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Biomedical subjects

K Harada

Publications and source records attributed to K Harada.

At least 487 records · Page 27Linked to original sources
PubMed1996

Comparison of the antagonistic activity of tamsulosin and doxazosin at vascular alpha 1-adrenoceptors in humans.

alpha 1-Adrenoceptor blockers such as prazosin and doxazosin are used to treat hypertension as well as benign prostatic hyperplasia (BPH), whereas the new alpha 1-adrenoceptor blocker tamsulosin is used only for BPH and does not reduce blood pressure at the doses used to relax prostatic smooth muscle. In contrast to prazosin, tamsulosin has a higher affinity for prostatic than vascular alpha 1-adrenoceptors in vitro. The functional correlate of this observation in humans is the subject of this study. The alpha 1-adrenoceptor blockade by oral tamsulosin (0.2 mg), doxazosin (1 mg) or placebo on finger tip vascular and dorsal hand venous alpha 1-adrenoceptors stimulated by cold treatment (immersion in ice water) and the alpha 1-adrenoceptor agonist phenylephrine, was thus studied in a 3-way crossover study in eight, healthy, male adults. Finger tip vasoconstriction after cold stimulation was assessed by laser Doppler flowmetry. A linear variable differential transformer was used to assess the drug effect on phenylephrine-induced venoconstriction. All study parameters were assessed at around 2 and 3.5 h after oral intake of doxazosin and tamsulosin respectively. The drug plasma levels were not significantly different. No significant differences were found for blood pressure or heart rate in the three treatments in supine and erect position. The reduction in finger tip blood flow after cold stimulation was significantly smaller after doxazosin treatment (P < 0.01) than after tamsulosin or placebo, whereas there was no significant difference between tamsulosin and placebo treatments. The infusion rate of phenylephrine producing a half-maximum venoconstriction was significantly larger after doxazosin than after tamsulosin (P < 0.05) or placebo (P < 0.01), whereas there was again no significant difference between tamsulosin and placebo treatments. The data suggest that, at doses producing equal plasma levels after single oral doses in human subjects, the blocking activity at vascular alpha 1-adrenoceptors is lower for tamsulosin than for doxazosin.

Administration, Oral↗
PubMed1996

Effect of alpha 1-adrenoceptor antagonists, prazosin and urapidil, on a finger skin vasoconstrictor response to cold stimulation.

OBJECTIVES: Cold stimulation causes a finger skin vasoconstrictor response, which is regulated by stimulation of alpha-adrenergic receptors and is reduced by administration of prazosin. The purpose of this study was to investigate, using a laser Doppler flowmeter, whether the decrease in the finger skin vasoconstrictor response to cold stimulation produced by administration of two different alpha 1-adrenoceptor antagonists, prazosin and urapidil, was correlated with the corresponding plasma drug concentration, and whether this method could be used to evaluate the relative potency of these alpha 1-adrenoceptor antagonists in human subjects. METHOD: In thirteen healthy male subjects (20-42 y), finger tip skin blood flow was measured during cold stimulation before and 1, 2, 3, 6, and 9 h after administration of placebo, prazosin (1 mg) or urapidil (60 mg). RESULTS: Both prazosin and urapidil significantly decreased the vasoconstrictor response to cold stimulation. The degree of the decrement in the response indicated by the reduction ratio was significantly correlated with the plasma concentration of prazosin and urapidil. The alpha 1-adrenoceptor blocking activity of prazosin estimated by the regression lines was about 130-times more potent than that of urapidil. CONCLUSION: These findings suggest that the cold stimulation response of finger skin vasoconstriction may be used to evaluate the relative alpha 1-adrenoceptor blocking potency of drugs.

Administration, Oral↗
PubMed1996

Influence of age on venodilator effect of isoproterenol and amrinone.

