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Biomedical subjects

K Chiba

Publications and source records attributed to K Chiba.

At least 55 records · Page 3Linked to original sources
PubMed2001

Influence of the CYP2D6*10 allele on the metabolism of mexiletine by human liver microsomes.

AIMS: To study the influence of CYP2D6*10 on the formation of p-hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM) using microsomes from human liver of known genotypes. METHODS: Microsomes from human livers of genotype CYP2D6*1/*1 (n = 5), *1/*10 (n = 6) and *10/*10 (n = 6) were used in this study. The formation of PHM and HMM was determined by high-performance liquid chromatography. RESULTS: The formation rates of PHM and HMM were decreased by more than 50% and 85% in CYP2D6*1/*10 and *10/*10 microsomes, respectively, compared with *1/*1 microsomes. CONCLUSIONS: The metabolism of mexiletine to form PHM and HMM appears to be impaired to a significant extent in human liver microsomes from hetero- and homozygotes of CYP2D6*10.

Alleles↗
PubMed2001

Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH.

BACKGROUND: Omeprazole is mainly metabolized in the liver by CYP2C19, a genetically determined enzyme, whereas rabeprazole is mainly reduced non-enzymatically and partially metabolized by CYP2C19. The therapeutic effects of rabeprazole are therefore assumed to be less affected by an individual's CYP2C19 status. AIM: To investigate the acid inhibitory effects and plasma levels of omeprazole and rabeprazole with reference to different CYP2C19 genotypes. METHODS: Fifteen healthy volunteers took a daily dose of 20 mg of omeprazole or rabeprazole for 8 days. On post-dose days 1 and 8, 24-h profiles of intragastric pH were recorded and plasma concentrations of omeprazole, rabeprazole and their metabolites were determined. RESULTS: After single and repeated doses of omeprazole, the intragastric pH values and plasma concentrations of omeprazole and its metabolites were significantly dependent on the CYP2C19 genotype. Significant differences in the same kinetic and dynamic parameters were also observed after single doses of rabeprazole. Although the plasma levels of rabeprazole differed among the different CYP2C19 genotype groups after repeated doses, no significant differences in intragastric pH values were observed. CONCLUSIONS: The acid inhibitory effects of omeprazole and rabeprazole are significantly dependent on the CYP2C19 genotype status, as well as on their intrinsic pharmacokinetic and pharmacodynamic characteristics and dosing schemes.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2001

Frequencies of thiopurine S-methyltransferase mutant alleles (TPMT*2, *3A, *3B and *3C) in 151 healthy Japanese subjects and the inheritance of TPMT*3C in the family of a propositus.

AIMS: To determine the frequencies of four thiopurine S-methyltransferase (TPMT) mutant alleles, TPMT*2, *3A, *3B and *3C in a normal Japanese population. METHODS: Genotypes were determined in 151 Japanese subjects and in six family members of a propositus using polymerase chain reaction (PCR)-restriction fragment length polymorphism and allele-specific PCR assays. RESULTS: Only one TPMT*3C heterozygote was identified (gene frequency 0.3%). TPMT*2, *3A and *3B were not detected. In addition, TPMT*3C was found to have been inherited from the mother and passed on to the son of the propositus. CONCLUSIONS: TPMT*3C appears to be most prevalent among the known mutant allele of TPMT in a Japanese population which may have some relevance for the treatment of Japanese patients with thiopurine drugs.

Adult↗
PubMed2001

Activation of the mitogen-activated protein kinase cascade through nitric oxide synthesis as a mechanism of neuritogenic effect of genipin in PC12h cells.

Prominent neurite outgrowth induced by genipin, a plant-derived iridoid, was substantially inhibited by addition of NG-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase (NOS) inhibitor, and carboxy-PTIO, an NO scavenger, in PC12h cells. Increases of the NADPH-diaphorase activity and neuronal and inducible NOS proteins in cells preceded the neurite outgrowth after addition of genipin to medium. NO donors could induce the neurite outgrowth dose-dependently in the cells. On the other hand, an inhibitor of soluble guanylate cyclase (SGC), which is known to be a stimulatory target of NO, abolished greatly the genipin-induced neurite outgrowth. Addition of extracellular signal-regulated kinase (ERK) kinase inhibitors could almost completely abolish the neurite induction. L-NAME remarkably depressed genipin-stimulated phosphorylation of ERK-1 and -2. A neuritogenic effect of nerve growth factor (NGF) in PC12h cells was also remarkably inhibited by the NOS inhibitor, NO scavenger and SGC inhibitor. These findings suggest that induced NO production followed by cyclic GMP-mediated stimulation of the mitogen-activated protein kinase (MAPK) cascade is implicated in the neuritogenesis by genipin and NGF in PC12h cells.

