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Biomedical subjects

K Tagawa

Publications and source records attributed to K Tagawa.

At least 55 records · Page 3Linked to original sources
PubMed1995

A saturable tissue-angiotensin I converting enzyme (ACE) binding model for the pharmacokinetic analysis of imidapril, a new ACE inhibitor, and its active metabolite in human.

In order to obtain a rational explanation and analytical method of the unique pharmacokinetic behaviors of imidapril and imidaprilat in human, a new pharmacokinetic model was designed by introducing a saturable-reversible angiotensin I converting enzyme (ACE)-imidaprilat binding process and a linear imidapril-imidaprilat conversion process. According to the new model, six differential equations were given which considered the mass balance of both compounds in each component. Various pharmacokinetic parameters were estimated by the simultaneous curve fitting method using the plasma concentration data and the urinary excretion data of imidapril and imidaprilat in a multiple dosing study of healthy human volunteers. To validate the value of each parameter, this pharmacokinetic model was also applied to analyze the various plasma concentration data of both compounds in the single dosing studies with four different dosages, 2.5,5, 10, and 20 mg. Excellent curve fitting was obtained in every case, suggesting that the proposed pharmacokinetic model is applicable for predicting the plasma concentrations of imidapril and imidaprilat under various dosage conditions of clinical use.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Hypercoagulable state under low-intensity warfarin anticoagulation assessed with hemostatic markers in cardiac disorders.

The hemostatic condition under low-intensity anticoagulation in cardiac disorders is not fully elucidated. The aim of this study was to ascertain whether hemostatic molecular markers are a useful assessment for anticoagulation to detect the hypercoagulable state. A hematologic study was performed in 75 outpatients, without thromboembolic episodes, treated with low-intensity anticoagulation (average international normalized ratio [INR] 1.72) because of potential cardiac sources of arterial emboli, and in 40 age-matched control subjects. The average level of thrombin-antithrombin III complex (TAT) was significantly lower in patients than in control subjects (p = 0.005), and the mean value of D-dimer was not statistically different between patients and control subjects. Although TAT correlated moderately with D-dimer (r = 0.45, p = 0.0001), INR did not correlate with TAT or D-dimer. Elevated TAT > 3.0 ng/ml and/or D-dimer S 150 ng/ml were observed in 15 patients (20.0%), whereas the remaining 60 patients (80.0%) had no obvious increase in the level of TAT or D-dimer at overall INR. Antithrombin III activity did not correlate significantly with INR, but protein C activity and free protein S antigen showed a significant negative relation to INR (r = 0.82, r = 0.62, respectively, p = 0.0001). Low-intensity anticoagulation was sufficient to reduce coagulation and subsequent fibrinolytic activation in cardiac disorders, but may not be sufficient in some patients with elevated TAT or D-dimer concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombin III↗
PubMed1994

Beneficial effects of cyclosporine on reoxygenation injury in hypoxic rat liver.

The effect of CsA on hypoxia-reoxygenation injury was studied in perfused rat livers. CsA did not attenuate hypoxic injury, as assessed by the release of lactate dehydrogenase and mitochondrial aspartate aminotransferase. During reoxygenation, the release of lactate dehydrogenase was also not affected by CsA. However, the release of mitochondrial aspartate aminotransferase into the cytosol, which indicates mitochondrial injury, was significantly reduced by CsA. The effect of CsA on mitochondrial function during hypoxia-reoxygenation was also investigated. CsA administration increased both the respiratory control ratio and the adenine nucleotide content after reoxygenation in both isolated mitochondria and perfused livers. In addition, glucose production by perfused livers after reoxygenation was increased by CsA. We conclude that the beneficial effect of CsA on hypoxia-reoxygenation injury may be partly due to protection of the mitochondria against reoxygenation injury.

Animals↗
PubMed1994

Carbon tetrachloride increases sinusoidal efflux of reduced and oxidized glutathione in rats.

