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Biomedical subjects

Sunao Kaneko

Publications and source records attributed to Sunao Kaneko.

At least 37 records · Page 2Linked to original sources
PubMed2005

Dose-dependent interaction of paroxetine with risperidone in schizophrenic patients.

Augmentation with paroxetine (10-40 mg/d) for antipsychotic treatment may improve the negative symptoms in schizophrenic patients but involves a risk of drug-drug interaction. We studied the effects of paroxetine on plasma concentrations of risperidone and 9-hydroxyrisperidone and their clinical symptoms in risperidone-treated patients. Twelve schizophrenic inpatients with prevailingly negative symptoms receiving risperidone 4 mg/d were, in addition, treated with incremental doses of paroxetine for 12 weeks (10, 20, and 40 mg/d for 4 weeks each). Plasma concentrations of risperidone and 9-hydroxyrisperidone were quantified with liquid chromatography-mass spectrometry mass-mass spectrometry together with clinical assessments before and after each phase of the 3 paroxetine doses. Risperidone concentrations during coadministration of paroxetine 10, 20, and 40 mg/d were 3.8-fold (95% confidence interval, 3.2-5.8, P < 0.01), 7.1-fold (95% confidence interval, 5.3-16.5, P < 0.01), and 9.7-fold (95% confidence interval, 7.8-22.5, P < 0.01) higher than that before paroxetine coadministration, respectively. Active moiety (risperidone plus 9-hydroxyrisperidone) concentration was not increased during the paroxetine 10 mg/d (1.3-fold, not significant) or 20 mg/d (1.6-fold, not significant), but were significantly increased by 1.8-fold (95% confidence interval, 1.4-2.7, P < 0.05) during the paroxetine 40 mg/d. Significant improvement in negative symptoms was observed from 10 to 40 mg/d of paroxetine, whereas scores in extrapyramidal side effects during 20 and 40 mg/d of paroxetine were significantly higher than baseline score. This study indicates that paroxetine increases plasma risperidone concentration and active moiety concentration in a dose-dependent manner. Low-dose coadministration of paroxetine with risperidone may be safe and effective in the treatment of schizophrenic patients with negative symptoms.

Adult↗
PubMed2005

Genetics of idiopathic epilepsies.

PURPOSE: To search for clues to molecular genetics of common idiopathic epilepsy syndromes. Genetic defects have been identified recently in certain inherited epilepsy syndromes in which the phenotypes are similar to those of common idiopathic epilepsies. METHODS: Mutations identified as the causes of inherited idiopathic epilepsies were reviewed. RESULTS: Mutations of the genes encoding two subunits of the neuronal nicotinic acetylcholine receptor were found in autosomal dominant nocturnal frontal lobe epilepsy. Mutations of two K(+)-channel genes were identified in benign familial neonatal convulsions. Mutations of the genes encoding several subunits of the voltage-gated Na(+)-channel and gamma-aminobutyric acid (GABA)(A) receptor also were identified as the underlying causes of various epilepsy syndromes, such as autosomal dominant epilepsy with febrile seizures plus, benign familial neonatal infantile seizures, and autosomal dominant juvenile myoclonic epilepsy. Mutations within the same gene may result in different epilepsy phenotypes. Thus, the Na(+) channel, GABA(A) receptor, and their auxiliaries may be involved in the pathogenesis of various types of epilepsy. Some forms of juvenile myoclonic epilepsy, idiopathic generalized epilepsy, and absence epilepsy may result from mutations of Ca(2+) channels. Mutations of the Cl(-) channel have been recently found to be associated with a certain type of epilepsy. The recent discovery that mutations of LGI1, a gene encoding a nonchannel molecule, are associated with autosomal partial epilepsy with auditory features may provide a new insight into our understanding of the genetics of idiopathic epilepsy. CONCLUSIONS: These findings suggest the involvement of brain channelopathies in the pathogenesis of certain types of idiopathic epilepsy.

Codon, Nonsense↗
PubMed2005

[Clinical pharmacogenetics in the treatment of schizophrenia].

