicity was attributable to a nonsecretory, cell membrane-mediated mechanism. It appeared to selectively induce DNA fragmentation and apoptosis without plasma membrane damage and necrosis. This was further demonstrated by a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and confirmed by TEM. Among defined populations of immune cells, only NK cells showed an inherent ability to rapidly induce apoptotic death in solid tissue-derived malignant cells. This study demonstrates that NK cells are unique immune cells constitutively endowed with multiple mechanisms of destroying abnormal cells.

Apoptosis↗
PubMed1996

The role of apoptosis in antibody-dependent cell-mediated cytotoxicity against monolayers of human squamous cell carcinoma of the head and neck targets.

Antibody-dependent cellular cytotoxicity (ADCC) against squamous cell carcinoma of the head and neck (SCCHN) targets in the presence of human/mouse chimeric monoclonal antibodies (cMAbs), SF-25 and 323/A3, is mediated by natural killer (NK) cells. In 4-hr 51Cr-release assays with SSCHN targets in suspension, ADCC was always significantly better (P < 0.01) than that measured in parallel with the same target cells in monolayers. No differences were observed in the level of expression of the relevant antigens recognized by cMAbs on these targets. To better explain the difference, 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) monolayer and [3H]thymidine-release assays were used. Cytostasis and cell death measured in monolayer MTT assays and DNA fragmentation measured in [3H]thymidine-release assays were significantly higher (P = 0.028) than cytotoxicity determined using 51Cr-labeled SCCHN monolayers. Cell death observed in monolayer MTT assays was blocked by pretreating SCCHN targets with cycloheximide or actinomycin-D or by paraformaldehyde fixation of effector cells. The presence of apoptotic cells in monolayers co-incubated with effector cells was demonstrated in situ by labeling fragmented ends of DNA with fluorescein-conjugated dUTP and terminal deoxynucleotidyl transferase and also by flow cytometry of target cells obtained from such monolayers. Our results indicate that NK cells preferentially utilize membrane lysis (necrosis) in ADCC with tumor cell targets in single-cell suspensions. However, necrosis is not efficient in monolayers. In the presence of cMAbs, apoptosis is the primary mechanism of NK cell-mediated killing in monolayers of SCCHN targets, which were found to express receptors for tumor necrosis factor and fas ligand.

Animals↗
PubMed1996

Location of the non-heme iron center on the alpha subunit of photoreactive nitrile hydratase from Rhodococcus sp. N-771.

Nitrile hydratase (NHase) from Rhodococcus sp. N-771, which possesses a non-heme iron center binding nitric oxide (NO), is activated by light irradiation. To localize the iron center in the protein, we quantified Fe atoms and performed FTIR measurements of the isolated alpha and beta subunits. The native NHase and the isolated alpha subunit contained about 1.0 and 0.8 mol Fe per mol protein, respectively, whereas the beta subunit contained only a trace of Fe. An NO stretching band was observed at 1852 cm-1 in the FTIR spectrum of the alpha subunit, but not in that of the beta subunit. Upon light irradiation of the alpha subunit, the affinity of the Fe atom decreased and the NO band disappeared from the FTIR spectrum. These observations indicate that the non-heme iron center, which is responsible for the photoreaction, is present in the alpha subunit.

Amino Acid Sequence↗
PubMed1996

Design of a suitable formulation of FK613, a novel antiallergic agent, based on its pharmacokinetic and pharmacodynamic properties in healthy subjects.

