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Biomedical subjects

K Chiba

Publications and source records attributed to K Chiba.

At least 19 recordsLinked to original sources
PubMed1992

A novel orally active inhibitor of IL-1 generation: synthesis and structure-activity relationships of 3-(4-hydroxy-1-naphthalenyl)-2-propenoic acid derivatives.

A new series of 3-(4-hydroxy-1-naphthalenyl)-2-propenoic acids was prepared and the inhibitory activities of its members on IL-1 generation were evaluated both by in vitro systems using human monocytes and/or rat exudated macrophages stimulated with LPS, and by an in vivo system using the rat CMC-LPS air-pouch model. Many compounds in this series were found to be potent inhibitors of IL-1 generation both in vitro and in vivo. Structure-activity relationships indicated that in the rat CMC-LPS air-pouch model by oral administration the (Z)-2-substituted propenoic acids with 3-alkoxy, 5-alkyl, and 4-hydroxy substituents on the naphthalene ring exhibit optimal inhibition. Among the compounds evaluated, (Z)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthalenyl)-2-methyl-2-propeno ic acid (20a), which inhibited IL-1 generation from human monocytes with an IC50 value of 3.0 microM and had an IC50 value of 1.4 microM for rat exudated macrophages, showed the most potent inhibitory activity in the rat CMC-LPS model by oral administration. Compound 20a also showed antiinflammatory effects in animal models of inflammation.

Acrylates↗
PubMed1992

Simultaneous determination of omeprazole and its metabolites in plasma and urine by reversed-phase high-performance liquid chromatography with an alkaline-resistant polymer-coated C18 column.

Omeprazole (OPZ) is a proton pump inhibitor in gastric parietal cells. A reversed-phase high-performance liquid chromatographic method was developed that enables concentrations of OPZ and its major metabolites, omeprazole sulphone (OPZ-SFN) and hydroxy-omeprazole (H-OPZ), to be determined simultaneously in plasma and that of H-OPZ in urine. To prevent decomposition of OPZ, all the processes (extraction, injection and elution) were carried out under alkaline conditions. Recoveries of the analytes and internal standard were greater than 93.1%. The intra- and inter-assay coefficients of variation were less than 9.1 and 6.4% for plasma samples and less than 2.9 and 3.9% for urine samples, respectively. The minimum determinable concentration (relative standard deviation 10-15%) was 10 ng/ml for all analytes in plasma and H-OPZ in urine samples. The clinical applicability of this assay method was evaluated by determining plasma concentration-and urinary excretion-time courses of the respective analyte(s) in four healthy volunteers after an oral dose of 20 mg of OPZ. The present assay is considered to be simple, precise and accurate and suitable for the study of the kinetic disposition and metabolism of OPZ, which is an extensively metabolized drug in the human liver.

Adult↗
PubMed1992

The primary structure of the alpha subunit of a starfish guanosine-nucleotide-binding regulatory protein involved in 1-methyladenine-induced oocyte maturation.

Starfish-oocyte maturation induced by 1-methyladenine (MeAde) was inhibited by microinjection of pertussis toxin (PTX). The inhibition appeared to result from PTX-catalyzed ADP-ribosylation of a 39-kDa guanosine-nucleotide-binding regulatory protein (G protein) in the oocyte. These results strongly support the hypothesis that the MeAde-induced signals operate via a membrane receptor and are carried by the PTX-sensitive G protein. When PTX-injected oocytes were treated with dithiothreitol, 85% of them reinitiated meiosis, suggesting that dithiothreitol did not act on the MeAde receptor. We constructed a cDNA library from the immature ovary of starfish, Asterina pectinifera, and screened it with the cDNA of the alpha subunit of an inhibitory rat G protein (Gi-2). A positive cDNA clone contained an open reading frame of 1062 bases which had 74% identity with the rat Gi-2 cDNA. The deduced amino acid sequence was 85% and 89% identical to rat Gi-2 and rat Gi-1, respectively. The alpha subunit of the G protein purified from cortices of starfish oocytes was digested by trypsin and the resulting four peptides were microsequenced. Comparison of these amino acid sequences with the predicted one indicated that the isolated cDNA clone encoded the alpha subunit of the PTX-sensitive G protein in oocytes. The C-terminal sequence, KNNLKDCGLF, was identical to that of Gi, suggesting that the cysteine residue is the site of ADP-ribosylation.

