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Biomedical subjects

S Nagashima

Publications and source records attributed to S Nagashima.

At least 91 records · Page 5Linked to original sources
PubMed1991

Pharmacokinetic and pharmacodynamic profiles of vapiprost, a selective, long-lasting thromboxane receptor antagonist, after single and multiple oral administration to healthy volunteers.

A selective thromboxane A2 (TXA2) receptor blocking agent, vapiprost, was orally administered to healthy male Japanese volunteers to investigate the pharmacokinetic and pharmacodynamic properties. The time-profile of vapiprost concentration in plasma was determined and the effects of the drug on platelet aggregation in platelet-rich plasma (PRP) induced by a stable TXA2 receptor agonist U-46619, adenosine diphosphate (ADP) and collagen, and platelet aggregation in whole blood induced by U-46619 ex vivo were simultaneously examined and compared. In the single-dose study (5, 10, and 20 mg/man) the plasma concentrations of the drug were fitted well to a one-compartment open model with a first-order absorption. The area under plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) showed dose-related increases, whereas the mean elimination half-lives (t1/2) remained approximately constant within the range of 0.99-1.1 hour. The drug was hardly recovered unchanged in urine. The platelet aggregation in PRP induced by collagen or U-46619 and the secondary aggregation by ADP were inhibited; that induced by U-46619 was the most specifically and completely inhibited at 2 hours after administration of any dose. The duration for maintaining the significant inhibition tended to depend on the dose and ranged from 24 to 36 hours after administration, which was much longer than expected from the plasma concentration of drug. The time-profile of inhibiting whole blood platelet aggregation that was induced by U-46619 was almost parallel to that of platelet aggregation in PRP by the same aggregant. The bleeding time was slightly prolonged 2 and 8 hours after administrations of 10 and 20 mg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Effects of DPI 201-106, a novel cardiotonic agent, on hemodynamics, cardiac electrophysiology and arrhythmias induced by programmed ventricular stimulation in dogs with subacute myocardial infarction: a comparative study with dobutamine.

DPI 201-106 (DPI), a novel and potent cardiotonic agent, exhibits its effects by prolonging the open state of Na+ channels, resulting in an increase in action potential duration, and thus, is supposed to share the class III antiarrhythmic activity. The effects of DPI on the hemodynamics, intraventricular conduction and refractoriness of heart, and the incidence of arrhythmias induced by programmed electrical ventricular stimulation (PES) were compared with (+/-)-dobutamine. Dogs which survived for 5 to 7 days after the induction of myocardial infarction were used as the model. The presence of subacute myocardial infarction caused by occluding the left anterior descending coronary artery elicited a mild left ventricular dysfunction represented by a significant decrease in peak LV dp/dt by about 20%. Both i.v. bolus injection of DPI (1, 3 and 5 mg/kg) and i.v. continuous infusion of dobutamine (3, 5 and 10 micrograms/kg/min), which were administered in a cumulative manner, dose-dependently improved the hemodynamic parameters. At the higher doses of both DPI (3 and 5 mg/kg) and dobutamine (5 and 10 micrograms/kg/min) the control values were reached or even exceeded. DPI dose-dependently increased the effective refractory period (ERP) of both non-infarcted and infarcted ventricular myocardia to a similar degree, but the conduction time showed a frequency-dependent increase in the infarcted myocardium to a greater degree than in the non-infarcted myocardium after DPI. In contrast, dobutamine decreased the ERP in both non-infarcted and infarcted myocardia, and slightly increased the difference of refractoriness between the non-infarcted and infarcted zones with no effect on the intraventricular conduction. In the PES study, DPI (3 and 5 mg/kg) produced a significant decrease in the incidence of ventricular tachycardia, whereas dobutamine (5 and 10 micrograms/kg/min) tended to worsen the arrhythmias. These findings suggest that cardiotonic agents with a class III antiarrhythmic property such as DPI may be potentially useful for the management of heart failure accompanied by ischemic heart disease.

Animals↗
PubMed1991

Comparison of the effects of pirmenol and lidocaine on intraventricular conduction in canine myocardial infarction.

Effects of pirmenol hydrochloride and lidocaine hydrochloride on intraventricular conduction were examined in the infarcted heart of anesthetized dogs. The effects of the drugs on the excitation induced by ventricular stimulations were determined with coupling intervals between 150 and 1,000 ms. Effects of the drugs on the His bundle electrocardiograms were also examined. Pirmenol in doses of 1-5 mg/kg prolonged the conduction time in the infarcted zones over a wide range of coupling intervals. Pirmenol at 5 mg/kg blocked the delayed conduction at a short coupling interval in the infarcted zones. The effect of pirmenol on the conduction time in the normal zone was slight. Lidocaine in doses of 3 and 10 mg/kg prolonged the conduction time in the infarcted zone at a short coupling interval. Pirmenol did not significantly prolong PQ or AH interval. In conclusion, pirmenol selectively depressed the delayed conduction in the infarcted zone, which could result in a reentrant pathway. The effect of pirmenol on delayed conduction was dependent on the coupling interval and was quite different from that of lidocaine.

