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Biomedical subjects

E Matsushima

Publications and source records attributed to E Matsushima.

At least 19 recordsLinked to original sources
PubMed2003

Functional characterization of three human cytochrome p450 2E1 variants with amino acid substitutions.

1. Cytochrome p450 (p450) 2E1 is a hepatic enzyme of importance for the metabolism of xenobiotics such as drugs and environmental toxicants. Genetic polymorphisms of CYP2E1 in 5'-flanking and coding regions have been found previously in Caucasian and Chinese populations. 2. In order to investigate the effects of amino acid substitutions on the function of CYP2E1, the enzymes of all known CYP2E1 variants in the coding region (CYP2E1.2, CYP2E1.3 and CYP2E1.4) with Arg76His, Val389Ile and Val179Ile substitutions, respectively, as well as the wild-type CYP2E1 (CYP2E1.1) were expressed in COS-1 cells, and their chlorzoxazone 6-hydroxylation and 4-nitrophenol 2-hydroxylation activities were determined. 3. The protein level of CYP2E1.2 was reduced to 29% compared with that of CYP2E1.1. The profiles of the level of activity relative to CYP2E1.1 for chlorzoxazone 6-hydroxylation (300 microM substrate) and 4-nitrophenol 2-hydroxylation (150 microM substrate) were very similar. 4. Although the K(m) values were not significantly different among wild-type and variant CYP2E1s in any oxidation metabolism, the V(max) and V(max)/K(m) of CYP2E1.2 on the basis of the CYP2E1 protein level were 2.7-3.0-fold higher than those of CYP2E1.1. In contrast, the levels of CYP2E1 protein and catalytic activity of CYP2E1.3 and CYP2E1.4 were not affected by the corresponding amino acid substitutions. 5. The findings suggest that Arg76 is closely associated with the function of CYP2E1, and that the genetic polymorphism of CYP2E1 is one cause of interindividual differences in the toxicity of xenobiotics.

Amino Acid Substitution↗
PubMed2002

Enhancement of the antitumour activity of 5-fluorouracil (5-FU) by inhibiting dihydropyrimidine dehydrogenase activity (DPD) using 5-chloro-2,4-dihydroxypyridine (CDHP) in human tumour cells.

The purpose of this study was to evaluate the use of 5-chloro-2,4-dihydroxypyridine (CDHP), a potent inhibitor of dihydropyrimidine dehydrogenase (DPD), to enhance the antitumour activity of the fluoropyrimidines. In an in vitro study, CDHP did not influence cell proliferation by itself. However, CDHP did inhibit 5-fluorouracil (5-FU) degradation and enhanced 5-FU cytotoxicity in a concentration-dependent manner in two human tumour cell lines (MIAPaCa-2 and HuTu80) with relatively high basal DPD activity. CDHP exhibited a maximum effect at a molar ratio (CDHP:5-FU) of more than 0.2. However, CDHP did not have any effect on 5-FU cytotoxicity in the CAL27 tumour cell line, which has a relatively low basal DPD activity, even at concentrations where the DPD activity is almost completely inhibited. In an in vivo study, the maximal tolerable doses (MTD) of tegafur (FT) and a combination of FT and CDHP at a molar ratio of 1:0.4 (FT/CDHP) for nude mice were determined by oral administration for 14 consecutive days. After a single oral administration of either FT or FT/CDHP at the MTD, the 5-FU serum concentration-time profiles were almost the same for both treatment strategies. When nude mice bearing subcutaneous (s.c.) MIAPaCa-2 cells were treated with either FT or FT/CDHP at the MTD, the FT/CDHP treatment showed a significantly higher antitumour effect than the FT treatment (tumour growth inhibition: FT/CDHP, 51+/-12%; FT, 21+/-25%; P<0.05). However, the host-body weight suppression induced by FT/CDHP and FT was equivalent. These findings suggest that the combination of fluoropyrimidine and CDHP for the treatment of tumours with a high basal DPD elicits a greater antitumour effect than treatment with fluoropyrimidines alone and we suggest that CDHP inhibits the degradation of 5-FU in the tumour.