To elucidate the significance of the changes in plasma glutathione concentrations associated with carbon tetrachloride (CCl4)-induced liver damage, the changes in the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in plasma as well as in the liver were investigated in rats. In the liver, the concentration of GSH decreased, and that of GSSG increased 24 hr after the intraperitoneal administration of CCl4. In the right atrial plasma, the concentration of both GSH and GSSG increased. The GSH/GSSG ratio in the plasma decreased as did that in the liver. The net sinusoidal efflux of GSH and GSSG from the liver was calculated by subtracting their concentrations in plasma of the infrahepatic inferior vena cava from those of the suprahepatic inferior vena cava. The net efflux of GSH and GSSG started to increase as early as 3-6 hr after CCl4 administration, and reached a plateau 6 and 24 hr after CCl4 administration, respectively. On the other hand, an elongation of prothrombin time and leakage of alanine aminotransferase reached a maximum 24 and 48 hr after CCl4 administration, respectively. Vacuolization in the centri-lobular region and inflammatory infiltration started 3 and 6 hr after CCl4 administration, respectively, and progressed for 48 hr. These results suggest that CCl4 induced an increase in plasma concentrations of GSH as well as GSSG by increasing their efflux from the liver, and that the changes in plasma glutathione status might be a useful and sensitive marker for CCl4-induced liver damage.

Animals↗
PubMed1994

Endotoxin causes early changes in glutathione concentrations in rabbit plasma and liver.

The effects of endotoxin on glutathione concentrations in rabbit plasma and liver were investigated. Lipopolysaccharide (2 mg/kg) from Escherichia coli was administered intravenously to seven male Japanese rabbits. In the liver, the concentrations of reduced glutathione (GSH) started to decrease, and those of oxidized glutathione (GSSG) started to increase 1 hr after the endotoxin administration, resulting in a progressive decline in the hepatic GSH/GSSG ratio. In the arterial plasma, the concentrations of both GSH and GSSG started to increase 1 hr after the endotoxin administration. Because the increase in the concentrations of GSSG was greater than that in the concentrations of GSH, the GSH/GSSG ratio in the plasma decreased as did that in the liver. These changes in glutathione concentrations occurred simultaneously with the increase in serum osmolality, but earlier than the decrease in the arterial ketone body ratio, both of which are thought to be useful markers for liver damage. It was concluded that endotoxin induced an increase in the plasma concentrations of GSH as well as GSSG, and that the changes in plasma glutathione status might be useful markers of endotoxin-induced damage in organs, including the liver.

Animals↗
PubMed1994

Changes in biliary glutathione level during ischemia-reperfusion of rat liver.

Changes in hepatic and biliary glutathione levels were studied in rat liver treated with tert-butyl hydroperoxide (t-BuOOH) and subjected to ischemia-reperfusion. Immediately after t-BuOOH administration, the oxidized glutathione (GSSG) values and reduced glutathione (GSSG/GSH) ratio in the bile increased dose-dependently and then returned to control level within 10 min, whereas the hepatic ATP level and bile flow rate were not affected by t-BuOOH at doses of up to 1.0 mmol/kg. These data suggested that the liver remains viable on treatment with up to 1.0 mmole/kg t-BuOOH, and that hepatocytes can rapidly dismute t-BuOOH at up to this dose. The hepatic GSH and GSSG levels did not vary appreciably during ischemia for 10 or 30 min or during subsequent reperfusion, but the GSSG/GSH ratio increased after ischemia for 30 min. The rate of bile flow and the biliary level of GSH decreased after ischemia for 30 min in proportion to the decrease in the hepatic ATP level. However, the biliary GSSG concentration did not vary on reperfusion, although GSSG secretion into the bile is also related to the hepatic ATP level. As a result, the GSSG/GSH ratio in the bile increased during reperfusion after ischemia for 30 min. This increased ratio is thought to reflect oxidation of hepatic GSH by hydroperoxide produced during reperfusion. The GSSG/GSH ratio in the bile after 30 min ischemia corresponded to that observed after a small dose (0.07 mmole/kg body wt) of t-BuOOH, which hepatocytes could dismute rapidly without loss of their viability.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1994

Enzyme release from mitochondria during reoxygenation of rat liver.

Reoxygenation-induced release of mitochondrial aspartate aminotransferase (mAST) into the cytosol was studied using perfused rat liver. As the absolute activity of mAST in the perfusate did not indicate the degree of mitochondrial enzyme release, the following 3 methods were applied: measurement of the mAST to total AST ratio in the efferent perfusate, the digitonin infusion method, and measurement of mAST activity in the cytosolic compartment isolated from perfused livers. The results by all 3 methods were consistent and showed that mitochondrial injury occurs on reoxygenation. The mitochondrial Ca2+ content was proportional to the extent of mAST release during reoxygenation, indicating involvement of Ca2+ in the enzyme release. CsA, a potent inhibitor of Ca(2+)-induced increase in permeability of the mitochondrial membrane, completely prevented mAST release on reoxygenation. We conclude that during reoxygenation of hypoxic liver, mAST leaks into the cytosol in a Ca(2+)-dependent, CsA-sensitive manner.