Numerous investigations on metabolic enzymes, cytochrome P450 (CYP), have been conducted since 1990. In the psychiatric field, the focus has been on CYP2D6, which is a major enzyme involved in metabolism of antidepressants and antipsychotics. Poor metabolizers (deficit metabolizers) for CYP2D6 represent 7% among Caucasians, while they accouut for less than 1% of Asians. The frequency of a mutated allele for CYP2D6*10, which leads to the decrease in CYP2D6 activity, is 40% in Asians. It has been reported that steady-state plasma concentration of haloperidol in subjects with mutated alleles for CYP2D6 is significantly higher than that in subjects without mutated alleles. At the same time, steady-state plasma concentration of risperidone is very different between CYP2D6 genotypes. In addition, several studies suggest that better efficacy or higher scores of side effects are observed in the subjects with mutated alleles for CYP2D6. Recently receptor polymorphism has become a concern and association between clinical response and polymorphism of dopamine and serotonin has been reported. In the dopamine D2, subjects with -141C Ins allele in -141C Ins/Del polymorphism and subjects with A1 allele in Taq1A have a better response to dopamine antagonists. Association between Ser allele and typical antipsychotics and between Gly allele and atypical antipsychotics has been investigated. There are still no data indicating significant association between dopamine D1 and clinical response to antipsychotics. Clinical pharmacogenetical studies from both a pharmacokinetical and a pharmacogynamical point of view are required in order to introduce and practice individualized medicine in psychiatric field easily.

Alleles↗
PubMed2005

[Psychophysiological basis of smells].

There has been an increase in the use of psychophysiological techniques, especially event-related potentials (ERPs) to evaluate the effects of odor on the central nervous system. In the study of ERPs related to odor, there are two main methods of the odor presentation: (1) to investigate the olfactory ERP (OERP) or chemosensory ERP (CSERP), that is to calculate electrophysiological responses to odor stimulation as a trigger; (2) to compare ERP of mental functioning during the odor exposed condition with that of no odor exposure. The amplitude of contingent negative variation (CNV) varies with the odorant being present, when the odor is presented as a trigger and when it is administrated during a task. It is suggested that CNV changes depend on not only the odorant but the anticipation, expectation and emotion of the subject. The latency of the N1 component becomes shorter with increasing concentrations of odors. The N1 amplitude does not depend on the odor concentration while the amplitude of the auditory N1 strongly depends on the stimulus intensity. There is only one report that the olfactory mismatch negativity (MMN) is present in the CSERP. On the other hand, auditory MMN is not affected by odor administration. In relation to the P3 component, rare odors evoked a larger amplitude in contrast to frequent odors, as well as P3 evoked by other modalities. These ERP studies with odors are expected to be applied to such clinical settings as the differentiation between the anosmic patients and normosmic persons, the functional evaluation of patients with brain tumors, the earlier detection of dementia, and the objective evaluation of aromatherapy.

Aromatherapy↗
PubMed2004

Sound perception affected by nonlinear variation of accuracy in memory trace.

The mismatch negativity (MMN) reflects the neural representation of the acoustic environment stored in sensory memory. The short phase of sensory memory corresponds to the temporal window of integration (TWI) which integrates the neighboring sounds into a unitary event. We measured the magnetic MMN (MMNm) and the discriminative reaction time (RT) responding to an omitted segment incorporated into a complex sound. Consequently, for the late omitted segments, the MMNm amplitudes were decreased, and those latencies and the RTs were prolonged. The percentages of the correct responses were also reduced for the late omitted segments. In sum, the discriminative sensitivity nonlinearly declined toward the end of the TWI, suggesting that the time-wise accuracy of the neural trace nonlinearly varies in sensory memory.

Acoustic Stimulation↗
PubMed2004

Defective function of GABA-containing synaptic vesicles in mice lacking the AP-3B clathrin adaptor.

AP-3 is a member of the adaptor protein (AP) complex family that regulates the vesicular transport of cargo proteins in the secretory and endocytic pathways. There are two isoforms of AP-3: the ubiquitously expressed AP-3A and the neuron-specific AP-3B. Although the physiological role of AP-3A has recently been elucidated, that of AP-3B remains unsolved. To address this question, we generated mice lacking mu3B, a subunit of AP-3B. mu3B-/- mice suffered from spontaneous epileptic seizures. Morphological abnormalities were observed at synapses in these mice. Biochemical studies demonstrated the impairment of gamma-aminobutyric acid (GABA) release because of, at least in part, the reduction of vesicular GABA transporter in mu3B-/- mice. This facilitated the induction of long-term potentiation in the hippocampus and the abnormal propagation of neuronal excitability via the temporoammonic pathway. Thus, AP-3B plays a critical role in the normal formation and function of a subset of synaptic vesicles. This work adds a new aspect to the pathogenesis of epilepsy.