Animals↗
PubMed2001

Traumatic subluxation of the axis after hyperflexion injury of the cervical spine in children.

Six cases of children (four boys and two girls, mean age 11 years) who had traumatic subluxation of the axis (C2) were reviewed retrospectively. Initial radiographs demonstrated no detectable vertebral fracture in any of the children. However, a slight anterior subluxation of C2 was observed in three of the patients. Radiographs, taken at 1 month after injury in all but one patient, revealed a progression of the subluxation and a local kyphosis in all of the patients. Four of the children were treated conservatively with a cervical brace, and an improvement of both the kyphosis and the anterior slippage of C2 was obtained accompanied by an anteroposterior growth of the C3 vertebral body. The kyphosis of two of the patients became severe and, ultimately, these patients underwent fusion surgery. At the follow-up, none of the patients presented with any significant symptom. For the correct diagnosis of traumatic subluxation of C2, sequential radiographs to confirm the progression of subluxation and local kyphosis are mandatory. Conservative treatment rather than early surgical treatment may be chosen for this injury, because mild and moderate kyphosis can be corrected spontaneously by remodeling of the cervical spine.

Adolescent↗
PubMed2001

Effect of polyacetylenes on the neurite outgrowth of neuronal culture cells and scopolamine-induced memory impairment in mice.

Polyacetylenic alcohols and their linoleates isolated from Panax ginseng C. A. MEYER and Cirsium japonicum DC., of which the lipophilic extracts had been found to affect the neuritogenesis of cultured paraneurons, were demonstrated to have a significant neuritogenic effect on PC12h and Neuro2a cells. Panaxynol and the acetylenic triol in particular were highly efficient at concentrations > or = 2 microm. Panaxynol (20 mg/kg/d, i.p., for 3 d) was confirmed to improve scopolamine-induced memory deficit in mice (Y-maze task). It is suggested that the promotion of neuritogenesis in cultured paraneurons by the addition of panaxynol is related its ability to improve memory deficits in animals.

Acetylene↗
PubMed2001

Prevention of the neurotoxicity of the amyloid beta protein by genipin.

Genipin, which was shown in our previous investigation to have prominent neuritogenic activity in paraneurons such as PC12h cells, was studied to determine whether it could prevent the toxicity of Alzheimer's amyloid beta protein (Abeta) in cultured hippocampal neurons. Increased release of lactate dehydrogenase from hippocampal neurons after 2 d of Abeta25-35 administration was prevented dose dependently by the addition of genipin 20-40 microm. Morphological observations and trypan blue staining of cells confirmed the protection of hippocampal neurons from Abeta toxicity by genipin. Geniposide had less effect in preventing Abeta toxicity.

Amyloid beta-Peptides↗
PubMed2001

Development of new surgical treatments in spinal surgery: expansive open-door laminoplasty and percutaneous nucleotomy.

The outstanding achievements of two renowned spine surgeons, who are alumni of the Department of Orthopaedic Surgery, Keio University, are described. Anterior decompression followed by fusion and laminectomy had been the standard techniques for cervical myelopathy due to disc herniation, spondylosis and ossification of the posterior longitudinal ligament. However, both techniques were not without certain comorbidities. Dr. Kiyoshi Hirabayashi devised an epoch-making expansive open-door laminoplasty, in which both sufficient posterior decompression and preservation of cervical stability are achieved simultaneously with reduced risk of such complications. Dr. Sadahisa Hijikata is the pioneer of a totally new concept treatment, percutaneous nucleotomy, for lumbar disc herniation, one of the most prevailing diseases that cause low back pain and sciatica. He devised this technique to avoid prolonged conservative treatment with associated suffering of the patients and to minimize the chance of morbidity that is occasionally associated with an open surgery. This technique, together with chemonucleolysis, has led to the establishment of intradical or intermediate treatments which lie between conservative and surgical treatments. Both techniques have not only brought the relief of pain and suffering in numerous patients, but have also opened the door to the development of many new modified procedures and technologies. Most importantly, these two techniques still remain as the most viable choice among various similar modifications. The rationale, indictions, technique as well as the present status and future perspective for these two innovative yet fundamental techniques are introduced and discussed.

Cervical Vertebrae↗
PubMed2001

Surgical management of idiopathic spinal cord herniation: a review of nine cases treated by the enlargement of the dural defect.

