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Biomedical subjects

M Nakashima

Publications and source records attributed to M Nakashima.

At least 379 records · Page 21Linked to original sources
PubMed1992

Effects of SUN-1165, N-(2,6-dimethylphenyl)-8-pyrrolizidine acetamide hydrochloride hemihydrate, a new class I antiarrhythmic drug, on ventricular arrhythmias, intraventricular conduction, and the refractory period in canine myocardial infarction.

Effects of SUN-1165, a class I antiarrhythmic drug, on ventricular arrhythmias, intraventricular conduction, and the effective refractory period (ERP) were examined in a canine model of myocardial infarction and compared with those of lidocaine. The antiarrhythmic effects were examined on the arrhythmias developed 24 h after left anterior descending coronary artery (LAD) ligation and ventricular premature stimulation-induced arrhythmias 5-7 days after LAD ligation. Effects on intraventricular conduction and ERP were also examined in animals 5-7 days after LAD ligation. The intraventricular conduction time (CT) was determined by excitation induced by a ventricular stimulation at various coupling intervals from 200 to 1,000 ms. SUN-1165 (1 and 3 mg/kg) showed a marked reduction in the frequency of ventricular ectopic beats 24 h after LAD ligation and was more potent than lidocaine. SUN-1165 (1 and 3 mg/kg) prolonged CT in the infarcted zones over a wide range of the coupling intervals and produced block of severely delayed conduction. In contrast, lidocaine prolonged CT only at short coupling intervals. Ventricular premature stimulation produced ventricular arrhythmias, which were prevented by pretreatment with SUN-1165 (3 mg/kg). ERP was prolonged by SUN-1165 (3 mg/kg). In conclusion, SUN-1165 showed antiarrhythmic effects in a canine model of myocardial infarction. A selective depression of delayed conduction in the infarcted zone and a prolongation of ERP probably contribute to this antiarrhythmic effect.

Animals↗
PubMed1992

448-detector optical recording system: development and application to Aplysia gill-withdrawal reflex.

The spatial resolution of a fast, multichannel, optical recording apparatus has been improved in an attempt to increase the completeness of optical recordings of neuron activity responsible for the Aplysia gill-withdrawal reflex. We developed a new optical apparatus, increasing the number of pixels to 448. Action potential activity from 168 to 192 neurons could be detected. Hence, the number of optically detected neurons increased about 2.5 times in comparison with a previously used 100- or 124-detector optical apparatus. Because optically detected action potential signals were shown to be due to the cell body of a neuron, it was possible to know its position as well as its approximate size. The distribution of the detected active neurons and those neurons that showed an apparent change in spike frequency to the siphon stimulation were determined.

Action Potentials↗
PubMed1992

Interferon-alpha and dexamethasone inhibit adhesion of T cells to endothelial cells and synovial cells.

We investigated whether interferon-gamma (IFN-gamma), interferon-alpha (IFN-alpha) and glucocorticoids affected the adhesion of T cells to human umbilical endothelial cells or human synovial cells. About 30% of peripheral blood T cells could bind to unstimulated endothelial cells, but only a few T cells could bind to unstimulated synovial cells. When both endothelial cells and synovial cells were cultured with recombinant IFN-gamma (rIFN-gamma), the percentage of T cell binding to both types of cells increased in a dose-dependent manner. rIFN-alpha and dexamethasone blocked the T cell binding to unstimulated endothelial cells. Furthermore, rIFN-alpha and dexamethasone suppressed T cell binding to both endothelial cells and synovial cells stimulated by IFN-gamma, and also inhibited intercellular adhesion molecule-1 (ICAM-1) expression on both endothelial cells and synovial cells stimulated by IFN-gamma. These results suggest that IFN-alpha and glucocorticoids may inhibit T cell binding to endothelial cells or synovial cells by modulating adhesion molecule expression on these cells.

Arthritis, Rheumatoid↗
PubMed1992

Effects of vapiprost, a novel thromboxane receptor antagonist, on thrombus formation and vascular patency after thrombolysis by tissue-type plasminogen activator.