Adaptor Protein Complex 3↗
PubMed2004

Determination of exocytosis mechanisms of DOPA in rat striatum using in vivo microdialysis.

To explore the exocytosis mechanism of striatal 3,4-dihydroxyphenylalanine (DOPA), this study determined the interaction between voltage-sensitive Ca2+-channel (VSCC) and SNARE on releases of DOPA and glutamate in rat striatum using microdialysis. Inhibitors of VSCCs and SNAREs did not affect basal glutamate release but decreased basal DOPA release, however, blocking effects of P-type-VSCC and synaptobrevin inhibitors were weaker than those of N-type-VSCC and syntaxin. The K+-evoked releases of DOPA and glutamate were reduced by inhibitors of P-type-VSCC and synaptobrevin predominantly and by inhibitors of N-type-VSCC and syntaxin weakly. However, interaction study between VSCC and SNARE on K+-evoked DOPA release indicates that DOPA release is regulated by different exocytosis mechanism from glutamate and monoamine during the depolarization stage (N-type-VSCC/P-type-VSCC/synaptobrevin and/or combination with N-type-VSCC/synaptobrevin and P-type-VSCC/synaptobrevin). Therefore we conclude that striatal DOPA release might be regulated by its specific exocytosis mechanism via different from dopaminergic presynaptic vesicle.

Analysis of Variance↗
PubMed2004

Mutations in EFHC1 cause juvenile myoclonic epilepsy.

Juvenile myoclonic epilepsy (JME) is the most frequent cause of hereditary grand mal seizures. We previously mapped and narrowed a region associated with JME on chromosome 6p12-p11 (EJM1). Here, we describe a new gene in this region, EFHC1, which encodes a protein with an EF-hand motif. Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals. Overexpression of EFHC1 in mouse hippocampal primary culture neurons induced apoptosis that was significantly lowered by the mutations. Apoptosis was specifically suppressed by SNX-482, an antagonist of R-type voltage-dependent Ca(2+) channel (Ca(v)2.3). EFHC1 and Ca(v)2.3 immunomaterials overlapped in mouse brain, and EFHC1 coimmunoprecipitated with the Ca(v)2.3 C terminus. In patch-clamp analysis, EFHC1 specifically increased R-type Ca(2+) currents that were reversed by the mutations associated with JME.

Animals↗
PubMed2004

Pharmacological discrimination of protein kinase associated exocytosis mechanisms between dopamine and 3,4-dihydroxyphenylalanine in rat striatum using in vivo microdialysis.

To explore the exocytosis mechanism of dopamine and its precursor, 3,4-dihydroxyphenylalanine (DOPA), we determined the effects of protein-kinase, cyclic-AMP-dependent protein-kinase (PKA), Ca(2+)-phospholipid-dependent protein-kinase (PKC) and Ca(2+)-calmodulin-dependent protein-kinase II (CaMK-II) on dopamine and DOPA releases in rat striatum using microdialysis. Basal DOPA and dopamine releases were reduced by PKC and CaMK-II inhibitors predominantly, and PKA inhibitor weakly. Ca(2+)-evoked releases were reduced by PKC and CaMK-II inhibitors, but not by PKA inhibitor. K(+)-evoked (20 min) releases were reduced by PKA and CaMK-II inhibitors predominantly, and PKC inhibitor weakly. Sustained K(+)-evoked (120 min) releases of DOPA and dopamine were reduced by CaMK-II inhibitor, but not by PKC or PKA. DOPA accumulation was reduced by PKA and CaMK-II inhibitors strongly, and PKC inhibitor weakly. Therefore, the present study demonstrates that striatal DOPA exocytosis is regulated by a similar protein kinase-associated exocytosis mechanism as that of dopamine.

Animals↗
PubMed2004

Both 3,4-dihydroxyphenylalanine and dopamine releases are regulated by Ca2+-induced Ca2+ releasing system in rat striatum.

