Biomedical subjects

M Nakashima

Publications and source records attributed to M Nakashima.

At least 649 records · Page 36Linked to original sources

PubMedDate not supplied

UV-dependent quinolone-induced human erythrocyte membrane lipid peroxidation: studies on the phototoxicity of Y-26611, a new quinolone derivative.

Quinolone antibacterial drugs are widely used as oral therapeutic agents. However, in some patients they cause ultraviolet (UV)-dependent dermatitis. Using lipid peroxidation as an index of phototoxicity, we studied the effects of a new quinolone derivative, Y-26611 together with ofloxacin, sparofloxicin and lomefloxacin on washed human erythrocyte suspensions. Irradiation of erythrocytes with UV-A or UV-B for 60 min. in the presence of Y-26611 (30-600 micrograms/ml) strong dose dependent lipid peroxidation, up to 17.01 nmoles/ml was induced. Under identical conditions, lipid peroxidation induced by up to 600 micrograms/ml ofloxacin, sparofloxacin or lomefloxacin were 0.94, 3.36 and 2.98 nmoles/ml respectively. The lipid peroxidation was entirely dependent on both UV as well as the drug. The lipid peroxidation responses to drug+UV could completely be inhibited by sodium azide (hydroxyl radical, HO. and single oxygen, 1O2 scavenger) or by phenyl N-tert-butylnitrone (PBN, HO. and superoxide anion radical, O2- scavenger). It is likely that reactive oxygen species generated by interaction between UV-sensitized drug molecules and oxygen molecules mediate erythrocyte membrane lipid peroxidation. The method used in this study is rapid and convenient for screening drugs for UV-dependent cytotoxicity.

4-Quinolones↗

PubMedDate not supplied

Clinical evaluation of Ramosetron injections in the treatment of cisplatin-induced nausea and vomiting.

A phase III, double-blind, placebo-controlled study was performed to examine the safety and efficacy of ramosetron in cancer patients with cisplatin-induced nausea/vomiting. Patients were divided into two groups: group R received 0.3 mg ramosetron intravenously and group P received placebo. Eighty-eight patients were enrolled, 44 in each group; 84 (43 in group R, 41 in group P) were included in the clinical efficacy analysis and 86 (44 in group R, 42 in group P) in the safety analysis. Ramosetron was significantly more clinically effective than placebo against nausea, vomiting and anorexia; 65.1% of patients in group R experienced no vomiting in the first 6 h of observation compared with 7.3% of those receiving placebo. No serious adverse reactions or significant differences in safety were observed between the groups. Based on these results, ramosetron injection is effective in the treatment of cisplatin-induced nausea/vomiting and its clinical usefulness is demonstrated here.

Adult↗

PubMedDate not supplied

Comparative clinical study of cefcapene pivoxil and cefteram pivoxil in chronic respiratory tract infections by a double-blind method.

In a double-blind study, the efficacy and safety of the novel cephem antibiotic cefcapene pivoxil (CFPN-PI; 450 mg/day) was compared with cefteram pivoxil (CFTM-PI; 600 mg/day) in 171 patients with chronic respiratory tract infections. There was no significant difference between the clinical efficacy of the two drugs (80.2% for CFPN-PI versus 78.9% for CFTM-PI). There was no significant difference in the rate of elimination of the causative bacteria (60.5% for CFPN-PI versus 65.9% for CFTM-PI). Side-effects were observed in 6.0% of patients treated with CFPN-PI compared with 6.4% of patients treated with CFTM-PI. There were no significant differences in incidence of abnormal laboratory findings following treatment with the two drugs (13.9% for each), and none of the side-effects was severe. We conclude that CFPN-PI (450 mg/day) was as effective and as well tolerated as CFTM-PI (600 mg/day) in the treatment of chronic respiratory tract infections.

Adult↗

PubMedDate not supplied

Pharmacodynamic study of procaterol hydrochloride dry powder inhaler: evaluation of pharmacodynamic equivalence between procaterol hydrochloride dry powder inhaler and procaterol hydrochloride metered-dose inhaler in asthma patients in a randomized, double-dummy, double-blind crossover manner.