1. A thrombus was induced in the rat femoral artery by endothelial damage due to the photochemical reaction between systemically-injected Rose Bengal and transillumination with green light (wavelength: 540 nm). The artery of the control rat was completely occluded in 302.8 +/- 27.0 s after the initiation of the reaction. 2. Pretreatment with vapiprost (0.1, 0.3 and 1.0 mg kg-1, i.v., 5 min before the reaction) prolonged the time required to occlude the femoral artery in a dose-dependent manner. The efficacy of vapiprost on the time required for occlusion was over 10 times higher than that of aspirin which was administered 30 min before the reaction. 3. The thrombolytic effects of tissue-type plasminogen activator (tPA) on the established arterial thrombus in the presence and absence of vapiprost were also studied in the same model. When vapiprost (0.3 mg kg-1, i.v.) was administered just before tPA infusion (100 micrograms kg-1 min-1 for 30 min), the time required to reperfuse the occluded artery was reduced, the incidence of the reperfusion was increased and the arterial blood flow after reperfusion was improved. 4. When vapiprost (1.0 mg kg-1 daily p.o.) was administered for 1 week after the establishment of reperfusion by tPA combined with vapiprost, the patency of the reperfused artery was improved and the femoral arterial blood flow was better preserved than after treatment with only tPA. 5. These findings suggest that this thromboxane receptor antagonist may be a useful adjunct to anti-thrombotic therapy. The combination therapy with tPA may be more effective than treatment with tPA alone and provides greater protection against reocclusion after reperfusion.

Animals↗
PubMed1992

Phase I clinical studies of S-1108: safety and pharmacokinetics in a multiple-administration study with special emphasis on the influence on carnitine body stores.

S-1108, the prodrug of S-1006, was given to healthy volunteers three times a day (TID) for 8 days in a dose of 200 mg in a crossover placebo-controlled study. The safety of S-1108 and the pharmacokinetics of S-1006 and pivalic acid liberated from pivaloyloxymethyl ester of S-1108 were investigated. There were no abnormal symptoms or signs, as observed by physical and laboratory tests. The half-life and area under the concentration-time curve of S-1006 was reduced from 1.11 +/- 0.17 h at the first dose to 0.87 +/- 0.18 h at the last dose and from 7.30 +/- 1.10 to 5.20 +/- 0.85 micrograms.h/ml, respectively. However, there was no significant difference in the peak concentration between the two doses. Pivalic acid was found to be completely detoxified by conjugation with carnitine. The total urinary recovery of pivalic acid as pivaloylcarnitine was 98.7 +/- 3.6%, resulting in an increase of daily carnitine urinary excretion two- to threefold the predose value. During the multiple administration of S-1108, the plasma carnitine concentration was reduced to and maintained at 50 to 70% of the control value, suggesting that there might be enough carnitine store in the body to detoxify the pivalic acid in a dose of 200 mg TID. Moreover, the reduced plasma carnitine was rapidly returned to the control value within a few days after the cessation of the administration of 200 mg TID.

Adult↗
PubMed1992

Primary Sjögren's syndrome with antibodies to HTLV-I: clinical and laboratory features.

The prevalence of antibodies to human T lymphotropic virus type I (HTLV-I) was studied in patients with primary Sjögren's syndrome. Thirteen of 36 serum samples were positive by enzyme linked immunosorbent assay (ELISA) and particle agglutination assay for antibodies to HTLV-I and were confirmed by western blotting. The presence of antibodies to HTLV-I may signify an HTLV-I carrier state. These patients had a high occurrence of extraglandular manifestations such as uveitis, myopathy, and recurrent high fever compared with patients who did not have antibodies to HTLV-I. Patients with antibodies to HTLV-I had an increased spontaneous proliferation of peripheral blood mononuclear cells compared with those without the antibodies. The proportions of activated and memory T cells (HLA-DR+ CD3+, CD25+ CD3+, and CD29+ CD4+ cells) were higher in HTLV-I carriers than in non-carriers. The presence of antibodies to HTLV-I in some patients with primary Sjögren's syndrome suggests that HTLV-I may cause primary Sjögren's syndrome or its extraglandular manifestations, or both.

Adult↗
PubMed1992

Effects on the rabbit coronary artery of LP-805, a new type of releaser of endothelium-derived relaxing factor and a K+ channel opener.