Adenine↗
PubMed1992

Properties of 1-methyladenine receptors in starfish oocyte membranes: involvement of pertussis toxin-sensitive GTP-binding protein in the receptor-mediated signal transduction.

In response to a meiosis-inducing hormone, 1-methyladenine (1-MA), starfish oocytes undergo reinitiation of meiosis with germinal vesicle breakdown. The 1-MA-initiated signal is, however, inhibited by prior microinjection of pertussis toxin into the oocytes, suggesting that a guanine nucleotide-binding protein (G protein) serving as the substrate of pertussis toxin is involved in the 1-MA receptor-mediated signal. We thus investigated properties of 1-MA receptors by means of binding of the radiolabeled ligand to the oocyte membranes. There were apparently two forms of 1-MA receptors with high and low affinities in the membranes. The high-affinity form was converted into the low-affinity one in the presence of a non-hydrolyzable analogue of GTP. A 39-kDa protein, which had been identified as the alpha-subunit of the major substrate G protein for pertussis toxin, was also ADP-ribosylated by cholera toxin only when 1-MA was added to the membranes. The ADP-ribosylated 39-kDa alpha-subunit could be immunoprecipitated with antibodies raised against the carboxy-terminal site of mammalian inhibitory G-alpha. These results indicate that 1-MA receptors are functionally coupled with the 39-kDa pertussis toxin-substrate G protein in starfish oocyte membranes.

Adenine↗
PubMed1992

Kinetics of the reconstitution of hemoglobin from semihemoglobins alpha and beta with heme.

Kinetics of the reconstitution of hemoglobin from semihemoglobins alpha and beta with hemin dicyanide have been investigated using three kinds of stopped-flow technique (Soret absorption, fluorescence quenching of tryptophan, and Soret CD). The semihemoglobins alpha and beta are occupied by heme in the alpha and beta chains, respectively, the other chain being heme-free. Based on the kinetic results, the following scheme for the reconstitution is proposed; First, hemin dicyanide enters the pocket-like site of the apo chains. Second, in semihemoglobin alpha, the CN-ligand in the fifth coordination position of iron is replaced by the imidazole ring of the proximal His immediately after the heme insertion. In contrast, semihemoglobin beta changes its conformation after the heme insertion, and this is followed by the ligand replacement. Finally, the partial structure changes induced by the ligand replacement propagate onto the whole molecule and the final conformation is attained. The results indicate that semihemoglobin alpha retains a more rigid and organized structure, and more closely approaches its final structure than does semihemoglobin beta.

Animals↗
PubMed1992

Incidence of S-mephenytoin hydroxylation deficiency in a Korean population and the interphenotypic differences in diazepam pharmacokinetics.

We studied the genetically determined hydroxylation polymorphism of S-mephenytoin in a Korean population (N = 206) and the pharmacokinetics of diazepam and demethyldiazepam after an oral 8 mg dose of diazepam administered to the nine extensive metabolizers and eight poor metabolizers recruited from the population. The log10 percentage of 4-hydroxymephenytoin excreted in the urine 8 hours after administration showed a bimodal distribution with an antimode of 0.3. The frequency of occurrence of the poor metabolizers was 12.6% in the population. In the panel study of diazepam in relation to the mephenytoin phenotype, there was a significant correlation between the oral clearance of diazepam and log10 urinary excretion of 4-hydroxymephenytoin (rs = 0.777, p less than 0.01). The plasma half-life of diazepam in the poor metabolizers was longer than that in the extensive metabolizers (mean +/- SEM, 91.0 +/- 5.6 and 59.7 +/- 5.4 hours, p less than 0.005), and the poor metabolizers had the lower clearance of diazepam than the extensive metabolizers (9.4 +/- 0.5 and 17.0 +/- 1.4 ml/min, p less than 0.001). In addition, the plasma half-life of demethyldiazepam showed a statistically significant (p less than 0.001) difference between the extensive metabolizers (95.9 +/- 11.3 hours) and poor metabolizers (213.1 +/- 10.7 hours), and correlated with the log10 urinary excretion of 4-hydroxymephenytoin (rs = -0.615, p less than 0.01). The findings indicate that the Korean subjects have a greater incidence of poor metabolizer phenotype of mephenytoin hydroxylation compared with that reported from white subjects and that the metabolism of diazepam and demethyldiazepam is related to the genetically determined mephenytoin hydroxylation polymorphism in Korean subjects.

