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Biomedical subjects

M Sekiguchi

Publications and source records attributed to M Sekiguchi.

At least 757 records · Page 42Linked to original sources
PubMedDate not supplied

Pharmacokinetics of droloxifene in mice, rats, monkeys, premenopausal and postmenopausal patients.

The pharmacokinetics of droloxifene have been studied in female mice, rats, monkeys, and premenopausal and postmenopausal patients. Droloxifene was rapidly and almost completely absorbed after oral dosing. The bioavailability was 8% in mice, 18% in rats and 11% in monkeys due to extensive first-pass metabolism. Droloxifene is widely distributed as demonstrated by its large volume of distribution and the fact that radioactivity in most tissues and organs was higher than in the blood. After oral dosing, the serum and plasma concentrations of unchanged drug declined with terminal half-lives of 1.6 h in mice, 4.3 h in rats, 10.6 h in monkeys and 25 h in patients. The systemic clearance was in the order of mice > rats > monkeys, and nearly equalled the hepatic blood flow in each species. Most of the 14C from [14C]-droloxifene administered orally and i.v. to rats and monkeys was excreted in the faeces. Droloxifene was metabolized extensively by phase I and phase II metabolism. 3-methoxy-4-hydroxy droloxifene was the major metabolite in rat faeces. The metabolites in rat and monkey faeces were not so different qualitatively. Pharmacokinetic parameters were not significantly different between premenopausal and postmenopausal patients.

Adult↗
PubMedDate not supplied

Immunohistochemical localization of endothelin in human vascular endothelial cells.

The cellular localization of endothelin (ET), a novel vasoconstrictor peptide, was studied in human vascular tissues by immunohistochemistry. Distinct and diffuse staining for ET-like immunoreactivity was demonstrated in the cytoplasm of vascular endothelial cells, but not in smooth muscle cells or adventitial fibroblasts. The specificity was confirmed by the negative results following immunoabsorption. These findings suggest that human vascular endothelial cells function as an endocrine and/or paracrine cells for ET secretion.

Adult↗
PubMedDate not supplied

Metabolic and morphological changes of the heart in Chinese hamsters (CHAD strain) with spontaneous long-term diabetes.

We studied the effect of spontaneous long-term (9-10 months) diabetes on the heart of Chinese hamsters (CHAD strain) to elucidate the relationship between diabetes mellitus and cardiomyopathy. The diabetic hamsters, aged approximately 11 months, showed body weight loss, hyperglycemia (mean fasting plasma glucose 402 mg/dl), hypoinsulinemia, hyperlipidemia and ketonemia. The diabetic hamsters showed reduced activities of cytoplasmic glycolytic key enzymes; hexokinase, pyruvate kinase and phosphofructokinase, increases in cardiac glycogen and glucose-6-phosphate contents and a 40% decrease in cardiac ATP content, indicating decreased energy production. An accumulation of myocardial triglyceride and cholesterol was found in the diabetic hamsters. In addition, the cardiac norepinephrine content was increased in the diabetic hamsters, suggesting the presence of autonomic nervous disorder. Increased heart weight and thickening of the septum and both ventricular walls were found in the diabetic hamsters. Light-microscopic analysis revealed that 42.9% of the diabetic hamsters had myocardial degeneration without any vascular lesion of extramural large and intramural small vessels, whereas the non-diabetic controls had no myocardial or vascular lesions. These data suggest that the diabetic Chinese hamsters had cardiomyopathy, which is possibly caused by extravascular factors such as metabolic or autonomic nervous disorder although conclusive evidence is lacking.

Animals↗
PubMedDate not supplied

Enhanced embryonic nonmuscle myosin heavy chain isoform and matrix metalloproteinase expression in aortic abdominal aneurysm with rapid progression.