Therapeutic equivalence between procaterol hydrochloride dry powder inhaler (Meptin DPI) and procaterol hydrochloride metered-dose inhaler (Meptin MDI), the currently marketed formulation, was assessed in 16 patients with bronchial asthma. The study was conducted in a randomized, double-dummy, double-blind crossover manner, using forced expiratory volume in the first second (FEV1) as an index of bronchodilatory effect. In Period I, the patients received 20 mcg of either Meptin DPI or Meptin MDI, and then crossed over in Period II after a washout interval of 3--28 days. Pharmacodynamic equivalence was accessed using AUC (FEV1)/h and peak FEV1 as indices, and the data were analyzed by analysis of variance (ANOVA). Factors used for the analysis were the treatment group and/or carryover effect, patients within each group, period, and treatment. The 90% confidence intervals for the differences between the two treatments were --0.0995 to --0.0204 (L) for mean AUC (FEV1)/h and --0.102 to --0.022 (L) for mean peak FEV1, both within the acceptance criteria of --0.15 to 0.15 (L). Meptin DPI was therefore assessed as being equivalent to the current Meptin MDI.

Adrenergic beta-Agonists↗

PubMedDate not supplied

Safety study of lazabemide (Ro19-6327), a new MAO-B inhibitor, on cardiac arrhythmias and blood pressure of patients with Parkinson's disease.

To evaluate whether lazabemide has proarrhythmic or hypotensive potency in Parkinson's disease (PD), we conducted an 8-week, double-blind, placcbo-controlled, parallel group study with use of 24-hour ambulatory electrocardiographic (ECG) monitoring. Fifty-one patients with PD who did not have clinically apparent heart disease were randomized in a double-blind fashion to receive either lazabemide (n = 25) or placebo (n = 26) treatments. Lazabemide therapy did not induce clinically significant arrhythmias. A paroxysmal atrioventricular (AV) block, which progressed from first-degree AV block, was found in one patient in the lazabemide group. This was determined not to be a new AV block. However, the causality of lazabemide in prolongation of the pause was not ruled out completely. In addition, the asymptomatic fall in systolic blood pressure seen 3 minutes after standing up was observed to be more pronounced in the lazabemide group than in the placebo group. The mean decrease of systolic blood pressure was 10 mmHg greater in the lazabemide group than in the placebo group. In conclusion, lazabemide did not induce any clinically significant arrhythmias in patients without clinically apparent heart disease. However, it may increase the asymptomatic, orthostatic drop in systolic blood pressure.

Aged↗

PubMedDate not supplied

IL-1-mediated expression of membrane type matrix-metalloproteinase in rheumatoid osteoblasts.

OBJECTIVE: To determine whether the activation of metalloproteinases can be achieved by the interaction of the inflammatory cytokine, IL-1 beta, with rheumatoid osteoblasts. RESULTS: MMP-2 is not secreted by rheumatoid osteoblasts as a proenzyme; however, IL-1 beta stimulation induced the secretion of MMP-2 as an active form from rheumatoid osteoblasts. This MMP-2 activating activity was detected significantly in IL-1 beta-stimulated rheumatoid osteoblasts. In support of this result, IL-1 beta stimulation induced the expression of membrane type matrix-metalloproteinase (MT-MMP), a newly-identified MMP-2 specific activator, in rheumatoid osteoblasts. CONCLUSION: These results suggest that IL-1 beta induces MMP-2 activation in part by up-regulating MT-MMP expression and represents a new mechanism for cytokine-mediated articular destruction in RA.

Arthritis, Rheumatoid↗

PubMedDate not supplied

Clinicopathologic study on cholangiolocellular carcinoma.

We clinicopathologically studied 6 resected cases of cholangiolocarcinoma (CLC) including 2 referred cases from other hospitals. The frequency of CLC was 0.56% of the 708 consecutively resected cases of primary liver cancer and the mean age of CLC cases was 66 years. Three of the 6 cases (50%) were hepatitis C virus antibody (HCVab) positive, one (17%) was hepatitis B virus surface antigen (HBsAg) positive, and 2 (33%) were negative to both HCVAb and HBsAg. Serum levels of alpha-fetoprotein were slightly elavated only in 1 case. Clinically, 4 cases were diagnosed as hepatocellular carcinoma (HCC) and 2 cases as cholangiocellular carcinoma (CCC). Grossly, CLCs were whitish in color and solid, not encapsulated, and resembled CCC. Histologically, the tumor cells had eosinophilic cytoplasm with ovoid nuclei, and mild atypia. The tumor proliferated in an anastomosing pattern of Hering's canal-like small glands with an abundant fibrous stroma. Four of the 6 tumors (83%) consisted of only CLC and other 2 tumors contained CCC-like area and HCC-like area in a part of the nodules, respectively. Immunohistochemically, all tumors were positive to cytokeratin (CK) 7. CK8 were also positive in all of 6 cases. These results revealed that CLC had the clinical features resembling HCC but the morphologic features resembling CCC. It is suggested that CLC cells might be derived from Hering's canal or stem cells which have the intermediate features between hepatocytes and bile duct epithelium.

