Nobutada Tashiro

The Effects of Genetic Polymorphisms of CYP2C9 and CYP2C 19 on Phenytoin Metabolism in Japanese Adult Patients with Epilepsy: Studies in Stereoselective Hydroxylation and Population Pharmacokinetics

Summary: Purpose: The aim of this study was to clarify the effects of genetic polymorphisms of cytochrome P450 (CYP) 2C9 and 2C19 on the metabolism of phenytoin (PHT). In addition, a population pharmacokinetic analysis was performed.

Involvement of γ-aminobutyric acid neurotransmission in phencyclidine-induced dopamine release in the medial prefrontal cortex

The present study was designed to examine the possible involvement of γ-aminobutyric acid (GABA) neurotransmission in the mechanism of phencyclidine (1-(1-phenylcyclohexyl)piperidine; PCP)-induced dopamine release in the medial prefrontal cortex, using in vivo microdialysis in awake, freely moving rats. Local perfusion via the dialysis probe into the medial prefrontal cortex with PCP (100 and 500 μM) and dizocilpine ((+)-5-methyl-10,11-dihydroxy-5-H-dibenzo(a,d)cyclo-heptan-5,10-imine; MK-801, 10 and 50 μM), a selective non-competitive NMDA receptor antagonist, was found to increase extracellular dopamine levels. Co-perfusion with NMDA (1 mM) or the GABAA receptor agonist muscimol (50 μM) attenuated the effects of PCP (500 μM) and MK-801 (50 μM) on extracellular dopamine levels. The dopamine reuptake inhibitor nomifensine (50 μM) also produced an increase in extracellular dopamine levels in the medial prefrontal cortex, but this effect was not affected by co-perfusion with muscimol (50 μM). On the other hand, local perfusion with PCP (100 and 500 μM) and MK-801 (10 and 50 μM), but not nomifensine (50 μM), reduced extracellular GABA levels in the medial prefrontal cortex. Co-perfusion with NMDA (1 mM) reduced the effects of PCP (500 μM) and MK-801 (50 μM) on extracellular GABA levels. These results suggest that PCP may facilitate dopamine release in the medial prefrontal cortex, at least in part, by the inhibition of GABA release via the antagonism of NMDA receptors.

Effect of phenycyclidine on dopamine release in the rat prefrontal cortex; an in vivo microdialysis study

The effect of phencyclidine (PCP) on the extracellular dopamine levels in the rat prefrontal cortex was investigated using an in vivo brain dialysis technique. PCP increased extracellular dopamine levels in the prefrontal cortex of freely-moving rats after the systemic (7.5 mg/kg i.p.) or the local injection (100 microM and 500 microM). The local injection of MK-801, which is a more selective and potent NMDA receptor antagonist than PCP also increased the extracellular dopamine levels (from 10 microM to 100 microM). These results suggest that part of the effect of PCP is attributable to its antagonist effect on the NMDA receptor.

Positive associations of polymorphisms in the metabotropic glutamate receptor type 3 gene (GRM3) with schizophrenia

Objectives Glutamatergic dysfunction is one of the major hypotheses of schizophrenia pathophysiology. We have been conducting systematic studies on the association between glutamate receptors and schizophrenia. We focused on the metabotropic glutamate receptor type 3 gene (GRM3) as a candidate for schizophrenia susceptibility. Methods We genotyped Japanese schizophrenics (n = 100) and controls (n = 100) for six single nucleotide polymorphisms (SNPs) located in the GRM3 region at intervals of approximately 50 kb. Statistical differences in genotype, allele and haplotype frequencies between cases and controls were evaluated by the &KHgr;2 test and Fishers exact probability test at a significance level of 0.05. Haplotype frequencies were estimated by the EM algorithm. Results A case‐control association study identified a significant difference in allele frequency distribution of a SNP, rs1468412, between schizophrenics and controls (P=0.011). We also observed significant differences in haplotype frequencies estimated from SNP frequencies between schizophrenics and controls. The haplotype constructed from three SNPs, including rs1468412, showed a significant association with schizophrenia (P=8.30 × 10−4). Conclusions Our data indicate that at least one susceptibility locus for schizophrenia is situated within or very close to the GRM3 region in the Japanese patients.

Genetic polymorphism of the CYP2C subfamily and excessive serum phenytoin concentration with central nervous system intoxication

The authors report on a Japanese adult male patient with a long history of partial seizures that were poorly controlled by conventional doses of phenytoin and other drugs. His treatment was complicated by toxic symptoms and an excessive serum phenytoin concentration, 32.6 microg/mL at a dose of 187.5 mg/day. Polymerase chain reaction-restriction fragment length polymorphism analysis disclosed heterozygosity involving cytochrome P450 subfamilies 2C9 (*1/*3) and 2C19 (*1/*3). Currently, it is generally accepted that the former mutation is responsible for the CYP2C9 poor metabolizer phenotype. Pharmacokinetic parameters were estimated by a kinetic analysis, MULTI, using 17 observed dose-concentration data sets: a lower Vmax (5.6 mg/kg/day) and a higher Km (11.5 microg/mL) were observed. Although phenytoin is metabolized predominantly by CYP2C9 with a minor contribution of CYP2C19, patients with the Leu359 variant should be monitored closely when treated with a moderate to high daily dose of phenytoin.