Animals↗
PubMed2001

Stability of exploratory eye movements as a marker of schizophrenia--a WHO multi-center study. World Health Organization.

The exploratory eye movements of patients with schizophrenia reportedly differ from those of patients without schizophrenia and healthy controls. In an attempt to determine whether exploratory eye movements provide valid markers for schizophrenia, the present collaborative study was conducted in six countries to analyze the stability of and variation in the following parameters of exploratory eye movements: the number of eye fixations (NEFs) and mean eye scanning length (MESL) in a retention task; the cognitive search score (CSS) that indicates how frequently the eye focused on each important area of a figure in order to recognize it in a comparison task; and the responsive search score (RSS), which reflects the frequency of eye fixations on each section of a figure in response to questioning in a comparison task. In addition, we investigated the validity of the currently employed discriminant function to extract a common feature of schizophrenia by applying it to the findings of the present study. The exploratory eye movements of 145 patients with schizophrenia, 116 depressed patients and 124 healthy controls at seven WHO collaborative centers in six countries were measured using eye mark recorders during viewing of stationary S-shaped figures in two sequential tasks. The RSSs of patients with schizophrenia were found to be significantly lower than those of depressed patients or healthy controls irrespective of geographical location, with no significant difference existing between the RSSs for depressed patients and those for healthy controls. By inserting the RSS and NEF data for each subject into the formula used to calculate discriminant function, patients with schizophrenia could be discriminated from depressed patients and healthy controls with a sensitivity of 89.0% and a specificity of 86.7%. The RSS is an exploratory eye movement parameter that detected schizophrenia irrespective of culture, race and various other subject variables. Furthermore, it is indicative of the stable, significant difference that exists between subjects with and without schizophrenia. The results of discriminant analysis confirm the previously reported validity of discriminant function.

Adult↗
PubMed2001

Improvement in precision of the liquid chromatographic-electrospray ionization tandem mass spectrometric analysis of 3'-C-ethynylcytidine in rat plasma.

During the development of the liquid chromatography with electrospray ionization-tandem mass spectrometry for the quantitative determination of 3'-C-ethynylcytidine (I) in rat plasma, ion suppression caused by the matrix components was observed for I and its structural analogue, 3'-C-ethylcytidine (II) as the internal standard. In the method initially designed, I/II peak area ratios varied according to the degree of matrix effect, which led to the poor precision of the assay. From the examination of the ion suppression behavior for I and II, it was assumed that this phenomenon is attributed to the difference in the retention time between I and II. Based on this assumption, therefore, the methanol content in the mobile phase was changed from 5 to 25% so as to make I and II the same retention time. As a result of this modification of the initial method, the precision expressed as relative standard deviation was improved from 5.2-16.2 to 2.7-4.2% in intra-assay and from 6.8-14.9 to 3.5-7.2% in inter-assay validations.

Animals↗
PubMed2001

Relationship between exploratory eye movements and clinical course in schizophrenic patients.

Exploratory eye movements are psychophysiological indicators of schizophrenia as well as smooth pursuit eye movements. To investigate whether these eye movements change in accordance with the clinical course of the condition in schizophrenia, exploratory eye movements (number of eye fixations, mean eye scanning length, responsive search score, evaluation of reproduced Fig. 1 and 2) of 28 schizophrenic patients were evaluated in repeat test design, conducted an average of 8 months apart. Subjects were first-medicated schizophrenics, half were outpatients and the remaining half were inpatients at the Neuropsychiatry ward of Tokyo Medical and Dental University Hospital. Exploratory eye movement patterns did not improve despite an improvement in clinical symptoms of schizophrenia. This result and those of previous studies of the exploratory eye movements of schizophrenic patients' families suggest that exploratory eye movements reflect a schizophrenic vulnerability marker. Furthermore, decreased mean eye scanning length (MESL) values were observed in subjects who showed unimproved symptoms, particularly negative symptoms over an extended period of time. The result suggests that a decrease in the MESL value may be the most sensitive indicator in the development of chronicity in schizophrenia.