OBJECT: Spinal cord herniation is a rare cause of progressive myelopathy and can be corrected surgically. In most previous reports, closure of the dural defect was the recommended procedure. The object of this paper is to describe a new procedure in which spinal cord constriction is released by enlarging the hiatus; additionally the postoperative results will be discussed. METHODS: In nine patients with spinal cord herniation, enlargement of the dural defect was performed. In eight patients, neurological deficits resolved immediately after surgery. In one patient with a severe preoperative neurological deficit whose spinal cord herniated massively, deterioration occurred postoperatively. To date, no recurrence of herniation has been observed. CONCLUSIONS: The goals of surgery are to reduce the herniation, return the spinal cord to the normal position, and prevent the recurrence of herniation. The use of sutures to close the dural defect has been the method of choice to date. The surgical space in front of the spinal cord, however, is insufficient to accommodate this procedure safely. Because symptoms are caused by the constriction of the spinal cord at the hiatus, surgical expansion of the hiatus allows the goals of surgery to be achieved. This procedure, which is technically easier and less invasive with regard to the vulnerable spinal cord than the closure of the dural defect, could be a viable alternative for the treatment of this rare disease.

Adult↗
PubMed2001

Role of CYP2C19 in stereoselective hydroxylation of mephobarbital by human liver microsomes.

The 4-hydroxylation of mephobarbital enantiomers was investigated by using human liver microsomes from the extensive metabolizers (EM) and poor metabolizers of CYP2C19. The 4-hydroxylase activity of R-mephobarbital in the EM microsomes was >10 times higher than that of S-mephobarbital. In the poor metabolizer microsomes, the 4-hydroxylase activity of R-mephobarbital was much lower than that in the EM microsomes, and the ratio of 4-hydroxylase activity of R-mephobarbital to that of S-mephobarbital was also lower than that in the EM microsomes. Moreover, the 4-hydroxylase activity of R-mephobarbital showed a high correlation (r = 0.985, p<0.001) with the 4'-hydroxylase activity of S-mephenytoin in a panel of nine human liver microsomes. Anti-CYP2C antibody inhibited R-mephobarbital 4-hydroxylase activity by 85% of the control activity. R-Mephobarbital competitively inhibited S-mephenytoin 4'-hydroxylase activity (K(i) = 34 microM), while S-mephenytoin inhibited R-mephobarbital 4-hydroxylase activity (K(i) = 103 microM). Among the seven cDNA-expressed CYPs studied, only CYP2C19 catalyzed R-mephobarbital 4-hydroxylation. These findings suggest that the 4-hydroxylation of mephobarbital catalyzed by CYP2C19 is preferential for R-enantiomer in human liver microsomes.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Kinetics of testosterone 6beta-hydroxylation in the reconstituted system with similar ratios of purified CYP3A4, NADPH-cytochrome p450 oxidoreductase and cytochrome B5 to human liver microsomes.

Kinetics of testosterone 6beta-hydroxylation were determined using a reconstituted system that consisted of CYP3A4, cytochrome b5 and NADPH-cytochrome P450 oxidoreductase (OR) with similar ratios as those seen in human liver microsomes and compared with those determined using human liver microsomes. Two reconstituted systems were constructed in accordance with two human liver microsomal samples that showed extremely high and low ratios of OR/CYP3A4. The Km values of testosterone 6beta-hydroxylation obtained from the reconstituted systems with high and low OR/CYP3A4 ratios were 29.3 and 35.2 microM, respectively, which were similar to that of the corresponding human liver microsomal samples (23.2 and 40.0 microM, respectively). However, Vmax values obtained from the reconstituted systems (3.7 and 0.8 pmol/min/pmol CYP3A4) were much lower than those from the human liver microsomes (44.2 and 31.1 pmol/min/pmol CYP3A4). The results suggest that the interaction between substrate and CYP3A4 in the reconstituted systems appear to be similar to human liver microsomes but that the velocity of the substrate metabolism in the reconstituted systems is different from that in human liver microsomes. In conclusion, our reconstituted systems could be used for the determination of affinity but not for the determination of the maximum velocity of substrate metabolism. Further studies on the protein-protein interactions between CYP3A4, OR, cytochrome b5 and/or a specific lipid environment are required to establish a reconstituted system showing similar kinetic properties to those of human liver microsomes.

Cytochrome P-450 CYP3A↗
PubMed2001

Synthesis of branched polysaccharides by polymerization of 6-O-t-butyldimethylsilyl-D-glucal through stereoregular haloglycosylation.