The pharmacokinetic and pharmacodynamic properties of FK613, a novel indolyl piperidine derivative, were investigated after oral administrations of 5, 10 and 20 mg in hard gelatin capsules to healthy male volunteers. FK613 was rapidly and almost completely absorbed, and >89% was recovered in the urine as the unchanged form. The urinary excretion of FK613 was linearly correlated with plasma concentration and its low water solubility was the main concern regarding the safety. In another experiment using a double-blind crossover design, in which 0 (placebo), 5 and 20 mg FK613 were administered to determine the plasma concentration-effect relationship, suppression of the intradermal histamine-induced skin reaction by FK613 was observed. Thus, the maintenance of a plasma concentration of FK613 in the range of 80-250 ng center dot ml-1 was recommended to ensure the suppression of histamine-induced wheal by >50% and not to exceed the solubility in urine. To achieve this, a new hydrogel-type formulation of FK613 was developed, with the aim both of delaying its absorption, so as to suppress the sharp rise in plasma concentration, and of maintaining the effective concentration for a longer period of time. This formulation was administered after meals at the doses of 20, 30, 40, 50 and 60 mg, and at repeated doses of 40 mg twice daily for 6.5 days to evaluate the pharmacokinetics and safety in healthy subjects. The area under the plasma concentration curve increased linearly with dose, whereas maximum plasma concentration (Cmax) tended to peak as dose increased, indicating the desirable properties of this formulation. Although Cmax exceeded 250 ng/ml at doses of 30 mg or more, no urinary crystal formation was observed on careful inspection of urine.

Adult↗
PubMed1996

Effect of dietary fat content on oral bioavailability of menatetrenone in humans.

The purpose of this investigation was to determine the effects of fat content and frequency of meals on the oral bioavailability of menatetrenone (2-methyl-3-all-trans-tetraprenyl-1,4-naphthoquinone), a vitamin K2 with four isoprene units. In the first series of studies, menatetrenone (15 mg) was administered at breakfast time to 18 healthy male volunteers after meals with three different fat contents (meals A, B, and C) on three occasions in a crossover design. The three types of meals had almost the same calorie content (721-746 kcal) with varied fat contents (A, 8.8 g; B, 20.0 g; C, 34.9 g). The area under the plasma menatetrenone concentration-time curve within the first 24 h (AUC0-24) increased with increase of fat content: 371 +/- 194, 485 +/- 150, and 1024 +/- 341 ng.h/mL (mean +/- SD, n = 18) after meals A, B, and C, respectively. On the fourth occasion, the same dose of menatetrenone was administered to all volunteers after taking meal B, but in this case the lunch 5 h after drug administration was omitted from the protocol. The time profile of plasma menatetrenone showed a single peak when lunch was not taken, whereas it showed two peaks with lunch. On the fifth occasion, 12 out of 18 volunteers took the same dose of menatetrenone after a meal with the highest fat content (53.8 g of fat and 789 kcal; meal D), showing that AUC0-24 was almost the same as that for meal C, 1027 +/- 389 and 991 +/- 392 ng.h/mL (n = 12) for meals C and D, respectively. The oral bioavailability of lipid-soluble vitamin K was influenced by the fat content of a meal, although the increase in bioavailability seemed to reach a peak when the lipid content of the meal was > 35 g.

Administration, Oral↗
PubMed1996

Photoreactive nitrile hydratase: the photoreaction site is located on the alpha subunit.

Nitrile hydratase (NHase) from Rhodococcus sp. N-771 exists in active and inactive forms. The inactive NHase is immediately activated by light irradiation and changes to the active form. To characterize the photoreactive center, the inactive NHase was denatured by 6 M urea, and two kinds of subunits (alpha and beta) were separated and purified by anion-exchange chromatography. In a manner similar to the native NHase, the isolated alpha subunit showed two absorption peaks at 280 and 370 nm, which were diminished by light irradiation. However, irradiation failed to elicit the appearance of absorption peaks at around 400 nm and at 710 nm, which were characteristic of the activated enzyme. The beta subunit seemed not to possess any photoreactive chromophore because its absorption spectrum was not altered by light irradiation. Neither of the subunits showed NHase activity before and after light irradiation, but the inactive NHase was reconstituted by incubating the two subunits together in the dark at 4 degrees C for 1 h. Light irradiation of the beta subunit did not affect subsequent complex formation or NHase activity. However, the irradiated alpha subunit could not assemble with the beta subunit, and no activity was recovered. These results demonstrate that the chromophore(s) responsible for the photoactivation of NHase are entirely located on the alpha subunit, and imply that light irradiation induces conformational change of the alpha subunit.

Binding Sites↗
PubMed1996

Retrospective analysis of the treatment of patients with small cell lung cancer showing poor performance status.