Abdominal aortic aneurysms (AAAs) are characterized by structural deterioration of aortic wall leading to progressive dilatation. The histopathological changes in AAAs are particularly evident within the elastic media, which is normally comprised mainly of vascular smooth muscle cells (SMCs). There are vascular myosin heavy chain (MHC) isoforms; SM2 is specifically expressed in differentiated SMCs and SMemb is a nonmuscle-type MHC abundantly expressed in SMCs of the fetal aorta with an immature phenotype. Although AAA altered expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), pathophysiological role of SMC phenotypic modulation in the AAA progression remains uncertain. To determine whether phenotypic modulation in vascular SMCs contributes to arterial medial degeneration, we examined MHC expression in SMCs of AAA. Aortic specimens were obtained from patients with slowly progressed AAA (n = 12) and rapidly progressed AAA (n = 5), and compared with normal aortic tissue (n = 3). Immunohistochemical staining was performed for detection of SMemb, SM2, MMP (types 2 and 9) and TIMP (types 1 and 2). Faint SMemb and abundant SM2 were observed in normal aorta, while the balance shifted to SMemb predominance in AAAs. Compared with slowly progressed AAA tissue, rapidly expanded AAA tissue demonstrated marked increases in SMemb expression with suppressed SM2. Predominant SMemb expression indicates presence of phenotypic modulated SMCs and enhanced MMP; while abundant TIMP was seen in mature SMCs expressing SM2. SMemb expression is markedly increased in AAA with MMP enhancement, and a significant imbalance between SMemb and SM2 results in rapid progression of AAA.

Aged↗
PubMedDate not supplied

An ultrastructural study of cardiac myocytes in postmyocardial infarction ventricular aneurysm representative of chronic ischemic myocardium using semiquantitative and quantitative assessment.

To elucidate the characteristic myocytic changes in chronic ischemic myocardium, an electronmicroscopic (EM) study was carried out in surgically excised postmyocardial infarction left ventricular aneurysm (LVAN) (n = 15) using semiquantitative (in all 15 cases) and quantitative assessment methods (in 10 cases). The control group, representing normal ultrastructure, included left ventricular endomyocardial biopsy specimens of sick sinus syndrome (SSS) (n = 3), Wolff-Parkinson-White (WPW) Syndrome (n = 1), and intraoperative left ventricular endomyocardial biopsy in mitral stenosis (MS) (n = 3). Myocardial condition was assessed at the ultrastructural level according to the severity of morphologic changes, first semiquantitatively, thereafter with the use of the Image Processor-Analyzer LUZEX III for morphometric analysis. The most marked EM findings were mitochondrial regressive changes, glycogen accumulation, nuclear deformities, increased rough-surfaced endoplasmic reticulum at the perinuclear portion, lysis of myofibrils, and myofibrillar degeneration. The quantitative analysis revealed significant (p < 0.05) increase of glycogen deposition, only at the perinuclear portion in the LVAN group. The myofibril to mitochondria ratio at the intercalated disc (ID) portion of the cardiac myocytes significantly increased (p < 0.01) in the LVAN group as compared with the normal control group. Light microscopically evaluated quantitative analysis, using toluidine-blue stained semithin sections which underwent EM observation, showed that the fractional area of interstitial fibrous tissue was significantly increased in the LVAN group compared to the normal controls (p < 0.01). These results signify that in chronic ischemic myocardium, decreased consumption of glycogen in oxidative phosphorylation occurs in the surviving myocytes, and that hypertrophy of the myocytes appears. The results of this study may lead to the proper ultrastructural interpretation of biopsied human myocardium, regardless of etiology.

Adult↗
PubMedDate not supplied

A new type of cross-hatched wedged grid for biplanar serial angiography of the abdomen.

In an attempt to obtain an improved image in serial abdominal angiography, two new types of linear and cross-hatched grids were designed, called respectively the wedged grid and cross-hatched type of wedged grid. The grid ratio of the wedged grid ranges continuously from 12:1 to 8:1 from edge to edge. The cross-hatched wedged grid is a combination of two grids. The upper part is a linear wedged grid with a grid ratio ranging from 12:1 to 5:1. The lower part is a linear grid with a grid ratio of 5:1. The individual grids are placed at right angles to each other. Hence, the grid ratio of this combination ranges from 17:1 to 10:1. By using the special cross-hatched wedged grid, satisfactory biplanar abdominal angiography can be performed without significantly increasing radiation dosage.

Angiography↗
PubMedDate not supplied

A severe hepatic disorder with myelodysplastic syndrome, treated with cytarabine ocfosfate, in a dog.

An 8-year-old female Shih Tzu was presented with weight loss and vomiting. Alanine aminotransferase was high and abdominal radiographs revealed hepato- and splenomegaly. Mild anaemia, neutrophilia with left shift, eosinophilia, a thrombocytosis with dysplastic features of eosinophils and platelets, were detected. The animal was initially considered to have hepatitis and was treated accordingly, but clinical signs persisted. Histological examination of liver biopsy samples showed disruption of the hepatic lobule, with extensive infiltration by haemopoietic cells. Further investigation of the bone marrow suggested a diagnosis of myelodysplastic syndrome. The animal was treated with cytarabine ocfosfate, a prodrug of cytosine arabinoside, and appeared to recover.