Adult↗
PubMed1992

Activation of PC12 cells by lipophilic components of Panax ginseng.

The lipid soluble fraction of Panax ginseng C. A. Meyer has been found to possess a stimulatory effect on a para-neuronal culture cell line, namely PC12 cells. Addition of the diethyl ether extract (0.025-0.1 mg/ml) of Ginseng radix to a culture medium promoted the outgrowth of neurites from cells dose-dependently as well as their ready differentiation to respond to carbachol and high KCl-evoked membrane depolarization to induce free Ca2+ accumulation in the cells within a week of culture. Effective constituents of the extract were confined to four major substances detected in the extremely lipophilic front area on silica gel TLC.

Animals↗
PubMed1992

Steady-state pharmacokinetics and bioavailability of total and unbound disopyramide in children with cardiac arrhythmias.

We studied the pharmacokinetics of the total (protein-bound plus -unbound and unbound forms of disopyramide (DP) at steady-state in six children (aged 5.2 to 12.2 years) with cardiac arrhythmias who had received repeated oral DP therapy. Maximum concentrations after the oral dose were reached at 2.5 +/- 1.1 h (mean +/- SD) for both total and unbound DP. The bioavailabilities calculated from total and unbound plasma concentration-time curves were 99 +/- 23 and 89 +/- 27% of the dose, respectively. These parameters seen in our children are similar to those reported from adult subjects. The mean elimination half-lives (t1/2), volumes of distribution, and total body clearances (CL) of total and unbound DP were 3.15 +/- 0.64 and 2.50 +/- 0.37 h, 1.02 +/- 0.25 and 2.60 +/- 0.38 L/kg, and 3.79 +/- 0.82 and 13.12 +/- 2.60 ml/min/kg, respectively. These mean CL and t1/2 values are considerably greater and shorter, respectively, than those reported from adult subjects. The findings indicate that the greater doses of DP per kg of body weight reportedly required for attaining a therapeutic plasma drug level in pediatric age patients should be due to a greater drug CL in children than in adults. A sustained-release preparation of DP may be required for pediatric patients to minimize a large fluctuation of plasma drug levels during the dosing intervals.

Arrhythmias, Cardiac↗
PubMed1992

Utility of a one-point (3-hour postdose) plasma metabolic ratio as a phenotyping test using metoprolol in two east Asian populations.

We examined the utility of the postdose 3-h plasma metabolic ratio (MR) as a phenotyping method for assessing genetically determined debrisoquine-type oxidation polymorphism after an oral dose of 100 mg of metoprolol tartrate administered to 402 unrelated, healthy, and native East Asian (218 Korean and 184 Japanese) subjects. All of them were phenotyped simultaneously with the reported MR employing urine samples collected during an 8-h postdose period. In the two populations, the distribution histograms and probit plots of log10plasma MRs derived from the metoprolol/alpha-hydroxymetoprolol concentration values indicated a large gap between the extensive and poor metabolizers who were phenotyped by the reported criteria of the 8-h urinary MR. There were statistically significant (p less than 0.001) correlations (rs = 0.688 and 0.810, respectively) between the postdose urinary and plasma MRs in the Korean and Japanese populations. Two poor metabolizers (one each included in the two racial groups) identified according to the 8-h urinary MR gave the greatest plasma MRs (i.e., 549.7 among the Koreans and 150.0 among the Japanese). The results suggest that the one-point, postdose 3-h plasma MR is also useful for the phenotyping purpose of oxidation pharmacogenetic polymorphism of metoprolol, a widely prescribed beta-adrenoceptor blocking drug.

Adolescent↗
PubMed1992

Characterization of D-aspartic acid uptake by rat hippocampal slices and effect of ischemic conditions.