In this letter, we report synthesis of branched polysaccharide 2 by glycosylation of glucal-type monomer 1 with two free hydroxy groups at position 3 and 4. Monomer 1 polymerized with N-halosuccinimide promoter in acetonitrile solvent at room temperature--50 degrees C. The product was isolated as a petroleum ether insoluble fraction. The structure was determined by 1H and 13C NMR spectra as well as elemental analysis to be a polysaccharide consisting of 2-halo-2-deoxy-alpha-D-mannoside units, indicating that the polymerization proceeded via stereoregular glycosylation manner. The molecular weights determined by GPC with DMF were 3,300-4,000. The degree of branching was estimated by the NMR data of the product from the reaction of 2 with 3,5-dinitrobenzoyl chloride.

Journal Article↗
PubMed2000

The long-term evolutions and the regional characteristics of atmospheric methane concentrations in Nagoya, 1983-1997.

This study provides information on the long-term evolutions of the atmospheric methane (CH4) concentrations in Nagoya City, Japan, which were analyzed by using the continuous monitoring data observed at the eight observatory stations for 1983-1997. The 15-year records of the atmospheric CH4 concentrations were examined by means of a time-series analysis using a fast Fourier transform with a low-pass filter to elucidate the seasonal cycles and the long-term trends. The annual averages of the CH4 concentrations in Nagoya were 1.85 ppmv (parts per million by volume), 1.91 ppmv, and 1.90 ppmv in 1988, 1995 and 1997, respectively. Moreover, the annual average growth rate showed a drastic decrease from 17 ppbv (parts per billion by volume) year(-1) in 1992 to 2 ppbv year(-1) in 1993, and further down to 7 ppbv year(-1) in 1997. Comparison of the atmospheric CH4 records in Nagoya with those in global air of the northern hemisphere observed at Mauna Loa observatory in Hawaii, USA, allows us to estimate the excess concentration of CH4 in the urban atmosphere of Nagoya, which was 0.17 ppmv in 1988 and 0.15 ppmv in 1997. On a local scale, the atmospheric CH4 concentrations in the northern part of Nagoya City increased until 1992 and then gradually decreased from 1993 to 1997, although those in the south-western urban areas constantly increased at the averaged growth rate of 13 ppbv year(-1) for 1988-1997. The variation of the long-term trends of the CH4 concentrations in Nagoya may be ascribed to the emission changes from the CH4 sources due to the human activities such as waste dumping and landfills.

Air Pollution↗
PubMed2000

Proarrhythmic effects of fluoroquinolone antibacterial agents: in vivo effects as physiologic substrate for torsades.

Drug-induced prolongation of the QT interval is often associated with the onset of Torsades de Pointes (TdP) resulting in a life-threatening ventricular arrhythmia. The potential of the proarrhythmic effects of the new fluoroquinolone antibacterial agents, levofloxacin and sparfloxacin, was examined in the chronic complete atrioventricular block dogs with stable idioventricular automaticity using Holter ECG monitoring in conscious state (Experiment 1). Next, to better analyze the mechanisms of the proarrhythmic property, the cardiovascular effects of these two drugs were compared in the halothane-anesthetized dogs under the monitoring of ECG, His bundle electrogram, systemic and left ventricular pressure, monophasic action potential, cardiac output, and effective refractory period (Experiment 2). In Experiment 1, oral administration of 6 mg/kg (n = 4) as well as 60 mg/kg (n = 4) of levofloxacin did not induce any ventricular premature depolarization. On the other hand, oral administration of 60 mg/kg of sparfloxacin (n = 4) induced TdP leading to ventricular fibrillation in all animals within 24 h, while 6 mg/kg of sparfloxacin (n = 4) did not induce any ventricular premature depolarization. In Experiment 2, intravenous administration of 0.3 mg/kg as well as 3.0 mg/kg of levofloxacin slightly increased cardiac output, but no significant changes were detected in the other parameters (n = 6). On the other hand, intravenous administration of 0.3 mg/kg of sparfloxacin prolonged the effective refractory period. Additional administration of 3.0 mg/kg of sparfloxacin decreased the heart rate and prolonged the effective refractory period and ventricular repolarization phase in a similar extent, but no significant changes were detected in the other parameters (n = 6). These results suggest that backward shift of the relative repolarization period in a cardiac cycle may be the mechanism responsible for the torsadegenic effect of sparfloxacin.