Aged↗

PubMedDate not supplied

Quantitative analysis of telomerase activity: a potential diagnostic tool for colorectal carcinoma.

BACKGROUND/AIMS: We describe the results of the application of the nonradioactive F-TRAP (fluorescence-based telomeric repeat amplification protocol) assay for the diagnosis of colorectal carcinoma(s). We also investigated whether the level of telomerase activity in colorectal carcinoma can be distinguished from that in normal colorectal tissue or benign colorectal tumors, in which the presence of telomerase activity has also been demonstrated. In addition, we also investigated whether it could be a potential tumor progression marker. METHODOLOGY: The F-TRAP assay was performed, using biopsy specimens obtained from colonoscopic examinations, including 20 colorectal carcinoma, 10 tubular adenoma and 20 adjacent colorectal normal tissue specimens. In 15 carcinoma cases, the correlation between telomerase activity level and clinicopathological parameters was analyzed. RESULTS: The results showed that the level of telomerase activity in colorectal carcinomas (88.71 +/- 92.1 units; mean +/- SD) was much higher than that in normal colorectal tissues (3.34 +/- 8.57 units) or adenomas (7.8 +/- 10.27 units). By quantifying the level of telomerase activity using the F-TRAP assay, colorectal carcinomas can be distinguished from normal colorectal tissue or colorectal benign tumors. However, no significant correlation was observed between telomerase activity levels and clinicopathological parameters such as depth of tumor invasion, lymphatic and/or venous involvement, and regional lymph node metastasis and Dukes' stage. CONCLUSIONS: Quantitative analysis of the level of telomerase activity using the F-TRAP assay provides a useful diagnostic tool for colorectal carcinoma, but it would not be useful as a tumor progression marker.

Adenoma↗

PubMedDate not supplied

Augmented responsiveness to sympathetic nerve stimulation of isolated vas deferens of diabetic rats.

The responsiveness to nerve stimulation in the prostatic end of the rat vas deferens and the influence thereupon of streptozotocin-induced diabetes were examined. The rat vas deferens showed a biphasic contractile response to field stimulation: a rapid twitch contraction followed by a slower tonic contraction. Diabetic rats, at 8 and 12 weeks after induction of diabetes, showed a significant increase in the tonic response when compared with age-matched control rats. The twitch response was slightly increased in 12 week diabetic rats at low frequencies of stimulation. Treatment with insulin reversed the augmented response to nerve stimulation found in diabetic rats. The tonic phase in control rats was inhibited by prazosin (73.5%), and by alpha,beta-methylene ATP (34.6%). In diabetic rats at 12 weeks, about 30% of the tonic response was inhibited by prazosin; in the presence of prazosin, the response was still significantly augmented in comparison with that in control rats. In contrast, the tonic response in the presence of alpha,beta-methylene ATP was the same in diabetic and control rats. These results indicate that diabetes induces an increase in the purinergic component of the response to sympathetic nerve stimulation of the rat vas deferens.

Adenosine Triphosphate↗

PubMedDate not supplied

Comparison of the cardiac electrophysiologic effects of amitriptyline and clomipramine in the dog after myocardial infarction.