To clarify the striatal Ca2+-dependent monoaminergic exocytosis mechanisms, this study determined the effects of the Ca2+-induced Ca2+ releasing system (CICR), containing inositol-trisphosphate-receptor (IP3R) and ryanodine-receptor (RyR), on striatal releases of dopamine and its precursor, 3,4-dihydroxyphenylalanine (DOPA), using microdialysis. The basal dopamine release is regulated by IP3R but not by RyR, whereas basal DOPA release does not require CICR. The K+-evoked releases of DOPA and dopamine were enhanced by IP3R agonist, whereas RyR agonist reduced it. Additionally, inhibition of dopamine release induced by RyR hyperactivation was prevented by inhibition of L-type voltage-sensitive Ca2+-channel activity. These present results suggest that CICR-associated regulation of striatal releases of DOPA and dopamine is restrictive during the resting stage, whereas CICRs play an important role as a reserve mechanism of exocytosis of striatal DOPA and dopamine during the hyperexcitable stage.

Adenosine↗
PubMed2004

Protein kinase associated with gating and closing transmission mechanisms in temporoammonic pathway.

The entorhinal cortex (EC) is a major source of afferent input to the hippocampus via the perforant and temporoammonic pathways; however, the detailed transmission mechanism in the temporoammonic pathway remains to be clarified. Thus, we determined interaction among GABA(A), AMPA/glutamate receptors and protein kinases (PKA and PKC) in the exocytosis of GABA and glutamate using multiprobe microdialysis, as well as propagation of neuronal excitability using optical recording in the EC-Hippocampal formation. Multiprobe microdialysis demonstrated that EC-evoked GABA release in ventral CA1 was predominantly regulated by the PKC-related rather than PKA-related exocytosis mechanism and was augmented by the activation of glutamatergic transmission. Contrary to GABA release, EC-evoked glutamate release was predominantly regulated by PKA-related rather than PKC-related mechanisms and was suppressed by activation of GABAergic transmission. Optical recording demonstrated that there are two sub-pathways in the temporoammonic pathway; direct projects from EC layers (II-IV) to dendrites on pyramidal cells and GABAergic interneurons in ventral hippocampal CA1. PKC activation enhanced trisynaptic transmission, whether the GABA(A) receptor was functional or blocked, whereas PKC activation enhanced and inhibited temporoammonic transmission when the GABA(A) receptor was functional and blocked, respectively. Thus, GABAergic inhibition, which is regulated by PKC activity, in the temporoammonic pathway is more significant than that in the trisynaptic pathway.

Animals↗
PubMed2004

Establishment of new cloned enzyme donor immunoassays (CEDIA) for haloperidol and bromperidol.

The authors have developed and verified the precision and accuracy of new automated cloned enzyme donor immunoassays (CEDIA) for haloperidol and bromperidol, and cross-validations have been performed with conventional semiautomated EIA kits (MARKIT-M) and high-performance liquid chromatographic (HPLC) methods. The CEDIA method provides a quick (about 10 minutes) assay for haloperidol or bromperidol, requiring no serum/plasma pretreatment or predilution. The CEDIA haloperidol/bromperidol assay showed little or no cross reactivity with either their metabolites or many drugs commonly coprescribed. MARKIT-M revealed considerable cross reactivity values proportional to the spiked amounts of reduced metabolites. Precision, accuracy, recovery, and linearity testing for the CEDIA assay were all sufficient for clinical use. Significant linear correlations were found between CEDIA and HPLC in measuring haloperidol (CEDIA = 1.06 x HPLC + 0.869; n = 44, rs = 0.913, P < 0.001) and bromperidol (CEDIA = 1.06 x HPLC + 0.606; n = 56, rs = 0.914, P < 0.001) concentrations. This study has, therefore, demonstrated that the CEDIA assay has a quick run time with high precision and accuracy, and this method is a useful tool for the TDM of haloperidol or bromperidol.

Adult↗
PubMed2004

Steady-state pharmacokinetics of a new antipsychotic agent perospirone and its active metabolite, and its relationship with prolactin response.