The cellular uptake of D-aspartic acid (D-Asp) as a model compound for glutamic acid transport was studied in rat hippocampal slices. D-Asp is accumulated by both Na(+)-dependent and Na(+)-independent processes in hippocampal slices, and both processes are dependent on temperature. The Na(+)-dependent uptake is assumed to be high in affinity (apparent Km = 0.17 mM), but low in capacity, whereas the Na(+)-independent uptake is much lower in affinity (Km = 2.86 mM), but higher in capacity. L-Aspartic acid, L-glutamic acid, dihydrokainic acid, and threo-3-hydroxy-DL-aspartic acid markedly inhibited the uptake of D-Asp with Na+ in the medium, whereas D-glutamic acid, glycine, and L-lysine had no significant effect. The Na(+)-dependent uptake of D-Asp was significantly reduced under "hypoglycemic," "anoxic," and "ischemic" conditions, whereas the Na(+)-independent uptake was unaffected. Metabolic inhibitors such as NaCN and ICH2COOH significantly inhibited the Na(+)-dependent uptake, but not the Na(+)-independent uptake. These results suggest that the Na(+)-dependent component of D-Asp transport in rat hippocampal cells is inactivated under ischemic conditions, whereas the Na(+)-independent component is unaffected.

Animals↗
PubMed1992

[The mechanism of the renal excretion of disopyramide in rats. I].

The mechanism involved in the renal excretion of disopyramide (DPM) is still incompletely understood. The purpose of this study was to examine the renal handling of DPM and the interactions between DPM and several organic anionic or cationic drugs related to the renal tubular secretion, using the renal clearance and renal cortical slices uptake techniques in rats. The clearance ratio of DPM was greater than that of glomerular filtration and this suggests the tubular secretion of DPM. The clearance ratio of DPM did not change after infusion of either anionic drugs (p-aminohippurate and probenecid) or a cationic drug (cimetidine). The results of time and concentration-dependent experiments using renal cortical slices demonstrated that DPM was accumulated against a concentration gradient by a saturable process. Inhibition of uptake by 2,4-dinitrophenol and cyanide indicated an energy dependence. DPM uptake was considerably inhibited by the cationic drugs, cimetidine and quinine, suggesting that DPM was transported by the cation transport mechanism. Probenecid, a competitor for the anion transport mechanism, moderately inhibited DPM uptake.

Animals↗
PubMed1992

Inhibitory effect of acylphloroglucinol derivatives on the replication of vesicular stomatitis virus.

The antiviral activity of natural phloroglucinols and of synthesized mono- and diacylphloroglucinols, and 2,6-diacyl-4,4-dialkylcyclohexa-1,3,5-triones was investigated. A correlation between the acyl chain length and inhibitory activity against vesicular stomatitis virus (VSV) was observed. Potent antiviral activity was found in di-isovalerylphoroglucinol. 2,6-Diacyl-4,4-dialkylcyclohexa-1,3,5-triones inhibited replication of the virus with low cytotoxicity.

Animals↗
PubMed1992

[MR study of the brain stem in elderly subjects].

Findings in patients in whom brain stem lesions were suspected were studied by a high-field-strength (1.5 T) MR imager. MR scans were obtained in 97 patients over a 10-month period. The mean age was 71 years (range, 39-94 years). A high incidence of infarction and lesions showing a high signal on T2-weighted image, but an almost normal signal on the T1-weighted image were observed at the pons in elderly cases. Furthermore, cases in which these two findings were observed, had a high incidence of lesion at other regions than pons. Cases with a past history of hypertension had higher incidence of lesions at the pons than normotensive patients (alpha less than 0.01). These findings suggest that MRI examination in the elderly could detect a high incidence abnormal lesions at the brain stem as well as in basal ganglia.

Aged↗
PubMed1992

[A case of intrascrotal hemangioma].

Intrascrotal hemangioma is rare. A case is presented and the literature is reviewed. A 35 year-old male with the complaint of a painless right scrotal mass underwent right high orchiectomy because the mass was hard and difficult to separate from the right testicle in scrotal exploration. Histologic study revealed that the tumor consisted of a venous hemangioma and the greater part of it was displaced by organized connective tissue. It is extremely rare for a case of intrascrotal hemangioma to require orchiectomy.

Adult↗
PubMed1992

Metabolic and morphologic changes in the corneal endothelium. The effects of potassium cyanide, iodoacetamide, and ouabain.

