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Biomedical subjects

O Okazaki

Publications and source records attributed to O Okazaki.

At least 37 records · Page 2Linked to original sources
PubMed1997

Significance of downsloping ST-segment depression induced by low-level exercise in severe coronary artery disease. Assessment with myocardial ischemia and collateral perfusion.

Exercise-induced downsloping ST-segment depression is a common manifestation of severe myocardial ischemia. Although greater downsloping ST-segment depression is suspected to indicate more severe ischemia, its exact relationship to regional myocardial blood flow (RMBF) has not yet been clarified. We investigated the relationship between the magnitude of downsloping ST-segment depression and exercise-induced changes in RMBF and collateral perfusion. Nitrogen-13 ammonia positron emission tomography was performed in 6 healthy volunteers and 72 patients with angiographically proven coronary artery disease. The left ventricle was divided into 11 regions of interest, and RMBF in each region was measured at rest and during low-level supine bicycle exercise. Downsloping ST-segment depression of 0.1 mV or more at 80 milliseconds after the J point was accepted as significant. Low-level exercise induced downsloping depression of 0.1 to 0.2 mV in 10 patients (group D1) and downsloping depression of 0.2 mV or more in 8 patients (group D2). Multivessel disease was common in both group D1 (80% of patients) and group D2 (88% of patients). Collateral circulation was significantly more frequent in group D1 (90%) than in group D2 (13%, p < 0.01). Ischemic areas were larger and cardiac function was worse in group D2 than in group D1. The RMBF increased sufficiently in all regions (56 +/- 30%) with exercise in the healthy group. In group D1, RMBF was unchanged or decreased in ischemic areas (10 +/- 23%) but increased sufficiently in surrounding areas (50 +/- 32%). In group D2, RMBF was unchanged in ischemic areas (17 +/- 24%) and increased insufficiently in surrounding areas (41 +/- 21%). Therefore, exercise-induced downsloping ST-segment depression of 0.1 to 0.2 mV may reflect an underlying change in blood flow in viable myocardium with collateral perfusion, and downsloping depression of 0.2 mV or more may reflect more severely impaired myocardium without collateral perfusion.

Adult↗
PubMed1997

Effects of pantoprazole on xenobiotic metabolizing enzymes in rat liver microsomes: a comparison with other proton pump inhibitors.

The effects of pantoprazole on xenobiotic metabolizing enzymes in rat liver microsomes were examined. Groups of female Sprague-Dawley rats were orally administered pantoprazole and other proton pump inhibitors, omeprazole and lansoprazole, at 5, 50, or 300 mg/kg/day for 7 days, followed by assays to detect changes in the levels of liver microsomal protein, cytochrome P450, cytochrome b5, NADPH cytochrome c reductase, and drug metabolizing enzyme activities. Increases in total cytochrome P450 contents were evident after a 7-day high-dose administration of all the proton pump inhibitors tested, and the increase by treatment with pantoprazole was less than that with lansoprazole. The three proton pump inhibitors increased the enzymatic activities and cytochrome P450 enzyme levels of CYP1A, CYP2B, and CYP3A. CYP1A was less induced with pantoprazole than with omeprazole or lansoprazole. In contrast, CYP2B was more strongly induced with pantoprazole than with other proton pump inhibitors. NADPH cytochrome c reductase was induced with omeprazole and pantoprazole. The present results suggest that enzyme induction differs among these proton pump inhibitors not only quantitatively but also qualitatively.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1996

[Clinical use of beta-blocker an as antiarrhythmic agent].

It has been reported that beta-blocker treatment reduces the incidence of sudden cardiac death after myocardial infarction, possibly due to antiischemic and antiarrhythmic effects. Beta adrenoceptor blocking drugs are administered, as an antiarrhythmic agent in patients with hyperthyroidism, atrial fibrillation, atrial flutter and ventricular tachyarrhythmias. Even low dose beta-blocker administration reduces the incidence of PVC's. Beta blockers are expected to decrease the ventricular rate of persistent tachyarrhythmias resulting from excessive cardiac sympathetic tone. Existence of denervated areas in myocardium in the cases of ventricular tachyarrhythmias may be shown in the cardiac scintigram as abnormal myocardial uptake of 123I-MIBG.

Adrenergic beta-Antagonists↗
PubMed1996

Pharmacokinetics and stability of caldiamide sodium in rats.