In the rabbit epicardial coronary artery, 8-tert-butyl-6,7-dihydropyrolo[3,2-e]5-methylpyrazolo [1,5-a]pyrimidine-3-carbonitrile (LP-805, greater than 0.1 microM) hyperpolarized the muscle membrane in both proximal (diameter, 1-1.2 mm) and distal (diameter, 0.1-0.2 mm) regions of intact (+E) tissue, in which endothelium is present, and endothelium-denuded (-E) tissue. LP-805-induced hyperpolarization was inhibited by glibenclamide. In -E tissues in both regions, acetylcholine (ACh, greater than 0.1 microM) depolarized the membrane, and LP-805 inhibited the depolarization. However, in +E tissues, ACh (greater than 0.1 microM) transiently hyperpolarized the membrane that was not modified by glibenclamide (10 microM), charybdotoxin (100 nM), and NG-nitro-L-arginine (L-NNA, 100 microM). In -E tissues of both regions, LP-805 consistently inhibited the 10 microM ACh-induced contraction (IC50, 2.8 microM), and 10 microM glibenclamide shifted this concentration-response curve to the right (IC50, 20 microM). In +E tissues, LP-805 more potently inhibited the ACh-induced contraction (IC50, 0.3 microM), and this inhibition was prevented by L-NNA (100 microM) but not by indomethacin or glibenclamide (10 microM). In -E and +E tissues of both regions, LP-805 repolarized the high K(+)-induced depolarization (less than 20 mM) and relaxed the tissues precontracted by high K+ (less than 30 mM); these electrical and mechanical effects of LP-805 were prevented by glibenclamide (10 microM) in +E tissues. In +E tissues, the K(+)-induced contraction (less than 30 mM) was more strongly inhibited than in -E tissues, but after treatment with L-NNA, LP-805 relaxed -E and +E tissues precontracted to the same extent in the presence of high K+. LP-805 (10 microM) did not inhibit the Ca(2+)-induced contraction in skinned muscle tissues but did slightly inhibit the ACh-induced contraction in Ca(2+)-free solution containing 2 mM EGTA. Thus, LP-805 has a potent releasing action on endothelium-derived relaxing factor and also the potential to open the glibenclamide-sensitive K+ channel. These events would account for the dilation of the rabbit coronary artery exposed to LP-805.

Acetylcholine↗
PubMed1992

Effects of flecainide on ventricular arrhythmias, abnormal automaticity and activation in a canine model of myocardial infarction.

Effects of flecainide, a class I antiarrhythmic drug, on ventricular arrhythmias, ventricular abnormal automaticity and ventricular activation were examined in a canine model of myocardial infarction, and compared with those of lidocaine. The effects of the drugs were examined on (1) the arrhythmias developed 24 h after the left anterior descending coronary artery (LAD) ligation, (2) ventricular premature stimulation-induced arrhythmias 5 to 7 d after LAD ligation, (3) ventricular abnormal automaticity about 24 h after LAD ligation and (4) ventricular activation induced by a ventricular stimulation at various coupling intervals in animals 5 to 7 d after LAD ligation. Flecainide (1 and 3 mg/kg) showed a marked reduction in the frequency of ventricular ectopic beats 24 h after LAD ligation, and was more potent than lidocaine. The ventricular abnormal automaticity was inhibited by flecainide (1 and 3 mg/kg) and lidocaine (10 mg/kg). Flecainide (1 and 3 mg/kg) prolonged the activation time in the infarcted zones over a wide range of the coupling intervals, and produced block of seriously delayed activation. In contrast, lidocaine produced similar effects only at short coupling intervals. Ventricular premature stimulation produced ventricular arrhythmias, which were prevented by pretreatment with flecainide (3 mg/kg). In conclusion, flecainide showed antiarrhythmic effects in a canine model of myocardial infarction. A marked inhibition of ventricular abnormal automaticity and selective depression of delayed activation in the infarcted zone probably contribute to its antiarrhythmic effect.

Animals↗
PubMed1992

Comparison of the effects of halothane and propranolol on the effective refractory period and the ventricular activation in a canine myocardial infarction model.