The metabolic pathways of glycolysis and mitochondrial respiration in the corneal endothelial cell are the primary sources of the adenosine triphosphate (ATP) necessary to maintain endothelial structure and pump fluid to maintain the corneal stroma in its normally dehydrated and transparent state. The correlation between endothelial metabolism and morphology in rabbits was studied for 7 days after the application of three different agents: (1) iodoacetamide, used to inhibit ATP synthesis from both glycolysis and respiration; (2) potassium cyanide (KCN), used to inhibit ATP synthesis from respiration only; and (3) ouabain, used to inhibit fluid pumping but not ATP synthesis. After application of each of these three drugs to the corneal endothelium, changes in endothelial morphology were measured. The greatest change resulted from the use of iodoacetamide. Specular microscopic examination of the endothelium after the application of iodoacetamide showed progressive degradation of the integrity of the cellular structure; after 6 hr, there were no discernible cell borders. In those corneas treated with either KCN or ouabain, only minor changes in the endothelium were seen during the full 7 days of the investigation. Computer-assisted morphometric analysis showed an increase in the coefficient of variation of both cell area and perimeter in all cases. This increase was greater in the corneas treated with ouabain than those treated with either iodoacetamide or KCN. Redox fluorometry showed that the metabolic ratio (autofluorescence of reduced pyridine nucleotides divided by that of oxidized flavoproteins) decreased significantly in the iodoacetamide-treated corneas, increased significantly in the KCN group, and showed no significant change in the corneas in the ouabain group, all compared with a control group. The results showed that (1) when ATP produced by both glycolysis and respiration was inhibited by 0.1 mmol/l iodoacetamide, the endothelial cells could not survive, but (2) when ATP synthesis produced by respiration alone was inhibited by 1.0 mmol/l KCN, the cells could survive for at least 1 wk on the ATP produced by anaerobic glycolysis. Furthermore, the polymegathism seen after application of ouabain, a drug that is not believed to affect ATP synthesis but inhibits the endothelial pump function, is greater than that seen as a result of reduced pump function caused by inhibited respiration produced by 1.0 mmol/l KCN. Combining specular microscopy, computer-assisted morphometric analysis, redox fluorometry, and corneal pachymetry allowed correlations between corneal endothelial metabolism, pump function, and morphology to be studied.

Animals↗
PubMed1992

Disposition kinetics and metabolism of omeprazole in extensive and poor metabolizers of S-mephenytoin 4'-hydroxylation recruited from an Oriental population.

To explore the relationship between omeprazole disposition and genetically determined S-mephenytoin 4'-hydroxylation phenotype status, we examined the kinetic variables of omeprazole and its two primary metabolites in plasma (5-hydroxyomeprazole and omeprazole sulfone) and the excretion profile of its principal metabolite in urine (5-hydroxyomeprazole) in eight extensive (EMs) and eight poor metabolizers (PMs) recruited from a Korean population. Each subject received a p.o. dose of 20 mg of omeprazole as an enteric-coated formulation, and blood and urine samples were collected up to 24 hr postdose. Omeprazole and its metabolites were measured by high-performance liquid chromatography with ultraviolet detection. The mean omeprazole area under the concentration-time curve (AUC), elimination half-life (T1/2) and apparent p.o. clearance were significantly (P less than .001) greater, longer and lower, respectively, in PMs than in EMs. The mean peak concentration and AUC of 5-hydroxyomeprazole and AUC ratio of 5-hydroxyomeprazole to omeprazole were significantly (P less than .01 to .001) less in PMs than in EMs. The mean peak plasma concentration, AUC of omeprazole sulfone and ratio of omeprazole sulfone to omeprazole were greater (P less than .001) and T1/2 was longer (P less than .001) in PMs than in EMs. The mean cumulative urinary excretion of 5-hydroxyomeprazole up to 24 hr postdose was significantly (P less than .001) less in PMs than in EMs. In addition, the log10 4'-hydroxymephenytoin excreted in urine correlated significantly (P less than .01) with the apparent p.o. clearance of omeprazole and half-lives of omeprazole, 5-hydroxyomeprazole and omeprazole sulfone.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Pyridinylmethylsulfinylbenzimidazoles↗