The effects of the tricyclic antidepressants amitriptyline and clomipramine on intraventricular conduction, effective refractory period and incidence of ventricular arrhythmias induced by programmed stimulation, were studied in the dog heart after myocardial infarction. Amitriptyline, at doses of 1 to 3 mg/kg, significantly slowed ventricular conduction of the infarcted zones in a frequency-dependent and a dose-dependent manner. Amitriptyline, at doses of 2 and 3 mg/kg, slightly slowed conduction in normal zones. The effective refractory period was prolonged by amitriptyline at a dose of 2 mg/kg. Amitriptyline increased the incidence of ventricular arrhythmias induced by programmed stimulation. On the other hand, the depressant effect of clomipramine, at doses of 1 to 3 mg/kg, on the conduction of infarcted zones was lower than that of amitriptyline, whereas the severely depressed conduction in the infarcted zone was obviously slowed by clomipramine. The incidence of ventricular arrhythmias did not significantly increase with clomipramine. From the present results, clomipramine seems to have a lower cardiac toxicity than amitriptyline, although clomipramine produces a slight depression of conduction in infarcted zones.

Amitriptyline↗

PubMedDate not supplied

Alterations of cardiac adrenoceptors and calcium channels subsequent to production of aortic insufficiency in rats.

Aortic insufficiency (AI) was produced in rats by puncturing one of the aortic valves with a plastic rod inserted from the right carotid artery, and the subsequent changes in alpha- and beta-adrenoceptors and Ca2+ channels were investigated by means of radioligand binding assays. The positive inotropic effects of methoxamine (Met), isoproterenol (Iso) and Ca2+ were also examined in isolated left papillary muscles. The ratio of the whole heart weight to body weight in AI rats increased significantly as compared with sham-operated rats from 1 till 8 weeks after operation, showing that a cardiac hypertrophy had occurred due to the volume overload. Maximum binding sites (Bmax) for 3H-prazosin in cardiac ventricular muscles of AI rats significantly increased at 4 weeks and returned to the control level at 8 weeks when the AI was still patent. Bmax for 3H-dihydroalprenolol (3H-DHA) of AI rats significantly increased at 2 and 4 weeks and returned to the control level at 8 weeks. Bmax for 3H-nitrendipine binding of AI rats significantly decreased at 2 weeks and returned to the control level at 4 weeks. Affinities for these bindings, as expressed by values of dissociation constants, showed no significant changes. The sensitivities of papillary muscles to Met and Iso were significantly increased in AI rats at 4 weeks. Plasma immunoreactive alpha-atrial natriuretic polypeptide (alpha-ANP) concentration of AI rats tended to increase from 1 till 3 weeks and returned to the control level at 4 weeks but these changes were not significant. We conclude that the synthesis of new adrenoceptors keeps pace with the hypertrophic process and may even overshoot during a short period.

Animals↗

PubMedDate not supplied

Altered responsiveness of coronary arteries in hyperthyroid rats.

The effect of thyroid hormones on vascular responses to various agents was examined in the coronary vascular bed perfused by the Langendorff's method at a fixed flow rate with Krebs-Henseleit solution in isolated rat hearts. In this study, ventricular fibrillation was induced by electrical stimulation to avoid secondary influences derived from alteration of ventricular contractility by agents. Vasodilator responses of coronary arteries to isoproterenol and methacholine were significantly enhanced in hyperthyroid preparations compared with those observed in euthyroid ones, though vasodilator responses to histamine and adenosine were not affected by hyperthyroidism. Vasoconstrictor response to 5-hydroxytryptamine (5-HT) was significantly potentiated by hyperthyroidism though that to balium chloride was not affected. So, these alterations in vascular responses by hyperthyroidism are assumed not to be nonspecific but to be mediator-specific events. As vasoconstriction in coronary arteries lowers oxygen supply to myocardium, enhanced vasoconstrictivity of coronary arteries to 5-HT by hyperthyroidism may be responsible for an exacerbation of heart disease in the case of patients having agglutinative thrombus, which should be a source of 5-HT, in their coronary arteries.

Adenosine↗

PubMedDate not supplied

Relative electrophysiological potencies of quinidine, 3-OH quinidine and quinidine-N-oxide in guinea-pig heart.