The authors investigated steady-state pharmacokinetics of perospirone and its active metabolite hydroxyperospirone (ID-15036) and its prolactin response in 10 schizophrenic patients receiving 16 mg twice daily. Plasma concentrations of perospirone, hydroxyperospirone, and prolactin were monitored just before and up to 12 hours after the dosing. Thereafter, the dose was decreased to 8 mg twice daily in 8 patients, and drug concentrations were determined. The geometric means of peak concentration (Css(max)), time to Css(max) (tmax), area under the plasma concentration-time curve from 0 to 12 hours [AUC (0-12)], and elimination half-life at steady state were 8.8 ng/mL, 0.8 hours, 22.0 ng x h/mL, and 1.9 hours, respectively, for perospirone, and those of Css(max), tmax, and AUC (0-12) for hydroxyperospirone were 29.4 ng/mL, 1.1 hours, and 133.7 ng x h/mL, respectively. There were no differences in dose-normalized Css(max) or AUC (0-12) perospirone and hydroxyperospirone between 16 mg/day and 32 mg/day of perospirone. Changes in prolactin concentration from 1 to 2 hours after the dosing were parallel with drug concentrations, and almost normal ranges of prolactin concentration were observed before the morning dose despite steady state. The current study indicated that perospirone is rapidly absorbed and rapidly eliminated, which influences the prolactin response. The active metabolite hydroxyperospirone may play an important role in the antipsychotic effect because the plasma concentration of this metabolite is higher than that of the parent compound.

Adult↗
PubMed2004

Mutations of neuronal voltage-gated Na+ channel alpha 1 subunit gene SCN1A in core severe myoclonic epilepsy in infancy (SMEI) and in borderline SMEI (SMEB).

PURPOSE: Severe myoclonic epilepsy in infancy (SMEI) is a distinct epilepsy syndrome. Patients with borderline SMEI (SMEB) are a subgroup with clinical features similar to those of core SMEI but are not necessarily consistent with the accepted diagnostic criteria for core SMEI. The aim of this study was to delineate the genetic correlation between core SMEI and SMEB and to estimate the frequency of mutations in both phenotypes. METHODS: We examined 96 healthy volunteers and 58 unrelated individuals whose clinical features were consistent with either core SMEI (n = 31) or SMEB (n = 27). We screened for genetic abnormalities within exons and their flanking introns of the genes encoding major subunits of the Na+ channels (SCN1A, SCN2A, SCN1B, and SCN2B) by using a direct sequencing method. RESULTS: In both core SMEI and SMEB, various mutations of SCN1A including nonsense and missense mutations were identified, whereas no mutations of SCN2A, SCN1B, and SCN2B were found within the regions examined. All mutations were heterozygous and not found in 192 control chromosomes. Mutations were identified in 26 (44.8%) of the 58 individuals and were more frequent (p < 0.05) in core SMEI (19 of 31) than in SMEB (seven of 27), as assessed by the continuity-adjusted chi2 test. Mutations resulting in a molecular truncation were found only in core SMEI. Among the mutations, two missense mutations were found in both core SMEI and SMEB. CONCLUSIONS: Our findings confirm that SMEB is part of the SMEI spectrum and may expand the recognition of SMEI and suggest other responsible or modifying genes.

Amino Acid Sequence↗
PubMed2004

Physical and psychomotor development in the offspring born to mothers with epilepsy.

Psychomotor development of 71 children born to mothers with epilepsy was prospectively studied and compared to those of 99 controls matched for age, maternal educational level and age, and socioeconomic status. Intrauterine growth retardation disappeared before age 3 years. Assessment at age 1.5 years revealed that exposure to seizures, high dose of antiepileptic drugs (AEDs) in utero, and small head circumference at birth affected development quotient (DQ) scores of motor or linguistic abilities or both. DQ scores of motor ability of children of mothers with complex partial seizures were lower than those with simple partial seizures when assessed at age 3 years. Assessments at age 1.5 years revealed that the total daily dose of AEDs correlated negatively with DQ scores of motor ability, and at age 3 years, maternal educational level affected DQ scores of some fields, including linguistic ability. The effects of AED exposure in utero and the occurrence of maternal seizures on the development of offspring were found to matter more at the younger age, but later on, the child care environment and, in particular, maternal ability of child-rearing, became more important. Our findings indicate that careful and regular follow-ups are needed to monitor the developmental stages of children of mothers with epilepsy, and the introduction of a day nursery should be suggested if necessary.