OBJECTIVE: To investigate the influence of age on the venodilator effect of isoproterenol, a beta-adrenoceptor agonist, and amrinone, a selective phosphodiesterase (PDE) III inhibitor, in human subjects. METHODS: In eight young and eight elderly male subjects, the drugs were infused into a dorsal hand vein preconstricted with phenylephrine and its diameter was measured using a linear variable differential transformer. RESULTS: The maximum venodilation (Emax) induced by isoproterenol was significantly smaller and the infusion rate of isoproterenol required to induce 50% of maximum venodilation (ED50) was significantly larger in the elderly than in the young subjects [Emax: 29.8 vs 95.1%, ED50: 97.3 vs 51.6 ng.min-1]. A significant age-related change in Emax or ED50 was not observed for amrinone (Emax: 95.8 vs 100.8%, ED50: 40.1 vs 31.6 micrograms.min-1). CONCLUSION: The data show that the venodilator effect of amrinone is not influenced by age. As amrinone increases cyclic AMP by inhibition of PDE III, it is suggested that the action of cyclic AMP is not altered by age. The decreased effect of isoproterenol might be caused by reduced production of cyclic AMP in elderly subjects.

Adrenergic beta-Agonists↗
PubMed1996

Effect of ranitidine on renal clearance of lomefloxacin.

OBJECTIVE: To examine the effect of ranitidine on the renal clearance of lomefloxacin. SETTING: Department of Clinical Pharmacology, Jichi Medical School. METHODS: Lomefloxacin 200 mg and ranitidine 300 mg or its placebo were given orally in a randomised, double-blind, crossover design. Blood and urine samples were obtained during a 24-h period after dosing. RESULTS: The area under the plasma concentration-time curve and the elimination half-life of lomefloxacin were significantly increased following coadministration with ranitidine. These effects were caused by significant decreases in total (7.8%) and renal (22%) clearance of lomefloxacin. In contrast, creatinine clearance and urinary excretion of electrolytes were not influenced by ranitidine. CONCLUSION: As lomefloxacin and ranitidine are excreted in urine by renal tubular secretion, the present results suggest that the renal tubular secretion of lomefloxacin is diminished by ranitidine. As the reduction in lomefloxacin clearance is only marginal, it is probable that the drug interaction observed in this study is not of clinical significance.

Adult↗
PubMed1996

Morphological study of endothelin-1-induced contraction of cultured hepatic stellate cells on hydrated collagen gels.

Hepatic stellate cells become activated and aquire contractility on being cultured. In order to characterize the morphology of contracted and relaxed stellate cells, we performed light- and electron-microscopic analyses of cultured stellate cells on collagen gels. Incubation of stellate cells with medium alone, 10 nM endothelin (ET)-1, or 1 mM N6,2' dibutyryladenosine 3':5'-cyclic monophosphate (dBcAMP) for 48 h induced contraction of the underlying collagen gels to 83%, 57%, and 97%, respectively, of their original size. Stellate cells relaxed by dBcAMP exhibited a round cell body and extended several long thin cytoplasmic processes with several varicosities. Culture with ET-1 accelerated spreading of the stellate cells on collagen gels and decreased the number of processes. Each such flattened stellate cell attached itself to the underlying collagen matrix by bending its cell body. Collagen fibers around the cell were pulled toward the cell and stretched. Thus, the present study has revealed that ET-1-stimulated cultured stellate cells adduct associated collagen fibers by the retraction of cytoplasmic processes and the bending of their spread cell bodies.

Animals↗
PubMed1996

Mass spectrometric screening method for microcystins in cyanobacteria.