Adolescent↗
PubMed2001

The event-related potentials elicited by content and function words during the reading of sentences by patients with schizophrenia.

Thought disorder is one of the main symptoms observed in schizophrenia and has been investigated in terms of language dysfunction. The purpose of the present study was to find whether there were any differences in identifying and processing between content (semantic) and function (syntax) words, and to elucidate whether semantic or syntax is more impaired for the schizophrenics. Event-related potentials were recorded in 13 patients with schizophrenia and 14 healthy controls, while they silently read three sets of passages. Event-related potentials were recorded for content words (noun, verb) and function words (auxiliary verb, particle) separately. For the healthy control group, the mean amplitude of P200 for the content word class was greater than for the function word class with fronto-central dominance. In contrast, no such difference was found for the schizophrenics mainly due to the reduction of P200 amplitude of the content words. Larger P200 for the content than the function word class suggests that greater resources were used to identify the content words. Lack of this difference found in patients with schizophrenia suggested that the disturbances in the semantics may be more attributable to the linguistic impairment than those in the syntax.

Adult↗
PubMed2000

Serotonin 5-HT2 receptors in schizophrenic patients studied by positron emission tomography.

Using positron emission tomography (PET) and [11C]N-methylspiperone (NMSP), we examined 5-HT2 receptors in the cortex of schizophrenic patients in whom we previously observed decreased prefrontal D1 receptor binding. The subjects were 10 neuroleptic-naive schizophrenic patients, 7 schizophrenic patients who were drug-free but had previously been treated with neuroleptics, and 12 normal controls. A non-significant trend towards decreased prefrontal [11C]NMSP binding was observed in the neuroleptic-treated patients, suggesting a possible effect of previous neuroleptic treatment on the alteration in cortical 5-HT2 function. However, the neuroleptic-naive patients showed no noticeable difference in cortical [11C]NMSP binding compared to controls. Our results do not rule out the role of 5-HT2 function as a crucial site of therapeutic activity of schizophrenia, but they do suggest that cortical 5-HT2 receptors might not be primarily involved in the pathophysiology of schizophrenia.

Adult↗
PubMed2000

Extraosseous epidural IgD myeloma presenting with compression myelopathy.

An 85-year-old man presented with acute transverse myelopathy: flaccid paraplegia, superficial and deep sensory disturbance below Th6 and loss of urinary sensation. Spinal magnetic resonance image showed an epidural mass compressing the spinal cord at the level of C7 to Th2. Immunoelectrophoresis revealed the presence of immunoglobulin D (IgD)-lambda M protein. Chemotherapy markedly improved both the haematologic aspect and tumor size, but not the motor deficit. In IgD myeloma, extraosseous spreads occur frequently, but extraosseous epidural tumors causing compression myelopathy are relatively rare. To our knowledge, this is the fourth report of cases.

Aged↗
PubMed2000

Amantadine-induced multiple spike waves on an electroencephalogram of a schizophrenic patient.

Although amantadine is relatively free of side effects compared with levodopa, the incidence and severity of unwanted effects, such as hallucinations, insomnia and dizziness, markedly increase when the daily dose exceeds 200 mg. A 63-year-old schizophrenic female developed the Pisa syndrome following neuroleptic medication. She was started on a regimen of amantadine, 200 mg per day, on September 4, and the electroencephalogram (EEG) on September 11 was within normal limits. The dosage was increased to 300 mg on September 18 because there was no improvement and no side effects. Two days later a generalised convulsion occurred and an EEG revealed frequent multiple spikes or sharp waves with slow waves. No epileptic seizure has been observed since the amantadine was discontinued. The EEG on September 27 was again within normal limits. To our knowledge, the EEG of a patient with convulsion induced by amantadine has not been described previously. The epileptic mechanisms of amantadine have not been elucidated; however, it may be related to a modulating role of dopamine in the central nervous system.