Animals↗
PubMed1994

[Evaluation of the streptomycin twice weekly with INH and RFP for initial therapy of pulmonary tuberculosis].

For the purpose to compare the effectiveness of SM and EB as a third drug in the standard regimens and to know whether the addition of SM twice weekly to INH and RFP could be acceptable for the treatment of pulmonary tuberculosis, the efficacy, adverse effects and results of long-term follow-up of the groups consisting of 105 patients treated with SM twice weekly for 6 months in addition to INH and RFP for 9 months (S2 group) and 107 patients treated with EB for 6 months in addition to INH and RFP for 9 months (E group) were observed. The speed of negative conversion of sputum and that of X-ray findings improvement were slightly faster in S2 group than E group but the difference was statistically not significant. The incidence of adverse effects such as elevation of serum transaminase values, gastrointestinal troubles, drug allergy and others was not similar in two groups. The relapse was observed in 2 cases of S2 group and 5 cases of E group. We concluded that SM twice weekly to INH and RFP is similarly effective as EB in combination with INH and RFP, and the this regimen could be used as standard regimen for pulmonary tuberculosis.

Adult↗
PubMed1994

Increased sinusoidal efflux of reduced and oxidized glutathione in rats with endotoxin/D-galactosamine hepatitis.

The changes in the concentrations of reduced (GSH) and oxidized glutathione (GSSG) in the plasma as well as in the liver were investigated in rats with endotoxin hepatitis. Hepatitis was induced by intraperitoneal co-administration of small doses of Escherichia coli endotoxin and D-galactosamine. In the liver, the concentration of GSH decreased and that of GSSG increased 12 hr later. In the plasma taken from the right atrium, the concentration of both GSH and GSSG increased. The GSH/GSSG ratio in the plasma decreased, as it did in the liver. The net sinusoidal efflux of GSH and GSSG from the liver was calculated by subtracting their concentrations in plasma of the infrahepatic, suprarenal inferior vena cava from those of the suprahepatic inferior vena cava. The efflux started to increase as early as 2-4 hr after the injection of the toxins. In contrast, a leakage of alanine aminotransferase, an elongation of prothrombin time, an inhibition of starvation ketosis, and an increase in serum concentration of total bilirubin were detected as late as 6-8 hr after the injection. We conclude that endotoxin/D-galactosamine hepatitis induced an increase in plasma concentrations of GSH as well as GSSG by increasing the efflux of these peptides from the liver, and that changes in plasma glutathione status might be useful and sensitive markers for liver damage.

Animals↗
PubMed1993

Highly sensitive determination of imidapril, a new angiotensin I-converting enzyme inhibitor, and its active metabolite in human plasma and urine using high-performance liquid chromatography with fluorescent labelling reagent.

A method for the simultaneous determination of imidapril and its active metabolite in human plasma and urine has been developed using high-performance liquid chromatography with a fluorescent labelling reagent, 9-anthryldiazomethane. Imidapril and its active metabolite were extracted from human plasma and urine using a solid-phase extraction cartridge (Bond Elut C18). Two compounds in the eluate were derivatized with 9-anthryldiazomethane and purified with a solid-phase extraction cartridge (Bond Elut SI). The derivatives were analysed using high-performance liquid chromatography with fluorometry. The detection limits of imidapril and its active metabolite were 0.2 ng/ml in plasma and 10 ng/ml in urine. This method could be applied to the pharmacokinetic study of imidapril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Isolation of mitochondrial cyclophilin from bovine heart.

Peptidyl-Prolyl cis-trans isomerase was isolated from bovine heart mitochondrial matrix. The enzyme has a M(r) of 19,000 and its activity was inhibited by cyclosporin A (inhibition constant, 6.9 nM), but not by FK-506. The mitochondrial content of the enzyme is in good agreement with the number of binding sites for cyclosporin A (85 pmol/mg of matrix protein). Partial amino acid sequencing showed that the enzyme has a serine-rich N-terminal extension and is similar to human cyclophilin 3 (Bergsma et al. (1991) J. Biol. Chem. 266, 23204-23214) rather than the cytosolic and endoplasmic reticulum isoforms. We conclude that this protein is mitochondrial cyclophilin and a homologue of human cyclophilin 3.

Amino Acid Isomerases↗
PubMed1993

Ca(2+)-induced, phospholipase-independent injury during reoxygenation of anoxic mitochondria.