Gadodiamide (CAS 122795-43-1) injection (Omniscan) is a formulation composed of gadolinium (III) complexed with diethylenetriaminepentaacetic acid bis-methylamide (Gd DTPA-BMA) and the sodium calcium complex of the same ligand, known as caldiamide sodium (CAS 122760-91-2, NaCa DTPA-BMA), in a molar ratio of 20:1. Following intravenous dosing of NaCa DTPA-BMA (0.015 mmol/kg) in a 14C-labeled form, plasma concentrations of the drug declined rapidly with an elimination half-live of 0.31 h, a distribution volume of 244 ml/kg and a plasma clearance of 9.2 ml/min/kg. These results demonstrate that NaCa DTPA-BMA distributes into the extracellular fluid compartment and is renally excreted via glomerular filtration. Of the dose of radioactivity given, 86.6% was excreted in urine by 4 h after injection, and 95.3% in urine and 3.3% in feces by 120 h. In addition, experiments were done to clarify the in vivo metabolism of NaCa DTPA-BMA. Results show small quantities of transchelatd forms of NaCa DTPA-BMA in urine. HPLC analysis demonstrated these metabolites were the Zn and Cu forms of the drug, resulting from displacement of the Ca ion in the NaCa DTPA-BMA molecule by endogeneous Zn or Cu. Further analyses by HPLC and ICP-AES demonstrate that the unchanged parent drug, the Zn and the Cu forms occur in relative quantities of approximately 92%, 7%, and 1%, respectively. This demonstrates that the Ca ion in caldiamide sodium can be replaced by Zn or Cu ions in vivo, but only to a small extent.

Animals↗
PubMed1996

Placental transfer and milk secretion of gadodiamide injection in rats.

The disposition of gadodiamide (CAS 122795-43-1) injection (Omniscan), a nonionic paramagnetic contrast-enhancing medium developed for magnetic resonance imaging, was characterized in the pregnant and lactating rat. After a single intravenous dose of 0.3 mmol/kg 14C-labeled gadodiamide to rats on day 18 of gestation, the maximum levels of radioactivity in the fetus were attained at 5 min, and were approximately 170 times lower than those in the maternal plasma. The AUC ratio of fetal to maternal blood was less than 0.1. Moreover, the distribution percentage of radioactivity in the fetus were on the average 0.01% of the administered dose up to 4 h, and trace amounts of radioactivity were present in fetal tissues at 24 h after dosing. Whole body autoradiography showed that the smallest amounts of radioactivity were present in the fetus, whereas the highest concentrations of radioactivity were noted in the fetal membrane and the kidney at 24 h after dosing. These results indicate that exposure of the developing rat fetus to gadodiamide after maternal drug administration is quantitatively small. The radioactivity levels in the milk increased with time, reaching a maximum 1 h after dosing, and gradually decreased to levels below detection limits over 8 h. A comparison of the AUCs of milk and plasma showed the comparatively small amounts of the drug excreted into milk.

Animals↗
PubMed1995

Functional role of coronary collaterals with exercise in infarct-related myocardium.

We evaluated the regional myocardial blood flow in collateral dependent infarct-related areas to examine the functional role of coronary collaterals. Regional myocardial blood flow was measured by positron emission tomography with 13N-ammonia at rest and during low-grade exercise (bicycle ergometer fixed at 25 W for 6.5 min). The study was performed in 24 subjects, consisting of 19 patients with prior myocardial infarction, and five normal individuals. Regional myocardial blood flow was calculated using the radioactivity in myocardial tissue measured by positron emission tomography and the radioactivity in arterial blood. Concerning the infarct related area, the exercise caused myocardial blood flow to decrease by 18.4% (P < 0.01) in the collateral-dependent areas (n = 8) of angiographically positive collaterals, and to increase by 14.4% (P = not significant) in the areas (n = 10) of negative collaterals. Four patients in whom the myocardial blood flow in all walls, including the normal areas, decreased with exercise were excluded from this evaluation. Myocardial blood flow in collateral-dependent infarct-related areas appeared to decrease transiently by low-grade exercise. Our results suggest that collaterals increase the incidence of exercise-induced ischemia, but may protect the infarct related but viable myocardium from necrosis.

Adult↗
PubMed1995

Interpretations of cytochrome P450 mechanisms from kinetic studies.