A screening method for microcystins in cyanobacteria, which consists of the formation of 3-methoxy-2-methyl-4-phenylbutyric acid as an oxidation product of microcystins by ozonolysis, and detection of 3-methoxy-2-methyl-4-phenylbutyric acid by thermospray-liquid chromatography/mass spectrometry or electron ionization-gas chromatography/mass spectrometry using selected ion monitoring, was developed. The ozonolysis made it possible to significantly reduce the formation times of 3-methoxy-2-methyl-4-phenylbutyric acid because the previously required extraction, clean-up and other procedures could be entirely eliminated. The resulting intact 2-methyl-4-phenylbutyric acid was directly analyzed by thermospray-liquid or electron ionization-gas chromatography/mass spectrometry, and the procedures from ozonolysis to analysis of microcystins at the pmole levels were performed within only 30 min. The calibration curves obtained by thermospray-liquid or electron ionization-gas chromatography/mass spectrometry analysis showed a linear relationship from 14 to 830 pmole and from 2.5 to 100 pmole of microcystin-LR, respectively. The method was applied to the detection and determination of the total amount of microcystins in bloom and cultured samples, showing that it provided a means of not only screening for microcystins but of their accurate quantitation.

Calibration↗
PubMed1996

Dobutamine stress echocardiography for detection of coronary artery stenosis in children with Kawasaki disease.

OBJECTIVES: This study was designed to assess the feasibility and diagnostic accuracy of dobutamine stress echocardiography for detection of coronary artery stenosis in children with Kawasaki disease. BACKGROUND: Dobutamine stress echocardiography is valuable as an alternative test for detection of coronary artery disease in adult patients; however, its usefulness for children has been demonstrated only in limited cases. METHODS: Dobutamine stress echocardiography (up to 30 microgram/kg body weight per min) was performed in 50 patients at the convalescent stage of Kawasaki disease, including 26 patients with coronary sequelae documented by previous coronary angiography (sequelae group, 3 to 15 years old) and 24 patients with normal coronary arteries documented by echocardiography (normal group, 7 to 16 years old), who underwent quantitative coronary angiography on a separate day. Left ventricular regional wall motion divided into 16 segments was assessed in relation to the extent of coronary artery disease. A positive test response was defined as a new or worsened wall motion abnormalities. RESULTS: Significant coronary artery disease (> or = 50% diameter stenosis of major vessels) was present in 21 patients in the sequelae group. There was no significant difference in the maximal dose of dobutamine between the sequelae and normal groups ([mean +/- SD] 22.4 +/- 5.1 vs. 24.2 +/- 2.5 microgram/kg per min). Heart rate and systolic blood pressure were significantly increased (p < 0.01) at maximal dose of dobutamine compared with values at rest in both groups; consequently, the rate-pressure product exceeded 20,000 in 20 (40%) of the 50 patients during dobutamine infusion. Ten patients had self-limiting side effects; however, there were no serious complications from stress-induced ischemia. New wall motion abnormalities corresponding to the extent of coronary artery disease were detected in 19 of 21 patients in the sequelae group, whereas no wall motion abnormalities were detected in the normal group. Thus, the sensitivity and specificity of dobutamine stress echocardiography for the detection of coronary artery disease were 90% and 100%, respectively. CONCLUSIONS: We conclude that dobutamine stress echocardiography is a safe and accurate diagnostic method for detection of coronary artery stenosis in Kawasaki disease. Moreover, this is a possible alternative method for patients unable to exercise adequately, even if they are small children.

Adolescent↗
PubMed1996

MR findings and neurologic manifestations in Lowe oculocerebrorenal syndrome.

Two patients with oculocerebrorenal syndrome are described. Both had abnormal findings on electroencephalography and developed seizure episodes. Although Patient 2 manifested abnormal electroencephalographic findings at the age of 6 years, he did not develop seizures until the age of 9 years. Phenytoin was effective for controlling seizures in both patients. On magnetic resonance examination, there were two different types of lesions. The first lesion manifested high intensity on both T2- and proton density-weighted images, suggesting gliosis or demyelination. The second lesion manifested definitely low signals on both T1- and proton density-weighted images, implying a cystic lesion. However, these lesions on magnetic resonance examination were not correlated with the severity of clinical manifestations.