Animals↗
PubMed1991

Photochemically induced thrombosis model in rat femoral artery and evaluation of effects of heparin and tissue-type plasminogen activator with use of this model.

We report a new and reproducible model of thrombosis in the rat femoral artery. The thrombosis is initiated by endothelial injury subsequent to photochemical reaction between systemically injected rose bengal (10 mg/kg, i.v.) and transillumination of filtered xenon lamp (wave length: 540 nm) from the outside of the vessel. The blood flow of the femoral artery, which was monitored by a pulsed doppler flow meter, was fully stopped in 348.68 +/- 36.18 sec (n = 12) after i.v. injection of rose bengal under irradiation with green light. The formation of massive thrombosis was readily evident by visual inspection. The processes of primary endothelial injury and the subsequent formation of thrombosis during this manipulation were observed by light microscopy and analysed by the scanning and transmission electron microscopy. Pretreatment with heparin (30, 100 or 300 units/kg, i.v.) 10 min before rose bengal injection dose-dependently prolonged the time required to interrupt the blood flow. The thrombolytic activity of a tissue-type plasminogen activator (tPA) was also investigated. After the establishment of stable thrombotic occlusion of the femoral artery, infusion of tPA was started from the contralateral femoral vein for 30 min at the rate of 30 or 100 micrograms/kg/min. The occluded artery was reperfused in 2 out of 10 rats and in 9 out of 12 at the lower and higher rates of tPA infusion, respectively. That heparin could prevent the arterial occlusion and that tPA could reperfuse the occluded artery are observations consistent with the histopathological ones that the primary lesion of endothelium injured photochemically activates the platelet aggregation to form platelet-rich thrombus with extensions of erythrocyte-rich lesions. This model is expected to be a useful tool for evaluating the antithrombotic and thrombolytic agents.

Animals↗
PubMed1991

Ofloxacin in human hair determined by high performance liquid chromatography.

A procedure is presented for quantitating ofloxacin (OFLX) in human scalp hair by high performance liquid chromatography (HPLC) with a fluorescence detector. An octadecylsilane (ODS) column was used and the mobile phase was a mixture of potassium phosphate buffer (pH 2.6) and acetonitrile. The recovery of OFLX was 90.9-93.8% and within- and between-run precisions were 0.35-1.41% and 1.41-5.49% as the coefficient of variation (CV), respectively, when 5-50 ng OFLX was added to 1 mg blank hair. The calibration curve was linear in the range of 0.5-50 ng/tube (0.5 ml). Interference with other quinolone derivatives could be avoided according to the difference in their retention times or fluorescence spectra. Several pieces of hair were obtained from each of twelve healthy male volunteers, who had taken OFLX (100, 300 or 900 mg total dose) over a 1-3 day period 2 weeks before the hair sampling. In all hair samples except one obtained from a volunteer, who had taken the lowest dose, the 2-cm long segments nearest the scalp contained OFLX (5-45 ng/mg hair), while the upper segments did not. A highly significant positive correlation was observed between the total dose and the concentration of OFLX in the 2-cm long hair segments. Such a positive correlation was also revealed in rat hair sampled after repeated i.p. administration of OFLX over a 5-week period. These results suggest that the measurement of OFLX in hair by the present method would be useful for testing patient compliance in clinical pharmacology as well as for application to forensic science.

Adult↗
PubMed1991

Myeloid progenitor cell growth characteristics and effect of G-CSF in a patient with congenital cyclic neutropenia.

A 17-year-old male with congenital cyclic neutropenia was treated with recombinant human granulocyte colony stimulating factor (G-CSF) administered subcutaneously at 1 to 2 micrograms/kg per day. The peak and nadir counts of neutrophils and the peak counts of monocytes were significantly elevated, and the period of cycling decreased from 3 to 2 weeks. Bone marrow culture studies revealed the following abnormalities in granulocytic progenitor cells (CFU-G): a decrease in the concentrations of G-cluster forming cells, stimulated by a maximal dose of G-CSF, and a tendency of abnormally low responsive growth of the CFU-G to lower concentrations of G-CSF and GM-CSF. Our findings suggest that administration of G-CSF at relatively low doses overcomes or compensates for these abnormalities, though not completely, as fluctuation in the neutrophil counts persisted.

Bone Marrow↗
PubMed1990

Effects of antidepressants on the intraventricular conduction and the incidence of arrhythmias induced by programmed ventricular stimulation in the dog heart after myocardial infarction.