The effects of halothane on the effective refractory period (ERP) and the ventricular activation were examined in a canine myocardial infarction model, and compared with those of propranolol. Halothane reduced the heart rate and prolonged the ERP in both normal and infarcted zones. A prolongation of ERP with halothane was also observed during atrial pacing at the same rate as in control, but the effect was less than during sinus rhythm. Halothane (1 MAC) further delayed or blocked the delayed activation in the infarcted zones with only slight effects on the activation of the normal zones. Propranolol (0.2 mg/kg) prolonged ERP during sinus rhythm, but it did not affect either the ERP or ventricular activation during atrial pacing. In conclusion, halothane produced a selective depression of the delayed activation and the prolongation of ERP, which may be caused by both direct effects on the myocardium and secondary effects such as a reduction of the heart rate. These effects of halothane may contribute to its antiarrhythmic effects in the myocardial infarction model which have been previously reported.

Animals↗
PubMed1992

Simultaneous measurements of adenosine deaminase activity and tuberculostearic acid in pleural effusions for the diagnosis of tuberculous pleuritis.

Adenosine deaminase (ADA) activity and tuberculostearic acid (TSA) levels in pleural effusions were measured in 18 patients with active tuberculous pleuritis, 16 patients suspected of having tuberculous pleuritis, 14 patients with carcinomatous pleuritis, and 19 patients suffering from pleuritis of non-malignant and non-tuberculous etiology. In the patients with active tuberculous pleuritis, ADA was elevated in 56% and TSA was positive in 78%. In 83% of these patients, either ADA was elevated or TSA was positive. ADA was elevated together with a positive TSA in 50%. In contrast, TSA was positive in only 6% and ADA was elevated in 24% of the patients with non-tuberculous pleuritis, and none of these patients showed the combination of an elevation of ADA and a positive TSA. These results suggest that simultaneous measurements of both ADA and TSA in pleural effusions are useful for the diagnosis of tuberculous pleuritis.

Adenosine Deaminase↗
PubMed1992

Fibroblast growth factors released by wounded endothelial cells stimulate proliferation of synovial cells.

We demonstrated that vascular endothelial cells mechanically wounded by scraping from the substratum were able to release growth promoting factors for synovial cells as well as for endothelial cells. The wounded endothelial cell conditioned medium stimulated the proliferation of synovial cells derived from different human donors dose dependently and induced transit of growth arrested synovial cells (predominant in the G0 and G1 phases), through the S phase and into the G2 and M phases. When the wounded endothelial cell conditioned medium was applied to heparin-sepharose columns, mitogenic activity was eluted with 2.0 M NaCl. The mitogenic activity in wounded endothelial cell conditioned medium, which was heat sensitive, was inhibited by protamine sulfate and a specific mouse monoclonal antibody against basic fibroblast growth factor (bFGF). Our results are evidence that the wounded endothelial cell conditioned medium contained growth promoting factors for synovial cells, including bFGF. We also showed the presence of bFGF in the endothelial cells of the small blood vessels and stromal synovial fibroblast-like cells in patients with rheumatoid arthritis (RA). Our results suggest that the endothelial cells in the luxuriant capillaries in the synovial tissues from patients with RA may have a critical role in the stimulation of neighboring synovial cell proliferation, resulting in pronounced synovial hyperplasia.

Antibodies, Monoclonal↗
PubMed1992

Prediction of human pharmacokinetics of panipenem, a new carbapenem antibiotic, from animal data.

The prediction of human pharmacokinetics of Panipenem (PAPM), which is a new carbapenem antibiotic, was investigated using animal data. The plasma concentration-time curve after intravenous administration of PAPM in each animal showed biexponential elimination. There were good allometric correlations between pharmacokinetic parameters (CLtotal and Vd,ss) calculated from the plasma concentration in animal species and body weight of experimental animals. Predicted human pharmacokinetic parameters calculated by these allometric equations agreed with the values observed in humans.

Adult↗
PubMed1992

[Clinico-pharmacological evaluation of omeprazole, as a proton pump inhibitor, compared with H2-blockers].