Amantadine↗
PubMed2000

[Comparison of pharmacokinetics of 5-FU and alpha-fluoro-beta-alanine, a metabolite of 5-FU, in plasma after administration of UFT, tegafur, 5-FU or doxifluridine to rats].

Toxic effects (neurotoxicity and cardiotoxicity) of 5-FU and its derivatives have been reported by many investigators. These toxicities are considered to be caused by the inhibition of the TCA cycle by alpha-fluoro-beta-alanine (FBAL), a metabolite of 5-FU, and later metabolites. In this study, we focused on FBAL as an index of the above toxicities. We compared the concentrations of 5-FU and FBAL in plasma after administration of UFT, tegafur (FT), 5-FU or doxifluridine (5'-DFUR) to rats (75 mumol/kg) in order to evaluate which compound has the better balance of efficacy and toxicity. UFT exhibited the lowest FBAL concentration in plasma followed by FT, 5'-DFUR and 5-FU. The ratio of FBAL to 5-FU in Cmax and AUC after dosing of UFT was the lowest among these four test compounds. These data indicate that the lowest ratio of FBAL to 5-FU resulted from the inhibitory effect of uracil, a component of UFT, on the metabolism of 5-FU. In conclusion, the present results suggest that UFT has a better balance of efficacy and toxicity than FT, 5-FU and 5'-DFUR.

Administration, Oral↗
PubMed2000

[Cognitive dysfunction in schizophrenia--analysis using exploratory eye movements].

Studies of exploratory eye movements on patients with schizophrenia were reviewed. Cognitive dysfunction in schizophrenia was examined from two aspects: the schema by Neisser, and the reaction to an object or a stimulus using exploratory eye movements. The schema by which subjects view an object with a spacial spread and with a sequence of time was disturbed in schizophrenia patients, and this schema was not changeable in the response to various conditions in these patients compared with non-schizophrenic individuals. The responsive search score (RSS) in schizophrenia was extracted as the disturbance of schema in the interpersonal setting. The lowering of RSS was a common feature in many patients with schizophrenia and remarkably reflects a trait of schizophrenia. We discussed a relationship between the RSS and other trait markers in schizophrenia, and it was suggested that the concept of "Disturbance of Schema" can explain abnormal results of other indicators and can lead us to understand several theories of cognitive dysfunction in schizophrenia.

Cognition Disorders↗
PubMed2000

Tissue distribution and biotransformation of potassium oxonate after oral administration of a novel antitumor agent (drug combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate) to rats.

S-1, a new oral 5-fluorouracil (5-FU)-derivative antitumor agent, is composed of tegafur, 5-chloro-2,4-dihydropyridine, and potassium oxonate (Oxo). Oxo, which inhibits the phosphorylation of 5-FU, is added to reduce the gastrointestinal (GI) toxicity of the agent. In this study, we investigated the tissue distribution and the metabolic fate of Oxo in rats after oral administration of S-1. Oxo was mainly distributed to the intracellular sites of the small intestines in a much higher concentration than 5-FU, but little distributed to other tissues, including tumorous ones in which 5-FU was observed after oral administration of S-1. Plasma concentration-time profiles of Oxo and its metabolites after i.v. and oral administration of S-1 revealed that Oxo was mainly converted to cyanuric acid in the GI tract. Furthermore, the analysis of drug-related radioactivity in GI contents and in vitro studies suggested that Oxo was converted to cyanuric acid by two routes, the first being direct conversion by the gut flora in the cecum, and the second, conversion by xanthine oxidase or perhaps by aldehyde oxidase after degradation to 5-azauracil (5-AZU) by the gastric acid. These results indicate that, although a part of the administered Oxo was degraded in the GI tract, Oxo was mainly distributed to the intracellular sites of the small intestines in a much higher concentration than 5-FU and that little was distributed to other tissues, including tumors. We conclude that this is the reason why Oxo suppresses the GI toxicity of 5-FU without affecting its antitumor activity.