The effects of mianserin, a tetracyclic antidepressant, and adinazolam, a new triazolobenzodiazepine which has antidepressant activity, on intraventricular conduction and the incidence of arrhythmias induced by programmed ventricular stimulation were studied in the dog heart after myocardial infarction and compared to the effects of amitriptyline, a standard tricyclic antidepressant. Amitriptyline at a dose of 1 mg/kg significantly slowed ventricular conduction in a frequency-dependent manner and at doses of 2 and 3 mg/kg significantly slowed ventricular conduction in infarcted ventricular myocardium. Amitriptyline also significantly slowed ventricular conduction in normal myocardium. Amitriptyline increased the incidence of ventricular arrhythmias induced by the programmed ventricular stimulation and prolonged the intraventricular delayed conduction resulting in re-entrant ventricular arrhythmia. On the other hand, mianserin and adinazolam at doses of 1-3 mg/kg had no significant effects on intraventricular conduction in infarcted and normal myocardium and on the incidence of arrhythmias induced by programmed ventricular stimulation. From these results, we can expect that mianserin and adinazolam may have a much lower cardiac toxicity than amitriptyline.

Amitriptyline↗
PubMed1990

Antiarrhythmic effects of a benzothiazine derivative (SD-3211) and its stereoisomer (SA3212) in anaesthetized rats and isolated perfused rat hearts compared with bepridil.

The antiarrhythmic effects of a new calcium channel blocking agent (SD-3211) and its stereoisomer with additional sodium channel blocking activity (SA3212), were compared with those of a known antiarrhythmic drug (bepridil), using the left coronary artery ligation- and reperfusion-associated arrhythmia models both in isolated rat hearts and in anaesthetized rats. Isolated and perfused rat hearts were subjected to regional ischaemia for 15 min and subsequent reperfusion for 5 min. SD-3211 and SA3212 showed dose-dependently prolongations of the time interval between coronary ligation and first appearance of ventricular premature beats, reductions in the number of total ventricular premature beats during the ligation period and reductions in the incidence of reperfusion-induced ventricular fibrillation. The values of the negative logarithm of IC50 (mol/l) of SD-3211, SA3212 and bepridil were 7.97, 7.41 and 6.64 for the reduction of ventricular premature beats during ligation and 6.43, 7.49 and 6.17 for the reduction of ventricular fibrillation during reperfusion, respectively. In a separate study on force of concentration and coronary flow in perfused heart paced at 340-360 beats/min SD-3211 caused a significant negative inotropic effect between 10(-7) and 10(-6) mol/l. SA3212 at the concentration of less than 10(-6) mol/l did not result in any significant change in force of contraction. The coronary flow was increased dose-dependently by SA3212, while it was first increased and then reduced in the presence of higher concentration of SD-3211 (greater than 10(-7) mol/l). Hearts of anesthetized rats were also subjected to regional ischaemia for 7 min and subsequent reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗
PubMed1990

Interleukin 5 activity in sera from patients with eosinophilia.

Sera from 10 patients with eosinophilia contained eosinophil colony stimulating factor (Eo-CSF) activity. Using anti murine (m) interleukin-5 (IL-5) antibody, we demonstrated that this activity was mainly derived from IL-5. Administration of prednisolone to patients decreased both Eo-CSF activity in sera and the number of eosinophils in blood. These results extend our recent study demonstrating that T cells from eosinophilic patients produce IL-5 with IL-2 stimulation and may support the speculation that IL-5 is an important factor which induces eosinophilia.

Blood Cell Count↗
PubMed1989

T cells from eosinophilic patients produce interleukin-5 with interleukin-2 stimulation.

Anti-murine (m) interleukin-5 (IL-5) antibody was found to inhibit eosinophil (Eo) colony formation stimulated by recombinant human (rh) IL-5, but did not inhibit the production of Eo stimulated by rh IL-3 or granulocyte-macrophage colony-stimulating factor (GM-CSF). Conditioned medium (CM) prepared from eosinophilic patients' T cells with interleukin-2 (IL-2) stimulation (T-IL-2-CM), was found to contain CFU-Eo growth-stimulating factor. Using anti-mIL-5 antibody, we demonstrated that T-IL-2-CM from patients with eosinophilia contained a significant amount of IL-5. We also detected IL-5 mRNA in T cells from eosinophilic patients with IL-2 stimulation. These results suggest that IL-5 plays an important role in the induction of selective eosinophilia in humans and that IL-5 is produced from T cells with IL-2 stimulation.

Adult↗
PubMed1989

Prediction of individual dosage requirements for lignocaine: a validation study for Bayesian forecasting in Japanese patients.

