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Biomedical subjects

Y Iwasawa

Publications and source records attributed to Y Iwasawa.

At least 37 records · Page 2Linked to original sources

[Optimal reperfusion therapy in acute myocardial infarction: time to reperfusion and recanalization rate].

Rapid and complete reperfusion is important for the reduction of infarct size and mortality in acute myocardial infarction. The optimum reperfusion therapy with regard to the recanalization rate and the time elapsing between onset and complete reperfusion was evaluated. One hundred fifty-four patients with total occlusion of the infarct-related artery within 6 hours of the onset were classified into four therapy groups: PTCA group (n = 58) undergoing primary percutaneous transluminal coronary angioplasty (PTCA), t-PA-IC group (n = 44) receiving tissue plasminogen activator (t-PA) intracoronary infusion, t-PA-IV group (n = 14) receiving intravenous t-PA infusion, and mt-PA-IV group (n = 38) receiving intravenous mutant t-PA infusion. Although the recanalization rate was high in the PTCA group, there were no differences between the four groups as a supplement to immediate or rescue PTCA. The time elapsing between initiation of thrombolysis and complete reperfusion was shorter in the mt-PA-IV group than in the t-PA-IV group. Assuming the time from hospital arrival to initiation of intravenous thrombolysis was 20 min, the recanalization rate at 60 min after arrival in hospital was higher in the mt-PA-IV group than the PTCA and t-PA-IC groups. Although additional coronary angiography and PTCA may be required to improve the low recanalization rate compared with primary PTCA, intravenous infusion of mutant t-PA was the most promising therapy to achieve early reperfusion.

Aged↗

[A patient with disopyramide intoxication rescued by percutaneous cardiopulmonary support].

A 28-year-old man was admitted to our hospital in a hypotensive state 2 hours after taking 8,400 mg disopyramide. Infusion of catecholamine and gastric lavage restored normal blood pressure. However, 8 hours after taking the disopyramide he became hypotensive again and electrocardiographic findings revealed bizarre ventricular complexes resulting in ventricular flutter. Although standard cardiopulmonary resuscitation was not effective, his circulatory status was maintained by percutaneous cardiopulmonary support (PCPS). After 36 hours electrocardiography showed sinus rhythm, and his cardiac function became normal. Patients with severe cardiac dysfunction or cardiac arrest caused by disopyramide intoxication can be supported by PCPS until cardiac function is restored.

Adult↗

Application of a CdTe Solid-State Detector to Polarization-Dependent Total-Reflection Fluorescence XAFS Measurements.

A CdTe solid-state detector was applied to the measurement of polarization-dependent total-reflection fluorescence XAFS spectra. The data revealed that the detector has good sensitivity, and this, together with its compact size, make it appropriate for in-situ measurements and removal of X-ray Bragg diffraction. The detector efficiently recorded the high-energy K-edge XAFS spectra for molybdenum oxides supported on TiO(2) (110).

Journal Article↗

[Clinical significance of additional ST segment elevation immediately after successful reperfusion in patients with anterior wall acute myocardial infarction].

The clinical significance of additional ST segment elevation immediately after reperfusion in acute myocardial infarction (AMI) is still unclear. The influence of additional ST elevation on myocardial damage was examined in 62 patients with first anterior AMI. All patients had coronary reflow (thrombolysis in myocardial infarction: TIMI grade III) within 6 hours after the onset of infarction and no subsequent reocclusion for at least 14 days. The patients were classified into two groups: group ST (+), 26 patients with additional ST elevation (> or = 5 mm increase in sigma ST in lead V1-V6) immediately after reperfusion, and group ST(-), 36 patients without additional ST elevation. Myocardial damage was estimated by the number of abnormal Q wave before and 1 hour after reperfusion (nQpre and nQpost. There were no significant differences in the elapsed time, ECG indexes before reperfusion and regional wall motion (RWM: SD/chord; SD = standard deviation) in the acute phase and 14 days after the onset between the two groups. Moreover, within each group the patients were classified into two groups on the basis of RWM 14 days after the onset: group A = RWM < -2.5 in group ST (+) (n = 17); group B = RWM > or = -2.5 in group ST(+) (n = 9); group C = RWM < -2.5 in group ST (-) (n = 14); group D = RWM > or = -2.5 in group ST(-) (n = 22). There were no significant differences in the elapsed time between the four groups. nQpre was highest in group C and was lowest in group D (group A: 2.1, group B: 1.9, group C: 4.1, group D: 1.4), and nQpost was highest in group C and group A, and was lowest in group D (group A: 4.1, group B: 2.7, group C: 4.4, group D: 2.0). There was a significant increase in nQ after reperfusion (nQpost-nQpre) in group A and group B, which was greater in group A than in group B. The increase in sigma ST after reperfusion was greater in group A than in group B. There was no significant increase in nQ after reperfusion in group C and in group D, and both nQpre and nQpost were highest in group C, and lowest in group D. Infarct size was larger in group A and in group C than group B and group D, and there was no significant improvement in RWM in group A and in group C. In conclusion, additional ST elevation immediately after reperfusion seems to occur in patients with not so severe myocardial damage before reperfusion, and may reflect reperfusion injury. Additional ST elevation is not observed in patients with preceding extensive myocardial damage which may be irreversible or not still advanced at the time of reperfusion.