The relative potencies of the quinidine metabolites, 3-OH quinidine (3OHQ) and quinidine-N-oxide (QNO), to their parent drug, quinidine, were obtained electrophysiologically using guinea-pig hearts. The items examined were QT interval of local extracellular electrogram in a Langendorff's perfused heart, effective refractory period (ERP) and action potential duration at 90% repolarization (APD90) in the right papillary muscle. Quinidine (0.125-1 mg/l) and 3OHQ (0.5-4 mg/l) prolonged QT interval in a concentration-dependent manner and the relative potency of 3OHQ to quinidine was 0.25. The effect of QNO on QT interval within the range of concentration used (up to 8 mg/l) was small and the relative potency was 0.04 at the most. An apparent additive effect of 3OHQ to that of quinidine was revealed, but QNO of 4 mg/l has no effect on the concentration-effect relationship of quinidine for prolonging QT interval. These results were quite similar to those in humans reported previously. Quinidine (0.5-4 mg/l), 3OHQ (1-8 mg/l) and QNO (2-8 mg/l) prolonged APD90 in a concentration-dependent manner. These effects were accompanied by the prolongation of ERP in similar degrees. The relative potencies of 3OHQ to Q were 0.22 for APD90 and 0.27 for ERP and those of QNO were 0.087 for APD90 and 0.084 for ERP. Quinidine (10(-5) M) depressed the maximum upstroke of action potential (Vmax) in a frequency-dependent manner. 3OHQ of the same concentration also depressed it in the same manner to a much lesser extent and QNO had no effect. In conclusion, relative potencies of quinidine metabolites to quinidine for prolonging QT interval of local extracellular electrogram represent those to prolong APD90 and ERP, suggesting the relative potencies for antiarrhythmic activity in the same order. In the physiological range of concentrations of metabolites, 3OHQ may contribute to the antiarrhythmic effect of quinidine in an additive way, but QNO may have little effect when we take into account the fact that the free fraction of 3OHQ is 2.5 times that of quinidine.

Action Potentials↗

PubMedDate not supplied

Comparative effects of the antidepressants amitriptyline, mianserin and adinazolam on hemodynamics and ECG in myocardial infarcted dogs.

This study was undertaken to examine the effects of mianserin (MIA), a tetracyclic antidepressant, and adinazolam (ADI), a new benzodiazepine antidepressant on cardiac function and electrocardiogram in normal and infarcted hearts of anesthetized dogs, and to compare the effects with those of amitriptyline, a commonly used tricyclic antidepressant. The parameters measured were: heart rate (HR); mean arterial blood pressure (MP); aortic flow (AF); maximal rate of increase of left ventricular pressure (LV dp/dt); blood flow of left circumflex of left coronary artery (CAF) and PQ and QRS intervals. The double product (DP) was calculated from HR and the arterial pressure. AMI increased HR, DP, LV dp/dt and CAF in the normal group, while in the infarcted group, AMI increased HR, DP and CAF, but decreased LV dp/dt at 3 mg/kg. AMI at 2 and 3 mg/kg prolonged QRS intervals in the infarcted groups. MIA increased HR and DP in the normal group at doses of 1 mg/kg or more, while in the infarcted group it produced only slight effects in hemodynamic parameters and PQ and QRS intervals. ADI had little effect on hemodynamics and PQ and QRS intervals in the normal group. However, it decreased LV dp/dt, CAF, MP at 3 mg/kg in the infarcted group. In conclusion, AMI markedly influenced cardiac hemodynamics and QRS interval in the myocardial infarcted group, while, on the other hand, MIA and ADI, in clinical doses, had only a slight effect on hemodynamics and PQ and QRS intervals in the infarcted group. Thus MIA and ADI were safer than AMI in the animals with myocardial infarction.

Amitriptyline↗

PubMedDate not supplied

Extraction of light filth from whole peppermint leaves: collaborative study.

Results are reported for a collaborative study of a method for the extraction of light filth from whole peppermint leaves. A 5 g sample is defatted with isopropanol in a simple reflux appartus. Rat hairs, insect fragments, and whole insects are isolated by wet sieving on a No. 230 sieve, a deaerating boil in 40% isopropanol solution, flotation with Tween 80-Na4EDTA (1 + 1) and mineral oil-heptane (85 + 15), and trappings in a Wildman trap flask. Average recoveries obtained by 6 collaborators for 3 spike levels of rat hairs (5, 10, 15) were 83.3, 87.5, and 82.2%, respectively. For whole insects (5, 10, 15) recoveries averaged 85.0, 80.0 and 77.2% respectively; for insect fragments (20, 30, 50) recoveries averaged 79.6, 88.3, and 84.8%, respectively. The average recoveries for the 3 levels of each analyte were not significantly different. The method has been adopted official first action.