Reoxygenation of rat-liver mitochondria after anoxic incubation induced release of matrix proteins. As assessed by release of a matrix enzyme, it was proportional to the rate of H2O2 production. The release was not observed with low concentrations of extramitochondrial free Ca2+, indicating a Ca(2+)-dependent pathway. Phospholipase A2 was not involved in the reoxygenation injury, because non-esterified fatty acids did not increase on reoxygenation even when re-acylation was inhibited and because inhibitors of phospholipase A2 had little effect on enzyme release. Cyclosporin A, ATP, ADP and inhibitors of pyridine nucleotide oxidation had a protective effect, strongly suggesting involvement of so-called Ca(2+)-dependent permeability transition. Ca2+ was also released from reoxygenated mitochondria and inhibition of reuptake of released Ca2+ attenuated the enzyme release. Similar releases of aspartate aminotransferase and Ca2+ were observed with mitochondria in an oxygen radical-generating system, hypoxanthine and xanthine oxidase. In this system, lecithin-cardiolipin liposomes also released entrapped Ca2+ without disruption of the membrane. From these results, we conclude that during reoxygenation, Ca2+ release and subsequent reuptake induced permeability transition of mitochondria, resulting in reoxygenation injury.

Animals↗
PubMed1993

A case of chronic pancreatitis complicated by massive pericardial and right pleural effusion.

A 42-year-old man was admitted complaining of dyspnea. Chest X-ray showed an increase in cardiac size, and echocardiography revealed a large volume of pericardial effusion. Pancreatic enzyme levels were elevated in both serum and pericardial effusion. Computed tomography and endoscopic retrograde pancreatography demonstrated a fistula connecting a pancreatic pseudocyst with the pericardium and the right pleural cavity. Massive pericardial and right pleural effusion is an extremely rare complication of chronic pancreatitis. In this case, computed tomography and endoscopic retrograde pancreatography were useful for diagnosing the fistula.

Adult↗
PubMed1993

Inhibitory spectra of purified protease nexin-II and related proteins towards cellular proteinases.

Amyloid beta protein (beta/A4) is deposited in senile plaques of patients with Alzheimer's disease. This protein is derived from a larger membrane-associated protein, termed amyloid precursor protein (APP). The constitutive processing of APP occurs at the central portion of beta/A4, resulting in the release of large N-terminal peptides. We have purified these peptides from the culture medium of cDNA-transfected COS-1 cells. Some of the isoforms contain the Kunitz-type protease inhibitor (KPI) domain and strongly inhibit trypsin, chymotrypsin and plasmin, but do not inhibit kallikrein, prolyl endopeptidase or granzyme A. The peptides also do not inhibit cysteine proteases such as cathepsin B or calpain. Soluble APPs lacking the KPI domain fail to inhibit any of these proteases. The results indicate that the KPI domain in soluble APPs has protease inhibitory activity against certain serine proteases.

Amino Acid Sequence↗
PubMed1993

Mechanism of mitochondrial enzyme leakage during reoxygenation of the rat heart.

OBJECTIVE: The aim was to clarify the factors that induce enzyme release from mitochondria during anoxia and reoxygenation. METHODS: Isolated perfused hearts or isolated mitochondria were prepared from hearts excised from rats. The amounts of lactate dehydrogenase, cytoplasmic aspartate aminotransferase, and mitochondrial aspartate aminotransferase released into the coronary effluent from perfused heart preparations were measured. To distinguish the effect of mechanical stress from that of reoxygenation, a latex balloon was placed in the left ventricular cavity to impose mechanical stress and the heartbeat was controlled with a high K+ medium. A digitonin infusion technique was used to obtain only the cytosolic compartment of the cells for analysis of the amounts of mitochondrial enzymes released into the cytosol. The effect of anoxia followed by reoxygenation on enzyme release from isolated mitochondria was studied. RESULTS: On reoxygenation, mitochondrial aspartate aminotransferase was released as well as cytoplasmic enzymes, but, unlike cytoplasmic enzymes, the release was not influenced by mechanical stress. Mitochondrial injury by reoxygenation depended on the duration of the preceding anoxia. Reoxygenation of isolated mitochondria also induced enzyme release and the presence of ATP in the extramitochondrial space reduced the release of this enzyme. CONCLUSIONS: Enzyme leakage from mitochondria of myocardial cells occurs during reoxygenation, irrespective of mechanical stress, and this vulnerability to oxidative stress depends on the duration of the preceding anoxic period or the concentration of cytosolic ATP.

Adenine Nucleotides↗