The performance of the Bayesian feedback method for predicting lignocaine dosage developed by Vozeh et al. was evaluated in 53 Japanese patients, treated for either suppression or prophylaxis of ventricular arrhythmias, with respect to accuracy, precision, efficiency, and safety. The lignocaine serum concentrations at 12 h (C12) and 24 h (C24) after continuous infusion was started were predicted and compared retrospectively using the early concentration at 2-4 h (C2-4). The mean of the prediction error (PE) and the root mean-squared error (RMSE) were used as a measure of accuracy and precision. The 95% confidence interval of PE for C12 included zero, but those of PE for C24, whether C2-4 was used alone or in combination with C12, were less than zero, meaning that the prediction of C24 was significantly biased. The RMSE for C12 (13.2%) was less than that for C24 (16.2%), but the difference was not statistically significant. The fraction of measurements lying within the statistically approximate 68% prediction interval (+/- 1 SD) was used to evaluate the estimate of the SD of prediction. The fraction of measurements inside the prediction interval was significantly larger than the expected 68% for both C12 and C24 (p less than 0.05), showing that the estimate of the size of the PE is biased on the safer side. The clinical effects of lignocaine were also evaluated from the viewpoints of suppression of number of ventricular premature beats, prevention of more severe grades of arrhythmias, and toxicity. At least the appearance of toxicity, which four patients exhibited, was related to the lignocaine serum concentration (greater than 6 micrograms/ml).

Adult↗
PubMed1989

[CD8+ agranular lymphocyte proliferative disorder with T-cell receptor beta-chain gene rearrangement associated with thymoma and neutropenia].

A 58-year-old male with a 10-years history of thymoma was admitted to our hospital because of the respiratory infection. Hepatosplenomegaly and systemic lymphadenopathy were revealed on physical examination. Chest roentgenogram showed a large anterior mediastinal tumor and a right pleural effusion. Blood examination showed Hb 11.5 g/dl, leucocyte count 1,600/microliters (1% neutrophils, 34% monocytes, 65% lymphocytes) and platelet count 11.2 x 10(4)/microliters. The lymphocytes in the peripheral blood and pleural fluid were mostly small agranular mature lymphocytes and CD2+ 3+ 4- 8+. A monoclonal rearrangement of TCR beta chain gene was found using Southern blot analysis of the lymphocytes in the peripheral blood and pleural fluid. The CFU-GM colony formation by bone marrow cells was normal, and not suppressed by the patient's serum or peripheral blood lymphocytes. Neutrophil-associated IgG was increased with a direct immunofluorescence test. Serum IgG level was slightly decreased. Radiation therapy for thymoma exerted no effect. Treatment with prednisolone 60 mg daily resulted in complete disappearance of the pleural effusion and partial improvement of hepatosplenomegaly, thymoma and neutropenia. Histological examination of the thymoma revealed predominantly spindle cell type. He is still in good condition 21 months after diagnosis. This case seems to represent neoplastic proliferation of mature CD8+ T cells associated with thymoma.

Agranulocytosis↗
PubMed1988

Effect of human recombinant interleukin 5 and G-CSF on eosinophil colony formation.

Human recombinant (r) IL-5 was shown to have the activity to stimulate eosinophil (Eo) colony formation from human non-T, non-adherent bone marrow cells. The majority of these colonies were found to contain a small number of basophils, macrophages or neutrophils. Human rG-CSF, which alone did not stimulate Eo colony formation, showed an enhancing effect on Eo colony formation when added with IL-5. IL-5 seems to stimulate the proliferation and differentiation of CFU-Eo, while G-CSF acts on the early stage of eosinophilopoiesis.

Cell Differentiation↗
PubMed1988

A fluorescence polarization immunoassay evaluated for quantifying astromicin, a new aminoglycoside antibiotic.

We evaluated a fluorescence polarization immunoassay (FPIA) procedure for measuring astromicin, a new aminoglycoside antibiotic. The calibration curve can be stored for at least 32 days without loss of accuracy. There were no interferences from hemoglobin (up to 4000 mg/L) or bilirubin (up to 200 mg/L), nor were there any cross-reactivities with amikacin, gentamicin, or tobramycin. Within-run precision (CV) for 20 replicates, each at concentrations of 5, 15, and 25 mg/L, was 1.25-2.11%. Between-run precision for these same concentrations, measured on five occasions, was 2.13-2.74%. Linear-regression analyses of data by FPIA (y) and HPLC (x) for plasma obtained from six healthy male volunteers who were given 200 mg of astromicin by 30-min intravenous infusion and for sera prepared by adding arbitrary amounts of astromicin showed highly significant correlations: r = 0.996 (n = 66), y = 0.96x - 0.48 mg/L and r = 0.981 (n = 59), y = 0.96x - 0.25 mg/L, respectively. This assay offers a rapid, efficient, and accurate system for therapeutic monitoring of astromicin in blood.

Adult↗