Animals↗

PubMedDate not supplied

Cytokine combinations for induction of antigen-specific cytolytic T lymphocytes from peripheral blood lymphocytes.

We studied effects of varied cytokine combinations on allogeneic cytotoxic T lymphocyte (CTL) generation in a mixed lymphocyte-tumor cell culture. Sensitized with allogeneic melanoma cell line (MM-8.1 or MM-28), peripheral blood mononuclear cells (PBMC) were cultured in medium containing various combinations of cytokines that included human recombinant interleukin-2 (rIL-2) alone (MB-2), rIL-2 and rIL-4 (MB-2,4) and rIL-1, rIL-2, rIL-4 and rIL-6 (MB-1,2,4,6). Lymphocytes proliferated for more than 50 days and manifested stimulating cell-specific cytotoxicities in 1 of 5 cultures with MB-2, in 4 of 5 with MB-2,4 and in 5 of 5 with MB-1,2,4,6. Lymphocytes grew up to 10(6) fold in culture with MB-2,4 or MB-1,2,4,6 at day 90-100. Stimulating cell MM-8.1 (HLAABC+,DR-) induced CD3+, CD8+, CD56- CTLs and MM-28 (HLA-ABC+, DR+) mainly generated CD3+, CD4+, CD56- CTLs. Monoclonal antibodies against HLA-ABC and HLA-DR molecules suppressed the stimulating cell-specific cytolytic activity of CD8+ and CD4+ CTLs, respectively. These data indicate that combination of rIL-1, rIL-2, rIL-4 and rIL-6 offer an efficient system to generate allogeneic, tumor-specific CTLs from PBMCs and that HLA molecules expressed on stimulating cells play an important role in CTL generation.

Antigens, CD↗

PubMedDate not supplied

Effects of imipramine and amitriptyline on intraventricular conduction, effective refractory period, incidence of ventricular arrhythmias induced by programmed stimulation, and on electrocardiogram after myocardial infarction in dog.

The effects of imipramine and amitriptyline on intraventricular conduction, effective refractory period, incidence of ventricular arrhythmias induced by programmed stimulation and on electrocardiogram changes were studied after myocardial infarction in the dog. Amitriptyline, at doses of 1-3 mg/kg, significantly slowed the ventricular conduction of the infarcted zones in a dose- and frequency-dependent manner. Amitriptyline, at doses of 2 and 3 mg/kg, slowed the ventricular conduction slightly in the normal zone. The effective refractory period was prolonged by amitriptyline at a dose of 1 mg/kg. Amitriptyline increased the incidence of ventricular arrhythmias induced by programmed stimulation. Amitriptyline, at doses of 1-3 mg/kg, increased heart rate and prolonged the PQ, QRS and QT interval. Imipramine, at a dose of 3 mg/kg, slowed the conduction in infarcted zones to a lesser extent than amitriptyline. Imipramine, at doses of 1 and 2 mg/kg, did not significantly increase the incidence of ventricular arrhythmias. Imipramine, at a dose of 3 mg/kg, prolonged the QRS interval. From the present results it appears that imipramine has a lower cardiac toxicity than amitriptyline.

Amitriptyline↗

PubMedDate not supplied

A canine coronary artery thrombosis model: application of photochemically induced thrombosis.

A simple and reproducible canine model of platelet-rich coronary artery thrombosis, suitable for the evaluation of antithrombotic drugs, has been developed. In this model, thrombus was initiated in the left arterial descending coronary artery by means of transmural green light (540 nm) in the presence of i.v. administered rose bengal (a photosensitizer dye). The photochemical reaction between green light and rose bengal causes endothelial injury which is followed by platelet adhesion aggregation and formation of an occlusive platelet-rich thrombus at the site of the photochemical reaction. In 9 out of 12 animals, occlusion of the coronary artery occurred within 60 min after irradiation with green light and infusion of rose bengal. Infusion of tissue-type plasminogen activator (50,000 IU/kg) produced thrombolysis in 6 out of 9 animals within 60 min. Reocclusion was observed in 4 of these 6 animals. Photochemically induced thrombosis in the canine coronary artery provides a simple and platelet-rich thrombosis model suitable for the evaluation of antithrombotic and thrombolytic preparations.

Animals↗