To assess the feasibility of treatments for patients with small cell lung cancer (SCLC) showing a poor performance status (PS, Eastern Cooperative Oncology Group; ECOG 3 or 4), we retrospectively reviewed the outcome for 13 SCLC patients showing poor PS treated at the National Cancer Center Hospital between January 1984 and May 1994. The main factors which contributed to poor prognosis were superior vena cava (SVC) syndrome, massive pleural effusion, tracheal stenosis due to lymph node swelling, pericardial effusion and pulmonary fibrosis (causing dyspnea in combination), brain metastasis resulting in neurological disturbance, cachexia, Eaton-Lambert syndrome causing muscle weakness, retroperitoneal lymph node metastasis causing abdominal pain, peritoneal effusion due to abdominal lymph node swelling, vertebral metastasis causing paraplegia, and dermatomyositis/polymyositis (DM/PM) causing muscle weakness. All of the patients received chemotherapy with or without radiotherapy. The PS of 8 patients improved with treatment, but no improvement was seen in 5. We analyzed these 13 patients and considered the treatments for those with poor PS. Chemo-radiotherapy was tolerable in SCLC patients showing PS 3, and improved their PS if severe conditions or combined disease did not arise concurrently. It was further suggested that PS 4 patients with severe conditions or combined disease should not be given the treatments.

Adult↗
PubMed1996

Comparative study of pharmacokinetics of two new fluoroquinolones, balofloxacin and grepafloxacin, in elderly subjects.

Comparative pharmacokinetics and tolerability were studied in healthy elderly volunteers for two new fluoroquinolones, balofloxacin (Q-35) and grepafloxacin (OPC-17116), the main excretion routes being the renal and hepatic routes, respectively. Both agents were well tolerated in elderly subjects. In comparison with previously reported data from healthy younger adults, the absorption of balofloxacin was slightly delayed and urinary excretion was delayed and diminished. As a significant linear correlation was observed between renal clearance of balofloxacin and creatinine clearance, the delayed and diminished urinary recovery was attributed to the reduced renal function of the elderly subjects enrolled in the study. The absorption of grepafloxacin was also delayed, and the maximum plasma drug concentration and area under the plasma drug concentration-time curve were increased in the elderly by 31 and 48%, respectively, over those in younger adults on the basis of dose normalized to body weight. The plasma terminal elimination half-life and urinary recovery remained unchanged. Decreases in distribution volume and total body clearance in the elderly were considered to be the primary factors contributing to these differences.

Aged↗
PubMed1996

Cyclic peptides from higher plants. XXVIII. Antitumor activity and hepatic microsomal biotransformation of cyclic pentapeptides, astins, from Aster tataricus.

Antitumor activities on Sarcoma 180A of a series of cyclic pentapeptides, astins, isolated from the roots of Aster tataricus, were examined. The activities on various congeners of the dichlorinated proline residues prepared by chemical conversion and a hepatic microsomal biotransformation in rats suggested that 1,2-cis dichlorinated proline residues of astins A, B and C play an important role in the antitumor activity of astins.

Animals↗
PubMed1996

Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. IV. Synthesis and pharmacological evaluation of the oxidation products of (-)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride (YM060: ramosetron).

In physicochemical and pharmacokinetic evaluations of (--)-(R)-5-[(1-methyl-1H-indol-3-yl)carbonyl] -4,5,6,7-tetrahydro-1H-benzimidazole hydrochloride 1 (YM060: ramosetron), which is a highly potent 5-hydroxytryptamine(-HT3) receptor antagonist, 4-hydroxy-6-[(1-methyl-1H-indol-3-yl) carbonyl]4,5,6,7-tetrahydro-1H-benzimidazole 2 was identified as a degradation product and metabolite of 1. The (--)-(4R,6S)-isomer 2 was synthesized from the diketone derivative 3, via the stereoselective reduction of 3 followed by the stereocontrolled epimerization of the (--)-(4S,6S)-isomer 10, the epimer of 2. The stereochemistry of 2 and 10 was determined by NMR and HPLC studies. Compounds 2 and 10 were found to be potent 5-HT3 receptor antagonists, like 1. Among the other oxidation products, the diketone derivatives 3 and 7 and the dihydroxylated derivative 4 retained antagonistic activity similar to that of ondansetron. This is of interest, because they do not possess the amine group which is known to be necessary for high affinity to the 5-HT3 receptor.