Action Potentials↗
PubMed2000

Impact of longitudinal distance of the cervical spine on the results of expansive open-door laminoplasty.

STUDY DESIGN: A retrospective study in patients who underwent expansive open-door laminoplasty (ELAP) for cervical myelopathy and in whom the cervical alignment was nonlordotic at the final follow-up to analyze the correlation between the longitudinal distance of the cervical spine and surgical results. OBJECTIVES: To determine the impact of longitudinal distance of the cervical spine on surgical results of ELAP and to propose a new concept, the redundant spinal cord, that may influence patient selection for ELAP. SUMMARY OF BACKGROUND DATA: Results in many studies have demonstrated that postoperative cervical alignment has significant effect on surgical results, and spines that are malaligned are thought to deteriorate. The current surgical data showed that not all patients with postoperative malalignment had poor surgical results. Patients with cervical spondylotic myelopathy (CSM) tended to have better clinical results than those with ossification of the posterior longitudinal ligament (OPLL). METHODS: Results in 70 patients who underwent ELAP for cervical myelopathy with postoperative cervical malalignment were investigated. The longitudinal distance index (LDI) was defined as the length of a vertical line between the posteroinferior edges of C2 and C7 divided by the anteroposterior diameter of C4 and was measured on lateral neutral radiographs at final follow-up. Correlation between LDI and surgical results represented by Japanese Orthopedic Association scores and percentage of recovery were analyzed statistically in each patient. RESULTS: Patients with CSM had smaller LDI and better surgical results than those with OPLL. Weak but significant negative correlation was detected between LDI and percentage of recovery, indicating that longitudinal distance of the cervical spine may have some degree of impact on the surgical results of ELAP. CONCLUSION: A decrease in LDI represents shortening of the cervical spine caused by multiple disc degeneration and may influence surgical results of ELAP by inducing redundancy of the spinal cord in patients with postoperative malalignment.

Cervical Vertebrae↗
PubMed2000

High-performance liquid chromatography determination of N- and O-demethylase activities of chemicals in human liver microsomes: application of postcolumn fluorescence derivatization using Nash reagent.

Formaldehyde is liberated in the process of cytochrome P450 (CYP) mediated demethylation of a wide variety of compounds containing the CH(3)N or CH(3)O functionality. A highly sensitive method using a high-performance liquid chromatography (HPLC) system with postcolumn derivatization was developed to measure the liberated formaldehyde as N- and O-demethylase activity of drugs in human liver microsomes. Following the chromatographic separation of formaldehyde on a C18 column, the formaldehyde was reacted with the Nash reagent in the postcolumn reactor at 100 degrees C and detected by the fluorescence method. The results showed that the present method has excellent precision and accuracy. The intra- and interassay variances of this method were less than 10%. The newly developed HPLC method was found to be about 80-fold more sensitive than the colorimetric method in detection of formaldehyde. The N-demethylase activity of sertraline in rat liver microsomes determined by the present method did not differ from those detected by previous methods quantifying produced desmethyl metabolite. The present method has been successfully applied to determine the N-demethylase activities of several drugs, including aminopyrine, erythromycin, fluoxetine, S-mephenytoin, and sertraline, in human liver microsomes. This assay should be useful for generic analysis of N- and O-demethylase activities of xenobiotic and endobiotic chemicals by CYP enzymes.

Animals↗
PubMed2000

Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols.

A series of 2-substituted 2-aminopropane-1,3-diols was synthesized and evaluated for their lymphocyte-decreasing effect and immunosuppressive effect on rat skin allograft. A phenyl ring was introduced into the alkyl chain of the lead compound 3, which is an immunosuppressive agent structurally simplified from myriocin (1, ISP-I) via compound 2. The potency of the various compounds was dependent upon the position of the phenyl ring within the alkyl side chain. The most suitable length between the quaternary carbon atom and the phenyl ring was two carbon atoms. 2-Substituted 2-aminoethanols were successively synthesized and evaluated for their T-cell-decreasing effect and immunosuppressive effect using a popliteal lymph node gain assay in rats. The absolute configuration at the quaternary carbon affected the activity, and the (pro-S)-hydroxymethyl group of compound 6 was essential for potent immunosuppressive activity. Favorable substituents for the (pro-R)-hydroxymethyl group of 6 were hydroxyalkyl (hydroxyethyl and hydroxypropyl) or lower alkyl (methyl and ethyl) groups. 2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (6, FTY720) was found to possess considerable activity and is expected to be useful as an immunosuppressive drug for organ transplantation.

Animals↗