We evaluated the safety, tolerance, pharmacokinetics and pharmacodynamics of omeprazole, a new anti-ulcer agent chiefly on the basis of our studies in healthy male volunteers. The type and incidence of side effects of omeprazole have been reported to be similar to those of H2-antagonists, and in our studies too, omeprazole was estimated to be safe and tolerable. Following single doses, the increase in AUC was not proportional to the increase in dosage. In the multiple-dose study, the AUC was greater on day 7 than on day 1. This finding may be due to a partial saturation of first pass elimination. Repeated omeprazole treatment (20 mg once daily for 4 days) inhibited the basal and stimulated acid secretion. Though H2-blockers inhibit the basal and stimulated pepsin secretion, omeprazole inhibited the stimulated pepsin secretion only.

Adenosine Triphosphatases↗
PubMed1992

[Clinical characteristics and prognosis of secondary amyloidosis in patients with rheumatoid arthritis--renal involvement and therapy].

Secondary amyloidosis is an important complication that may have a strong influence on the prognosis of patients with rheumatoid arthritis (RA). We studied 21 RA patients with secondary amyloidosis. The two major initial signs were gastrointestinal symptoms and renal involvement. When 15 of the 21 patients were diagnosed as having secondary amyloidosis, they displayed renal involvement including proteinuria, hematuria and hypercreatininemia. The 15 patients with amyloidosis were either subjected to dialysis or died within 35 months on the average. The causes of death in 13 patients were cardiac failure, gastrointestinal bleeding and infection, which were strongly implicated with renal failure. Dialysis was applied to seven patients. Three of them were maintained with chronic dialysis. We discussed the induction-time and the method of dialysis in patients with amyloidosis secondary to RA.

Adolescent↗
PubMed1992

Bucillamine inhibits T cell adhesion to human endothelial cells.

We investigated the ability of bucillamine [N-(2-mercapto-2-methyl-propionyl)-L-cysteine] to prevent T cell adhesion to endothelial cells (EC) isolated from human umbilical vein. When EC were pretreated with bucillamine, T cell binding to the EC was suppressed in a dose dependent fashion. The T cells could bind preferentially to recombinant interferon-gamma (rIFN-gamma) treated EC compared with untreated EC. Bucillamine could also suppress T cell binding to rIFN-gamma treated EC as well as untreated EC. Addition of copper sulfate to bucillamine decreased significantly the percent T cell adhesion to the EC compared with bucillamine alone. The magnitude of inhibition by bucillamine and copper sulfate was similar in EC treated with rIFN-gamma as well as in untreated EC. H2O2 also inhibited the T cell binding to both untreated and rIFN-gamma treated EC. The inhibitory effects of bucillamine with or without copper sulfate on T cell binding to EC were abolished completely by catalase but not by superoxide dismutase. Our results suggest that hydrogen peroxide generated by bucillamine, with or without copper sulfate, inhibits T cell binding to EC. We believe, therefore, that bucillamine may suppress inflammation, such as that in rheumatoid synovitis, by reducing the emigration of chronic inflammatory cells from capillaries into tissue.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Pharmacokinetics of the new antiplatelet agent 2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine in human subjects.

The pharmacokinetics of KC-764 (2-methyl-3-(1,4,5,6-tetrahydronicotinoyl)pyrazolo[1,5-a]pyridine, CAS 94457-09-7) was studied in healthy male adult volunteers after single ascending oral dose and multiple dosing for 7 days. Serum KC-764 concentration attained the peak in 1 h and declined with a half-life of about 2 h at a single oral dose of 5, 10, 20 and 40 mg. No dose dependent pharmacokinetics of KC-764 was demonstrated. Three metabolites were detected in serum, but their concentrations were lower than that of KC-764. 48-h urinary recoveries after single doses were 41.6-46.6% of dose, not being dose-dependent. Urinary recovery of unchanged KC-764 was 1.1-1.6% of dose. Three metabolites were present in greater amount in urine than unchanged KC-764 and two metabolites were less than KC-764. There was little daily variation of serum concentrations and urinary excretion of KC-764 and its metabolites in the multiple dosing (20 mg twice a day) study. The daily and total urinary recovery were same as those after single doses. Food reduced Cmax and tended to delay tmax, but did not influence AUC0----infinity and urinary recovery. Serum protein binding of KC-764 was about 60%, being not dependent on total serum concentration.

Adult↗