Adolescent↗
PubMed1996

A keratin K14 gene mutation in a Japanese patient with the Dowling-Meara type of epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is caused by an aberration of the keratin intermediate filaments and recent studies indicated causal mutations in the keratin K14 and K5 genes. In this study, we examined keratin K14/5 gene mutation in a Japanese patient with EBS Dowling-Meara (EBSDM). The patient had a C to T transition at the first position of codon 125, which resulted in Arg-->Cys at the N-terminus of the rod domain in the keratin K14 gene. The mutation position described here was identical to those reported in some other EBSDM patients. Our result revealed mutation in the peptide initiating helical structure of keratin K14 and, together with the results of other workers, suggests that the mutation in the keratin K14 gene of EBSDM sufferers occurs in virtually every ethnic group and geographical area.

Alleles↗
PubMed1996

Detection of transforming growth factor-alpha protein and messenger RNA in hepatobiliary diseases by immunohistochemical and in situ hybridization techniques.

Transforming growth factor-alpha (TGF-alpha) is a cytokines related to cell proliferation and transformation. Immunoreactive TGF-alpha protein is expressed in regenerating hepatocytes and interlobular bile ducts as well as in hepatocellular carcinoma. Although TGF-alpha is thought to play an important role in the intrahepatic biliary tree, its role in cellular physiology is poorly understood. This study investigates the expression of TGF-alpha and its messenger RNA (mRNA) in various hepatobiliary diseases. The authors showed by immunohistochemistry that TGF-alpha and its receptor, epidermal growth factor receptor (EGFR), were expressed in interlobular bile ducts, proliferating bile ductules, and most hepatocytes in various hepatobiliary liver tissues. They also showed by Western blot analysis that TGF-alpha protein was present in hepatic bile samples obtained from patients with obstructive jaundice. In situ hybridization showed that TGF-alpha mRNA was localized in hepatocytes of some pathological liver tissues, but it was absent in biliary epithelial cells of the same tissues. These findings suggest that TGF-alpha protein is produced by hepatocytes, and hepatocyte stimulation occurred as autocrine growth regulation. The release of TGF-alpha into hepatic bile caused biliary proliferation and transformation through EGFR, present on the existing cell surface membrane of biliary epithelial cells.

Bile↗
PubMed1996

New approach for the treatment of medulloblastoma by transfection with glial fibrillary acidic protein gene.

Glial fibrillary acidic protein (GFAP) is one of the intermediate filaments found in mature normal astrocytes and differentiated glioma cells. It seems to be able to stabilize the cytoskeleton of the astrocyte and may play a role in maintaining astrocyte cell shape, in association with other cytoskeletal components such as microfilaments and microtubles. However, its tissue-specificity remains unclear. To clarify the effect of GFAP expression in brain tumour cells, transfer of the GFAP gene into the human medulloblastoma cell line, DAOY-1 (which does not express GFAP) was carried out using liposomes. Upon transfection, we observed the alterations in the characteristics of GFAP transfected cells. Cell growth, morphology and sensitivity to anticancer drugs were compared between GFAP gene transfected DAOY-1 and control DAOY-1 cells. Growth inhibition and increase of sensitivity to anticancer drugs were observed with GFAP expression in GFAP gene-transfected DAOY-1 cells. However, no morphological changes were noted.

Brain Neoplasms↗
PubMed1996

Detection and identification of metabolites of microcystins formed in vivo in mouse and rat livers.

The hepatic metabolism of microcystins (MCs), potent cyclic peptide hepatotoxins produced by cyanobacteria, was studied by i.p. injection in mice and rats. An immunoaffinity purification method using an anti-MC-LR monoclonal antibody showed a remarkable effect on the removal of contaminants in the hepatic cytosol and enabled us to analyze MCs and their metabolites by HPLC and Frit-FAB LC/MS. At 3, 6, and 24 h post-injection of MC-RR, a small percent of the applied dose was detected in all of the mouse livers together with several metabolites. Among them, GSH and Cys conjugates of MC-RR were identified at 3 and 24 h, respectively, by comparison with the chemically prepared standards, indicating that the thiols of GSH and Cys nucleophilically bound to the Mdha moiety of MCs. Another metabolite was presumed to be formed by both epoxidation followed by hydrolysis and sulfate conjugation in the Adda moiety and GSH conjugation in the Mdha moiety. In rat livers, MC-LR showed almost the same behavior as that of MC-RR in mouse livers. These results suggest that the conjugation of GSH with MCs may play a role in the metabolic pathway leading to detoxification of MCs.