Genetic polymorphisms and functional characterization of the 5′‐flanking region of the human CYP2C9 gene: In vitro and in vivo studies

Genetic polymorphisms were identified in the 5′‐flanking region of the human CYP2C9 gene, and their effects on the phenotype were evaluated on the basis of the luciferase reporter gene assay and the in vivo pharmacokinetics of phenytoin.

Association analysis of polymorphisms in the upstream region of the human dopamine D4 receptor gene (DRD4) with schizophrenia and personality traits.

AbstractThe human dopamine D4 receptor (DRD4) is of major interest in molecular studies of schizophrenia and personality traits. We examined the association of schizophrenia and polymorphisms in the upstream region of the DRD4 gene (−768G>A in the negative modulator region; −521C>T, −376C>T, and −291C>T in the cell type-specific promoter region; and −616C>G between the two regions) in 208 schizophrenic patients and 210 normal controls. No significant difference in genotype and allele frequencies was observed between the two groups, indicating that these polymorphisms do not make a major contribution to the pathogenesis of schizophrenia. We also studied the association of polymorphisms in the upstream region and a 48-bp repeat polymorphism in exon III of the DRD4 gene with personality traits in 173 Japanese individuals who completed the temperament and character inventory (TCI). The −768G>A polymorphism was significantly associated with reward dependence (P = 0.044), while no significant association was observed between novelty seeking and polymorphisms in the upstream region or the exon III repeat polymorphism of the DRD4 gene.

P300 in response to the subject's own face

The P300 event‐related potentials in response to self‐relevant stimuli has been reported to be different from those to non‐target stimuli under a passive attention condition. In the present study the P300 in response to the subjects own face was examined. Twelve right‐handed volunteers served as subjects. In two separate conditions, deviant (subjects own face and red square; 30%), non‐target (two unfamiliar faces; 30% each), and target (famous face; 10%) stimuli were randomly presented on a computer screen. P300 amplitudes in response to the red square were larger than those to the unfamiliar faces, but were significantly lower than those to the subjects own face. The subjects own face in normal population may have an intense relevance to the subjects which has an additional effect over the simple orienting response.

Postnatal depression in Japanese mothers and the reconsideration of ‘Satogaeri bunben’

Abstract Background : Postnatal depression occurs in 10–15% of Western women. In Japan, there is a traditional support system for perinatal women and there have been few prospective studies on postnatal depression in terms of cross‐cultural studies.

Effects of isoprenaline on contractions of directly stimulated fast and slow skeletal muscles of the guinea‐pig

1 The actions of isoprenaline on the contraction and the resting potential of the isolated extensor digitorum longus (EDL), a fast contracting muscle, and the soleus, a slow contracting muscle, of the guinea‐pig were investigated. Twitch tension was elicited by direct supramaximal stimulation and recorded isometrically. 2 The twitch tension of EDL elicited by pulses of 0·5–10 ms duration was increased in the presence of isoprenaline (1 μg/ml). Isoprenaline increased the twitch tension of the soleus elicited by a pulse of more than 5 ms duration, but decreased it when elicited by a pulse of less than 1 millisecond. These effects were blocked by propranolol (1–3 μg/ml) but not by phentolamine (1–5 μg/ml). 3 In EDL, isoprenaline prolonged the time to peak tension and the half‐relaxation time. The twitch of the soleus was shortened by isoprenaline due to an acceleration of relaxation. These findings were independent of stimulus duration. 4 The potentiating effects of isoprenaline on the twitch tension of EDL and the soleus were not observed in K+‐free Krebs solution and were abolished by ouabain (1 μg/ml) and by reduction of the temperature from 33° to 18° C. The effects of isoprenaline on the relaxation process were not affected by these treatments. 5 In EDL, the resting potential increased from 77·3 mV to 78·5 mV after isoprenaline, whereas in the soleus it increased from 691 to 74·7 mV. These effects were blocked by propranolol, K+‐deficiency, ouabain, and cooling to 18° C. Hyperpolarization by isoprenaline was increased by substitution of isethionate for the external chloride. 6 There was a good correlation between the potentiation of the mechanical response and the hyperpolarization of the membrane by isoprenaline. The hyperpolarization seems to be due to activation of the Na+‐K+ pump.