Adult↗

N-[2-[N'-pentyl-(6,6-dimethyl-2,4-heptadiynyl)amino]ethyl]- (2-methyl-1-naphthylthio)acetamide (FY-087). A new acyl coenzyme a:cholesterol acyltransferase (ACAT) inhibitor of diet-induced atherosclerosis formation in mice.

FY-087 (N-[2-[N'-pentyl-(6,6-dimethyl-2,4-heptadiynyl)amino]ethyl]- (2-methyl-1-naphthylthio)acetamide) was found to be a competitive inhibitor of human microsomal acyl coenzyme A:cholesterol acyltransferase (ACAT) with an IC50 value of 0.11 microM. Under our assay conditions, other ACAT inhibitors tested, specifically YM-750, E-5324, and melinamide, all of which are now in phase I clinical trials or in clinical use in Japan, inhibited this enzyme with IC50 values of 0.18, 0.14, and 3.2 microM, respectively. FY-087 also inhibited ACAT in acetyl-low density lipoprotein loaded human macrophages (THP-1 cells) with an IC50 of 0.17 microM. Following the oral administration of FY-087 (30 mg/kg) to rats, the plasma concentration of FY-087 reached 0.42 microgram/mL after 2 hr. This concentration of FY-087 was enough to inhibit blood vessel ACAT activity. Cholesterol-lowering and anti-atherogenic effects of FY-087 were examined using C57BL/6J mice fed an atherogenic diet. In this mouse model, treatment with FY-087 (28 mg/kg) inhibited the increase in plasma cholesterol levels by about 20% and decreased the hepatic accumulation of free and esterified cholesterol by 61 and 67%, respectively. FY-087 also significantly inhibited the atherogenic diet-induced increase in the fatty-streak lesion area of the proximal aorta by 57% in C57BL/6J mice. These results indicate that FY-087 is not only a therapeutically bioavailable ACAT inhibitor that lowers plasma cholesterol levels, but also an effective anti-atherogenic agent in mice fed an atherogenic diet.

Acyl Coenzyme A↗

Effects of NB-598, a potent squalene epoxidase inhibitor, on the apical membrane uptake of cholesterol and basolateral membrane secretion of lipids in Caco-2 cells.

Caco-2 cells grown on membrane filters were used as a model to study the effects of NB-598, an inhibitor of squalene epoxidase, on cholesterol absorption from the intestinal epithelia. NB-598 (10 microM) inhibited the synthesis of sterol and sterol ester from [14C]acetate without affecting the synthesis of other lipids such as phospholipids (PL), free fatty acids (FFA) and triacylglycerol (TG). When labeled lipid was apically loaded as a micellar lipid solution into Caco-2 cell cultures, NB-598 reduced basolaterally secreted radioactivity in cholesterol, cholesterol ester, PL and TG. Furthermore, NB-598 suppressed the basolateral secretion of apolipoprotein (apo) B. When microsomes prepared from control Caco-2 cells were incubated with 10 microM NB-598, acyl CoA:cholesterol acyltransferase (ACAT) activity was inhibited slightly. After incubating Caco-2 cells with 10 microM NB-598, a slight reduction in cellular ACAT activity was also observed. These results suggest that suppression of the secretion of particles containing apo B and reduction of cellular ACAT activity in the intestinal epithelia are part of the mechanism of the cholesterol-lowering effect of NB-598.

Anticholesteremic Agents↗

Effect of a novel squalene epoxidase inhibitor, NB-598, on the regulation of cholesterol metabolism in Hep G2 cells.