Abnormalities, Drug-Induced↗
PubMed2004

Marital status of patients with epilepsy with special reference to the influence of epileptic seizures on the patient's married life.

PURPOSE: We investigated the marital status of the patients with epilepsy to clarify the clinical factors impeding improvement of the quality of life in adults with epilepsy. METHODS: We examined the marital status of adult patients with epilepsy who did not have mental retardation and had been treated at Hirosaki University Hospital, Hirosaki, Japan, for >5 years. The present study included 278 patients (142 men and 136 women) ranging from age 20 to 60 years. RESULTS: Sixty-six men and 52 women were single. Seventy-six males and 84 females had been married. The present study investigated the proportion of patients in whom seizures were controlled at the time of marriage. Percentages were only 30% for men and 22% for women. This result showed that in many patients, seizures were not controlled when they were married, which suggests that seizures themselves may not markedly inhibit marriage. Thirteen men and 16 women (total, 29 patients) had experienced divorce. Epilepsy was the cause of divorce in seven of the 29 patients who had been divorced. Of these seven patients, only one patient had informed the spouse of the disease before marriage. In the remaining six patients, seizures were witnessed after marriage or the disease was revealed by medication, which resulted in divorces. CONCLUSIONS: Concerning the association between marriage and the job, a close relation was found between the presence or absence of marriage and the presence or absence of a job among male patients.

Adult↗
PubMed2004

Different inhibitory effect of fluvoxamine on omeprazole metabolism between CYP2C19 genotypes.

AIMS: Omeprazole is mainly metabolized by the polymorphic cytochrome P450 (CYP) 2C19. The inhibitory effect of fluvoxamine, an inhibitor of CYP2C19 as well as CYP1A2, on the metabolism of omeprazole was compared between different genotypes for CYP2C19. METHODS: Eighteen volunteers, of whom six were homozygous extensive metabolizers (EMs), six were heterozygous EMs and six were poor metabolizers (PMs) for CYP2C19, participated in the study. A randomized double-blind, placebo-controlled crossover study was performed. All subjects received two six-day courses of either daily 50 mg fluvoxamine or placebo in a randomized fashion with a single oral 40 mg dose of omeprazole on day six in both cases. Plasma concentrations of omeprazole and its metabolites, 5-hydroxyomeprazole, omeprazole sulphone, and fluvoxamine were monitored up to 8 h after the dosing. RESULTS: During placebo administration, geometric means of peak concentration (C(max)), under the plasma concentration-time curve from 0 to 8 h (AUC(0,8 h)) and elimination half-life (t(1/2)) of omeprazole were 900 ng ml(-1), 1481 ng ml(-1) h, and 0.6 h in homozygous EMs, 1648 ng ml(-1), 4225 ng ml(-1) h, and 1.1 h in heterozygous EMs, and 2991 ng ml(-1), 11537 ng ml(-1) h, and 2.8 h in PMs, respectively. Fluvoxamine treatment increased C(max) of omeprazole by 3.7-fold (95%CI, 2.4, 5.0-fold, P < 0.01) and 2.0-fold (1.4, 2.6-fold, P < 0.01), AUC(0,8 h) by 6.0-fold (3.3, 8.7-fold, P < 0.001) and 2.4-fold (1.7, 3.2-fold, P < 0.01), AUC(0, infinity ) by 6.2-fold (3.0, 9.3-fold, P < 0.01) and 2.5-fold (1.6, 3.4-fold, P < 0.001) and prolonged t((1/2)) by 2.6-fold (1.9, 3.4-fold, P < 0.001) and 1.4-fold (1.02, 1.7-fold, P < 0.05), respectively. However, no pharmacokinetic parameters were changed in PMs. The AUC(0,8 h) ratios of 5-hydroxyomeprazole to omeprazole were decreased with fluvoxamine in homozygous EMs (P < 0.05) and heterozygous EMs (P < 0.01). CONCLUSIONS: Even a low dose of fluvoxamine increased omeprazole exposure in EMs, but did not increase omeprazole exposure in PMs after a single oral dose of omeprazole. These findings confirm a potent inhibitory effect of fluvoxamine on CYP2C19 activity. The bioavailability of omeprazole might, to some extent, be increased through inhibition of P-glycoprotein during fluvoxamine treatment.

Adult↗