The catalytic mechanism of cytochrome P450 (P450) enzymes has generally been understood in terms of a classic cycle in which electron donation is often limiting and catalysis is understood in terms of hydrogen abstraction and rapid oxygen rebound. In the course of detailed investigations with kinetic hydrogen isotope effects we have studied two systems in which somewhat unusual isotope effects have been interpreted in terms of modifications of the general paradigm. The low isotope effects observed for N-demethylation reactions are in contrast to high values seen with P450-catalyzed C-hydroxylation and peroxidase-catalyzed N-demethylation and are consonant with a role for the P450 FeO2+ entity in base-catalyzed deprotonation of an aminium radical. With P450 2E1, kinetic deuterium isotope effects are seen on the apparent Km for the substrate (increased) but not on Vmax. The results are interpreted in terms of a mechanism where C-H bond cleavage is sensitive to deuterium substitution but a step following this is rate-limiting. This step may be product release.

Animals↗
PubMed1995

Comparison of body surface potential maps simulated with isotropic and anisotropic computer heart models.

Simulated body surface potential maps (SBSPM) with isotropic and anisotropic heart models were compared to investigate the effect of myocardial anisotropy on body surface electrocardiograms at a whole heart level. Rotative fiber orientations of total 90 degrees was incorporated into an isotropic heart model. The anisotropy of conduction velocity and intracellular electric conductivity was included in the simulation. SBSPM based on epicardial, intramural, and endocardial stimulation show high correlation with fiber orientations. On the other hand, the anisotropy cannot be distinguished from the SBSPM in the simulation of normal heart model.

Anisotropy↗
PubMed1995

Comparative simulation of excitation and body surface electrocardiogram with isotropic and anisotropic computer heart models.

Comparative simulations between isotropic and anisotropic computer heart models were conducted to study the effects of myocardial anisotropy on the excitation process of the heart and on body surface electrocardiogram. The isotropic heart model includes atria, ventricles, and a special conduction system, and is electrophysiologically specified by parameters relative to action potential, conduction velocity, automaticity, and pacing. The anisotropic heart model was created by incorporating rotating fiber directions into the ventricles of the isotropic heart model. The orientation of the myocardial fibers in the ventricles of the model was gradually rotated counterclockwise from the epicardial layer to the endocardial layer for a total rotation of 90 degrees. The anisotropy of conduction velocity and intracellular electric conductivity was included in the simulation. Comparative simulations of the normal heart, LBBB, and RBBB showed no significant differences between the two models in the excitation processes of the whole heart or in the body surface electrocardiograms. However, it was easier to induce ventricular fibrillation in the anisotropic model than in the isotropic model. The comparative simulation is useful for investigating the effects of myocardial anisotropy at the whole heart level and for evaluating limitations of the isotropic heart model.

Action Potentials↗
PubMed1995

Metabolism of irinotecan to SN-38 in a tissue-isolated tumor model.

The objective of this study is to investigate the metabolism of the antitumor drug, irinotecan (CPT-11), to its active metabolite, SN-38, in tumor tissue. Using Walker 256 carcinoma, we prepared a tissue-isolated tumor model: tumor preparation was continuously perfused with Krebs-Henseleit bicarbonate buffer containing 4% bovine serum albumin (BSA) and CPT-11 (10 micrograms/ml), and the concentration of SN-38 in the perfusate was monitored using HPLC. The concentration of SN-38 in the perfusate was gradually increased to a level of 9.69 ng/ml 60 min after the start of perfusion. As a control, an aliquot of the perfusate was separately incubated; however, no significant increase in SN-38 levels was observed. At the end of the perfusion, a part of the tumor tissue was homogenized and the level of SN-38 was determined; the levels in tumor tissue were 2.2-4.5 times higher than in the perfusate. From above results, CPT-11 was found to be metabolized to its active metabolite, SN-38, in tumor tissue--a desirable feature of an antitumor prodrug.

Animals↗
PubMed1995

Pharmacokinetics of SN-38 [(+)-(4S)-4,11-diethyl-4,9-dihydroxy-1H- pyrano[3',4':6,7]-indolizino[1,2-b]quinoline-3,14(4H,12H)-dione], an active metabolite of irinotecan, after a single intravenous dosing of 14C-SN-38 to rats.