Animals↗
PubMed1996

Covalent binding between bucillamine derivatives and human serum albumin.

PURPOSE: To clarify the mechanism of covalent binding between human serum albumin (HSA) and drugs containing thiol groups, we studied the interactions between HSA and bucillamine (BA) and its derivatives. METHODS: To determine the concentration of HSA-drug conjugate, we used columns of N-methylpyridium polymer cross-linked with ethylene glycol dimethacrylate (4VP-Me), and analyzed the reaction between HSA and BA derivatives kinetically. Following pseudo first-order reaction kinetics, the rate constants of reduction of non-mercaptoalbumin (HNA) to mercaptoalbumin (HMA) (ka) and formation of HSA-drug conjugate (kc) were determined. RESULTS: Formation of HSA-drug conjugate was observed only for drugs containing one thiol group. In compound IV, the plots of ka and kc against pH were found to be linear. The HSA-drug conjugate was affected by various factors such as pKa, pH, temparture and the microenviroment of Cys34. The increases in ka and kc against pH were mainly due to the increase in mercaptide ion concentration. Further, fatty acid affected the microenviroment of Cys34, which increased HSA-drug formation. CONCLUSIONS: Cys34 located in a crevice on the surface of the protein plays an important role on the formation of HSA-drug conjugate. These results may be useful for elucidating the reaction mechanisms between various proteins and thiol compounds.

Cysteine↗
PubMed1996

Doppler echocardiographic findings of indomethacin-induced occlusion of the fetal ductus arteriosus.

We present an unusual case of indomethacin-induced occlusion of the fetal ductus arteriosus, which occurred in one of twins. In fetal echocardiography, the characteristic findings, a to and fro regurgitation pattern at pulmonary valve and postvalvular dilation of the main pulmonary artery, were obtained in addition to right ventricular dilation and hypertrophy, tricuspid regurgitation, right atrium dilation, and pericardial effusion. This fetus developed fetal distress and was delivered by an emergency cesarean section at 35 weeks' gestation. We suggest that these fetal echocardiographic findings may be the end-stage signs of the fetal ductal occlusion as well as the signs for emergent delivery.

Adult↗
PubMed1996

Kinetic study of racemization of aspartyl residues in model peptides of alpha A-crystallin.

We have reported that two aspartyl (Asp-151 and Asp-58) residues in alpha A-crystallin in human eye lens were inverted to the D-isomer and isomerized to beta-aspartyl residues with age. We report here the kinetics of the Asp racemization of three model peptides corresponding to fragments of alpha A-crystallin: IQTGLD151ATHAER (T18 peptide), TVLD58SGISEVR (T6 peptide) and HFSPED84LTVK (T10 peptide, as a control). The rate constants of the racemization of Asp residues in these peptides were measured at pH 7.0, at five temperatures: 50, 60, 70, 80 and 90 degrees C. From the Arrhenius equation, we estimated the activation energy (E) of racemization and the time required for the Asp D/L ratio to approximate to 1.0 (D/L ratio of Asp = 0.99) at body temperature. For the peptide T18, E = 21.4 kcal/mol and t = 13.5 yr. For the peptide T6, E = 26.8 kcal/mol and r = 49.5 yr. For the control peptide T10, E = 28.3 kcal/mol and t = 78.1 yr. The racemization rate of Asp in these three peptides is parallel to that of Asp residues in alpha A-crystallin. The racemization rate of Asp in the T18 peptide was very rapid compared to that in the other peptides. This result also reflects the racemization rate in native alpha A-crystallin.

Amino Acid Sequence↗