Administration, Oral↗
PubMed2000

Bioactivation of tegafur to 5-fluorouracil is catalyzed by cytochrome P-450 2A6 in human liver microsomes in vitro.

Tegafur is a prodrug of 5-fluorouracil (5-FU) consisting of a new class of oral chemotherapeutic agents, tegafur/uracil and S-1, which are classified as dihydropyrimidine dehydrogenase inhibitory fluoropyrimidines. It is bioactivated to 5-FU via 5'-hydroxylation mediated by cytochrome P-450 (CYP). However, which isoform(s) of CYP is responsible for the bioactivation process of tegafur remains unclear. The purpose of the present study was to identify the human CYP isoform(s) involved in the metabolic activation of tegafur using human liver microsomes and cDNA-expressed human CYPs. The formation of 5-FU from tegafur in human liver microsomes showed biphase kinetics with Km and Vmax values for the high-affinity component of 0.43 +/- 0.05 mM and 4.02 +/- 1.70 nmol/mg/min (mean +/- SD, n = 4), respectively. In the correlation study using a panel of 10 human liver microsomes, the formation of 5-FU from tegafur showed a significant correlation (r = 0.98; P < 0.001) with coumarin 7-hydroxylation, a marker activity of CYP2A6. In addition, a specific substrate of CYP2A6 and anti-CYP2A6 antibody inhibited the formation of 5-FU by 90% in human liver microsomes. Moreover, cDNA-expressed CYP2A6 showed the highest activity for the formation of 5-FU among 10 cDNA-expressed CYPs, with a Km value similar to that found for the high-affinity component in human liver microsomes. These findings clearly suggest that CYP2A6 is a principal enzyme responsible for the bioactivation process of tegafur in human liver microsomes. However, to what extent the bioactivation of tegafur by CYP2A6 accounts for the formation of 5-FU in vivo remains unclear, because the formation of 5-FU from tegafur is also catalyzed by the soluble fraction of a 100,000 x g supernatant and also derived from spontaneous degradation of tegafur.

Antimetabolites, Antineoplastic↗
PubMed1999

An event-related potential study in schizophrenia using Japanese sentences.

To examine the neurophysiological and cognitive characteristics of language disorder in schizophrenia, the N400 component and late positive component (LPC) of event-related potentials (ERPs) were investigated in medicated schizophrenic patients and health comparison subjects. The subjects were required to indicate whether Japanese sentence completions were semantically congruous or incongruous. The ERPs for the range of 300-500 ms to the incongruous completions contained a more negative component (N400), followed by LPC, which was inversely more positive for the incongruous than congruous condition. The N400 effect and the mean amplitude of the LPC were reduced in the patients. The attenuated N400 effect in schizophrenics mainly originated from an enhanced negativity for the congruous completions, suggesting that the use of context is poor in schizophrenia.

Adult↗
PubMed1999

Attentional processing of emotional information in obsessive-compulsive disorder.

In order to investigate attentional processing of emotional information in obsessive-compulsive disorder (OCD), 14 patients with OCD and 28 normal control (NC) subjects were asked to name the background colors of anxiety-relevant, compulsion-relevant, positive and neutral words (an emotional Stroop color-naming test). The stimulus words were presented subliminally, and supraliminally. The time of subliminal presentation for each subject was determined in advance by the lexical decision task. In the subliminal condition, the delay for anxiety- and compulsion-relevant words, when compared with neutral words, was greater in OCD patients, while no difference was found in NC subjects. In the supraliminal condition, no delay was found for both OCD patients and NC subjects. In other words, OCD patients were more sensitive to threat information when it could not be identified with consciousness. Moreover, the present study compared checking OCD with cleaning OCD in the attentional processing of emotional information. As a result, it was found that checking OCD patients responded more slowly in naming the background color of subliminal emotional words than cleaning OCD patients. The results indicate that OCD patients, especially with checking compulsion, may have a deficit in automatic processing of threat information.

Adult↗