Irinotecan (CPT-11) is a camptothecin derivative used for the treatment of cancer. It is a prodrug that is metabolized to its active form, SN-38 [(+)-(4S)-4,11-diethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7]- indolizino[1,2-b]quinoline-3,14(4H,12H)-dione]. To clarify the pharmacokinetic difference between CPT-11 and SN-38, the plasma levels, tissue distribution and excretion of SN-38 were investigated after dosing rats with 14C-labeled SN-38. The plasma radioactivity showed bi-exponential decay with a terminal half-life of 9.91 h. TLC separation revealed that the plasma radioactivity consisted mainly of SN-38 at 5 min after dosing; however, it was soon replaced with SN-38 glucuronide (SN-38 Glu) and an unknown metabolite (M-2). The half-life of unchanged SN-38 after dosing with SN-38 was about 7 min, which was much shorter than that after dosing with CPT-11 (2.8 h) as reported previously. Its radioactivity was excreted mainly in feces (70.0% within 168 h), and biliary excretion (64.1% within 48 h) could account for the fecal excretion. The major component of urinary and biliary radioactivity was found by TLC to be SN-38. Whole body autoradiograms revealed that the tissue distribution of the radioactivity was low except in the liver and kidney. The radioactivity decreased rapidly and little was found in the body 24 h after dosing. In conclusion, SN-38 was excreted rapidly from bile and showed poor tissue distribution. These characteristics lead to a shorter SN-38 half-life, more so than dosing with CPT-11.

Animals↗
PubMed1995

Relation between cardiac index and regional myocardial blood flow in the non-infarcted wall using PET with 13NH3 in healed myocardial infarction.

It is not clear whether there is any relationship between cardiac output and myocardial blood flow in the infarcted heart. We measured regional myocardial blood flow (RMBF) quantitatively by positron emission tomography (PET) with 13N-ammonia at rest in 18 patients with prior myocardial infarction. RMBF was calculated using the radioactivity in myocardial tissue measured by PET and the radioactivity of arterial blood. Cardiac output was determined by the dilution method using 13NH3 as an indicator, and the relation between cardiac output and RMBF was evaluated at the same time during PET study. There was a good linear correlation between cardiac index (C.I.) and mean RMBF in non-infarcted myocardium (r = 0.45, p < 0.05), and non-infarcted size (r = 0.74, p < 0.01). There was an even better linear correlation between C.I. and sigma RMBF (representing the product of mean RMBF and non-infarcted size) as follows: y = 0.016x + 1.94, r = 0.76 (p < 0.001). It was indicated that the value of C.I. may be related to RMBF of non-infarcted myocardium and its size.

Aged↗
PubMed1995

Radical cation intermediates in N-dealkylation reactions.

1. A number of mechanistic possibilities exist for P450-catalysed N-dealkylation and have been considered over the years, including C- and N-hydroxylation and sequential electron transfer (SET). With peroxidases the evidence strongly favours SET and free radicals can be detected. Any mechanism must account for lack of incorporation of label from H218O into product by P450s and the high kinetic deuterium isotope effects that are seen in N-dealkylation reactions catalysed by peroxidases but not P450s. 2. Several lines of evidence support a role for SET in P450 amine oxidations, including Hammett analysis, products of dihydropyridine oxidations, and products of mechanism-based inhibition by strained cycloalkylamines. 3. The hypothesis was considered that the P450s act via base catalysis to deprotonate the aminium radical generated by SET, since the pKa has been estimated to be approximately 9. Dihydropyridine aminium radicals have low pKa (< 4) and are generally considered to have considerable kinetic acidity. None of the haemoproteins under consideration (including the peroxidases and haemoglobin) showed high kinetic hydrogen isotope effects for the oxidation of [4-2H]- or [4-3H]-labelled 1,4-dihydropyridines. These results are consonant with the view that P450s catalyse the deprotonation of N,N-dialkylaniline aminium radicals. 4. Since low isotope effects were seen with biomimetic metalloporphyrin models as well as P450s, the deprotonation is attributed to the (FeO)2+ entity, expected to be a strong base, and not the apoprotein. Thus, the FeO moiety of peroxidases is shielded, consistent with evidence by others that SET occurs through the porphyrin edge. Both P450s and peroxidases catalysed the oxidative N-demethylation of aminopyrine and N,N-dimethylaminothioanisole; however, only the peroxidases generated the stable coloured aminium radicals. 5. The rates of N-demethylation of variously para-substituted N,N-dimethylanilines can be used to undertake Hammett or Marcus analysis. The former yields rho = -0.6 and the latter an apparent E1/2 of approximately 1.8 for the formal (FeO)3+ entity of P4502B1. 6. Even in the oxidation of N,N-dialkylanilines, a finite rate of N-oxidation is seen (approximately 0.1% of N-dealkylation). The simplest paradigm has N-oxygenation and N-dealkylation both proceeding from a common aminium radical intermediate.