Animals↗
PubMedDate not supplied

Effects of intravenous disopyramide on coronary hemodynamics and vasodilator reserve in hypertrophic obstructive cardiomyopathy.

Disopyramide reduces the subaortic pressure gradients and improves the clinical symptoms of patients with hypertrophic obstructive cardiomyopathy. Changes in coronary hemodynamics and vasodilator reserve in response to this agent have not been evaluated in such patients. To assess the acute effects of intravenous administration of disopyramide on coronary hemodynamics, microvascular dilatory capacity, and balance between myocardial oxygen supply and demand in hypertrophic obstructive cardiomyopathy, we examined 12 patients using an intravascular Doppler catheter and spectral analysis. Intravenous disopyramide 100 mg over 10 min caused mild increases in heart rate and aortic systolic pressure and a significant fall in left ventricular systolic pressure, resulting in a 13% decrease in the product of heart rate and left ventricular systolic pressure (from 1.13 +/- 0.18 x 10(4) before disopyramide to 0.98 +/- 0.17 x 10(4) beats/min x mm Hg 10 min afterwards; p < 0.05) and a reduction in the resting peak systolic pressure gradients of the left ventricular outflow tract. There was a 14% reduction in coronary blood flow (from 93.5 +/- 13.2 to 80.3 +/- 11.6 ml/min; p < 0.05) with an increase in coronary resistance (from 0.94 +/- 0.16 to 1.23 +/- 0.21 mm Hg/ml/min; p < 0.001). The index of coronary vasodilator reserve remained unchanged. These findings suggest that intravenous disopyramide causes a coronary vasoconstrictive effect without significantly changing the coronary microvascular dilatory capacity, but this effect may not be harmful to the balance between myocardial oxygen supply and demand in patients with hypertrophic obstructive cardiomyopathy.

Adult↗
PubMedDate not supplied

Toxicological evaluation and disposition of DV-7751a, a new quinolone antimicrobial agent, administered orally to dogs and monkeys.

We examined the toxic potentials and disposition of DV-7751a administered repeatedly to immature beagle dogs and mature cynomolgus monkeys. In immature dogs (n = 3) orally given DV-7751a at 5, 10 and 15 mg/kg for 8 days, arthropathy in the femur of a dog receiving 15 mg/kg was observed at termination, but not at the lower doses. Serum concentrations at 2-6 h after the 7-day treatment were 0.8-1.5, 1.2-2.1 and 1.0-2.9 micrograms/ml at 5, 10 and 15 mg/kg, respectively. In mature monkeys (n = 3) treated orally with DV-7751a at 100 mg/kg for 14 days, no toxic effects were found except for mild diarrhea throughout the experiment. Serum concentrations at 2 to 4 h after the final treatment were 8.3 to 11.4 micrograms/ml. In both species, there were no significant differences in the serum drug concentration between the first and last (repeated) administration, indicating no drug accumulation. In monkeys, hydrolysis of the urine sample showed no effect on the concentration of DV-7751a, whereas that of the bile sample displayed a significant increase in its concentration, demonstrating that conjugated forms may be secreted into bile. This was confirmed by a thin-layer chromatogram-bioautogram, and at least two kinds of active metabolites including a polar substance seemed to exist in bile. These results raise the possibility that DV-7751a possesses joint toxicity, but dose not show any effect on the hepatic function under conditions of this study.

Administration, Oral↗
PubMedDate not supplied

Erythropoietin mRNA in hepatocellular carcinomas and kidney in male B6C3F1 mice with secondary polycythemia.

The purpose of this study was to investigate the cause of polycythemia occurring in hepatocellular carcinoma-bearing control male B6C3F1 mice from 2-yr carcinogenicity studies. Erythrocyte counts and plasma levels of erythropoietin in mice with hepatocellular carcinomas were significantly increased compared with the values in non-tumor-bearing mice. Erythropoietin mRNA in 4 of 5 non-tumor-bearing mice was detected in the kidney, but no visible signals for hepatic erythropoietin mRNA in 5 of 5 non-tumor-bearing mice were detected by the reverse transcriptase competitive polymerase chain reaction method. Erythropoietin mRNA was expressed in neoplastic hepatocytes from 8 of 9 hepatocellular carcinoma-bearing mice, and this expression was accompanied by decreased expression of erythropoietin mRNA in the kidneys from these mice. The present findings show that polycythemia in hepatocellular carcinoma-bearing mice occurs secondary to excess synthesis of erythropoietin mRNA by neoplastic hepatocytes.

Animals↗