Animals↗
PubMed1996

A prospective study of bronchoscopy for endotracheobronchial tuberculosis.

To clarify the role of bronchoscopy for endotracheobronchial tuberculosis (EBTB), we performed a prospective study in 45 patients with active pulmonary tuberculosis, in 15 (33%) of whom bronchoscopic findings related to EBTB were seen. The findings were classified into six types:edematous hyperemic, submucosal nodule, ulcerative (shallow and deep), polypoid, cicatrical, and compression type. Each of these types was related to the healing process and outcome after antituberculosis chemotherapy. Serial bronchoscopy revealed that lesions less advanced than the deep ulcerative type responded to chemotherapy; the deep ulcerative and polypoid types progressed to cicatrical bronchostenosis despite chemotherapy. In the follow-up of patients with lesions of the deep ulcerative and polypoid types, serial bronchoscopy after chemotherapy is recommended; these patients also require adjunctive therapy to prevent cicatrical bronchostenosis.

Biopsy↗
PubMed1995

Constitutive production of IL-2 by human carcinoma cells, expression of IL-2 receptor, and tumor cell growth.

Human carcinomas spontaneously express abundant IL-2R beta but little IL-2R alpha on the cell surface, contain mRNA for IL-2R beta- and IL-2R alpha-chains, and may be inhibited in growth by exogenous IL-2. To study the relationship between IL-2R expression and growth inhibition by IL-2, carcinoma cells were transduced with IL-2R alpha and IL-2R gamma cDNAs or IL-2R beta antisense cDNA. Transfectants with the IL-2R alpha gene expressed high levels of the alpha- and beta-receptor chains and showed increased binding of [125I]IL-2. Exogenous IL-2 at the picometer concentrations inhibited their growth, and Abs to IL-2R alpha- or IL-2R beta-chains reversed the inhibition. After transduction of IL-2R beta antisense cDNA, gastric carcinoma (HR) cells no longer expressed IL-2R beta-chain, and their proliferation was depressed in the absence of exogenous IL-2. Transduction of IL-2R gamma-chain cDNA into tumor cells increased sensitivity to growth inhibition by exogenous IL-2 of a squamous cell carcinoma line, but not of HR or renal cell carcinoma lines. All of the parental and transduced tumor cell lines were found to constitutively express intracellular IL-2, detectable by immunostaining or flow cytometry of permeabilized cells. IL-2 was present on the surface of some tumor cells. Intracellular IL-2R beta and IL-2R gamma proteins were also detectable in tumor cells. Using reverse-transcription PCR combined with Southern blots or in situ hybridization, mRNA for IL-2 was found to be present in parental and transduced tumor cells. Expression on human carcinomas of IL-2R beta, inhibition of their growth by IL-2R beta antisense cDNA, and their ability to constitutively produce IL-2 and its presence on the cell surface, all suggest that endogenous IL-2 may play a role in tumor cell growth.

Base Sequence↗
PubMed1995

Secretion of TNF-alpha from macrophages following induction with a lignin derivative.

Macrophages derived from rat bone marrow were treated with macrophage colony stimulating factor (M-CSF) to obtain a sufficient number of cells for the tumor necrosis factor (TNF-alpha) assay. The present study has been designed to investigate whether the production of TNF-alpha, which induces multinucleated giant cell formation, is regulated by polyanions such as lignin derivatives. ELISA for TNF-alpha showed that the polyanion induced TNF-alpha production by macrophages. The secretion of TNF-alpha from the cells reached a maximum at 3-6 h, and then showed a slight decline. Northern blotting of TNF-alpha mRNA showed that the amount of TNF-alpha reached a maximum within 1 h of macrophage culture in the presence of a lignin derivative. On the other hand, TNF-alpha mRNA was undetectable in the control cells. It was concluded that stimuli such as that provided by lignin derivatives increases the amount of TNF-alpha mRNA, which is then followed by translation of TNF-alpha.

Animals↗