Animals↗
PubMed1995

Mechanisms of cytochrome P450 1A2-mediated formation of N-hydroxy arylamines and heterocyclic amines and their reaction with guanyl residues.

Amine oxidation reactions are catalyzed by cytochrome P450 (P450) and peroxidase enzymes; both types of enzymes appear to function via aminium radical intermediates. N-Dealkylation is favored over N-oxygenation for secondary and tertiary amines with both kinds of enzymes, but in the peroxidase-like enzymes N-oxygenation is even less favorable because of apparent restriction of the Fe-O complex in the active site. Among the rat liver P450s many of the carcinogenic primary arylamines and heterocyclic amines are N-oxygenated by P450 1A2 to form the N-hydroxy arylamine derivatives. Studies with human liver P450s also indicate that P450 1A2 plays a major role in such reactions, although some arylamines such as 4,4'-methylene-bis (3-chloroaniline) and dapsone are preferentially N-oxygenated by P450 3A4. Caffeine N3-demethylation has been developed as a useful marker of P450 1A2 levels in humans; the knowledge that P450 1A2 is the major phenacetin O-deethylase also allows insight into previous human interaction studies. 2-Ethynylnaphthalene is a useful mechanism-based inactivator of rat and rabbit P450 1A2 but not human P450 1A2 enzymes; the peptides labeled in the enzymes have been identified, along with the region in rat P450 1A2 that is modified with the photoaffinity label 4-azidobiphenyl. Microcrystals of rabbit P450 1A2 have been obtained as a first course to realizing the three-dimensional structures of these enzymes. Evidence is also presented that the major C8-guanyl DNA adducts resulting from these arylamines and heterocyclic amines in DNA may be formed via rearrangement of an initial N7-guanyl-2-arylamine adduct: reaction of N-acetoxy-2-aminofluorene with C8-methylguanine derivatives led to the formation of stable N7-substituted species, and reaction of N-acetoxy-2-aminofluorene with C8-bromoguanine yielded N-(C8-guanosinyl)-2-aminofluorene in a reaction best rationalized by such a mechanism.

Amines↗
PubMed1994

High-performance liquid chromatographic determination of the new quinolone antibacterial agent DU-6859a in human serum and urine using solid-phase extraction with photolysis-fluorescence detection.

A sensitive and specific HPLC method for the determination of DU-6859a (I), a fluoroquinolone antibacterial agent, in human serum and urine was developed. Compound I and the internal standard extracted from serum and urine by means of a Bond Elut C8 LRC cartridge showed recoveries of 96%. The extracts were chromatographed on a reversed-phase column with photolysis-fluorescence detection. This unique detection method was 42.5 times more sensitive than intrinsic fluorescence detection, the limits of detection being in 3.43 ng/ml for serum and 4.35 ng/ml for urine. In addition, I was stable in serum and urine for at least 1 month at -20 degrees C. The proposed method was sensitive and selective enough to apply to pharmacokinetic studies of I in humans after a single oral dose of 100 mg.

Anti-Infective Agents↗
PubMed1994

Determination of regional myocardial blood flow with 13N-ammonia positron emission tomography during low-grade exercise for evaluating coronary artery stenosis.

We measured regional myocardial blood flow (RMBF) by positron emission tomography (PET) with 13N-ammonia at rest and during low-grade exercise using a bicycle ergometer fixed at 25 watts for 6.5 min. The ischemic area with severe coronary artery stenosis was evaluated in terms of quantitative RMBF. The study was performed in 46 subjects consisting of 19 patients with old myocardial infarction, 20 with effort angina pectoris, and 7 normal individuals. RMBF was calculated using the radioactivity in myocardial tissue measured by PET and the radioactivity in arterial blood. The PET data were compared with coronary arteriographic findings and ECG findings. When the analysis was restricted to the anterior wall of the myocardium, it was found that exercise caused RMBF to increase by 44.9% (n = 28) in normal area, to increase by 23.3% (n = 37) in severely stenotic area (stenosis > or = 90%), and to decrease by 17.4% (n = 20) in infarcted area. When we considered only the infarcted area of the entire heart, exercise caused RMBF to decrease by 26.6% (n = 30) in the area of angiographically positive collaterals, and to increase by 0.8% (n = 31) in the area of negative collaterals. Thus, we were able to quantitate the degree of ischemia in myocardium that was associated with severe coronary artery stenosis. By application of low-grade exercise, RMBF in normal myocardium increased, while RMBF in myocardium perfused by collaterals decreased.

Adult↗