We have reported previously that NB-598 competitively inhibits human squalene epoxidase and strongly inhibits cholesterol synthesis from [14C]acetate in cultured cells. Furthermore, multiple oral administration of NB-598 decreased serum cholesterol levels in dogs (Horie, M., Tsuchiya, Y., Hayashi, M., Iida, Y., Iwasawa, Y., Nagata, Y., Sawasaki, Y., Fukuzumi, H., Kitani, K., and Kamei, T. (1990) J. Biol. Chem. 265, 18075-18078). In the present study, the effects of NB-598 on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and low-density-lipoprotein (LDL) receptor were examined using a human hepatoma cell line Hep G2. Incubation of Hep G2 cells with NB-598 for 18 h increased HMG-CoA reductase activity in a dose-dependent manner. However, the increase in activity induced by NB-598 was lower than that induced by L-654,969 (a potent HMG-CoA reductase inhibitor), although NB-598 inhibited cholesterol synthesis more potently than L-654,969. On the other hand, HMG-CoA reductase mRNA was increased to the same extent by both inhibitors. These results demonstrate that NB-598 does not inhibit the synthesis of non-sterol derivative(s) of mevalonate, which regulate HMG-CoA reductase activity at the post-transcriptional level. NB-598 increased the binding of 125I-LDL to Hep G2 cells. LDL receptor mRNA was also induced by NB-598. In the presence of LDL or cycloheximide, NB-598 did not increase LDL receptor activity. These results demonstrate that the induction of LDL receptor activity by NB-598 is due to increases in mRNA and protein through the inhibition of cholesterol synthesis at the squalene epoxidase step. From these observations, squalene epoxidase inhibitor is expected to be highly effective in the treatment of hypercholesterolemia and also is very useful as a research tool for studying the regulation of cholesterol metabolism.

Acetates↗

NB-598: a potent competitive inhibitor of squalene epoxidase.

NB-598, (E)N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bith iophen-5-yl)methoxy]benzene-methanamine, was found to inhibit human microsomal squalene epoxidase (from Hep G2 cells) in a competitive manner. NB-598 inhibited cholesterol synthesis from [14C]acetate dose dependently in Hep G2 cells and increased the intracellular radioactivity of squalene. A single oral administration of NB-598 inhibited cholesterol synthesis from [14C]acetate in rats. Moreover, multiple oral administration of NB-598 to dogs decreased serum total and low density lipoprotein cholesterol levels and increased serum squalene levels. After termination of treatment, the reduced serum cholesterol and increased squalene levels returned to their control values.

Animals↗

Reversal of multidrug resistance by new dihydropyridines with lower calcium antagonistic activity.

BS compounds, a series of new dihydropyridines, successfully overcame multidrug resistance in P388/ADR cells in vitro. These agents synergistically potentiated the cytotoxicity of Adriamycin to P388/ADR cells at a concentration of 1-2 microM, whereas they showed hardly any synergistic effect in the parental cell line (P388/S) at the same concentration. They inhibited the active drug efflux in P388/ADR cells as well as the binding of [G-3H]-vinblastine to membrane vesicles from P388/ADR, which was increased in resistant P388 cells as compared with parental cells. Besides, unlike the activity of clinically used calcium antagonists, the calcium antagonistic activity associated with BS compounds was very weak: their arterial relaxation activity was less than 21% of that of verapamil. These data suggest that BS compounds specifically overcome multidrug resistance without the serious hypotensive side effects that accompany the use of verapamil or other calcium antagonists.

Animals↗

Metabolism of a new dihydropyridine calcium antagonist in rats and dogs.

1. The metabolism of a new dihydropyridine calcium channel blocker was studied in rats and dogs. The drug was extensively metabolized by both species after oral dosing. Metabolites were detected by two-dimensional t.l.c. after dosing with the 14C-labelled drug. Urinary metabolite patterns were quantitatively different in rats and dogs. 2. Ten metabolites were isolated from urine, bile and liver homogenate of male or female rats, and identified. 3. The main metabolic pathway was oxidation of the dihydropyridine moiety to the pyridine form, followed by the hydrolysis of the ester, oxidation of the methyl group at the 6-position, and oxidation of the isopropyl group. Other pathways were hydrolysis of the 3-isopropyl ester or 5-methyl ester group to the dihydropyridine monocarboxylic acid (M-2 and M-10, respectively). 4. The drug was metabolized in rats stereoselectively. M-2 and M-10 isolated from rat female urine were analysed by chiral stationary-phase h.p.l.c. and were mainly the enantiomers derived from (-)- and (+)-drug, respectively.

Animals↗

Studies on 4(1H)-quinazolinones. 5. Synthesis and antiinflammatory activity of 4(1H)-quinazolinone derivatives.

A number of new 4(1H)-quinazolinones were synthesized and evaluated in the carrageenin-induced paw edema test. Most of the compounds were obtained by the cyclization of the appropriately substituted anthranilamides with acid chlorides, followed by further chemical transformation. Structure-activity data suggest that 2-isopropyl-1-phenyl-, 2-cyclopropyl-1-phenyl-, and 1-isopropyl-2-phenyl-4(1H)-quinazolinones afford optimal potency and the presence of a halogen atom is preferred for activity. Adrenalectomy does not affect the antiinflammatory test results. The best result taking into account both efficacy and side effects was displayed by 1-isopropyl-(2-fluorophenyl)-4-(1H)-quinazolinone (50).

Adrenalectomy↗