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Biomedical subjects

Akihito Suzuki

Publications and source records attributed to Akihito Suzuki.

At least 19 recordsLinked to original sources
PubMed2006

No association between the TPH A218C polymorphism and personality traits in Japanese healthy subjects.

It has been suggested that the central serotonergic activity is implicated in personality traits. Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in serotonin synthesis. In the present study, the association between the TPH A218C polymorphism and personality traits assessed by the Temperament and Character Inventory (TCI) was examined in 345 Japanese healthy subjects. The TPH A218C polymorphism was determined by a PCR-RFLP method. There were no significant differences in the seven dimension scores of TCI among the A/A, A/C, and C/C genotype groups by the one-way ANOVA. There was a significant negative correlation between age and the NS scores. Females showed significantly higher scores of HA, RD, and ST, and significantly lower scores of SD than males. The multiple regression analysis using age, gender, and the TPH genotype as independent variables also showed no significant association between any dimension score and the genotype. The present study thus suggests that the TPH A218C polymorphism does not affect personality traits in Japanese healthy subjects.

Adult↗
PubMed2006

CYP2C19 polymorphism affects personality traits of Japanese females.

It has been suggested that personality traits are heritable. The polymorphic cytochrome P450 (CYP) 2C19 metabolizes sex hormones and 5-hydroxytryptamine, which are involved in multiple brain functions. In the present study, the relationship between the CYP2C19 polymorphism and personality traits was examined in 487 Japanese healthy volunteers. Personality traits were assessed by the Temperament and Character Inventory (TCI), and the two mutated alleles causing absent CYP2C19 activity were identified by a PCR-RFLP method. In females, the scores of reward dependence (p=0.026), cooperativeness (p=0.001), and self-transcendence (ST) (p=0.049) were significantly lower in poor metabolizers (PMs) than in extensive metabolizers (EMs). In males, none of the seven TCI dimensions was significantly different between EMs and PMs. The present study thus suggests that the CYP2C19 polymorphism affects personality traits of Japanese females.

Adult↗
PubMed2006

Rifampicin markedly decreases plasma concentration and hypnotic effect of brotizolam.

The purpose of the present study was to examine the effects of rifampicin on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam. Thirteen healthy male volunteers received rifampicin 450 mg/day, or matched placebo, for 7 days in a double-blind randomized crossover manner. On the sixth day they received a single oral 0.5-mg dose of brotizolam, and blood sampling was performed for 24 hours, together with an assessment of psychomotor function using the Digit Symbol Substitution Test and the Stanford Sleepiness Scale. Rifampicin treatment significantly (P<0.001) decreased the peak plasma concentration (69%), total area under the plasma concentration-time curve (90%) and elimination half-life (79%) of brotizolam. Rifampicin significantly increased the area under the score-time curve of the Digit Symbol Substitution Test (P<0.01), and decreased that of the Stanford Sleepiness Scale (P<0.05). The present study suggests that rifampicin markedly decreases plasma concentration and hypnotic effect of brotizolam and, therefore, this combination is not recommended in clinical practice.

Adult↗
PubMed2006

Effects of caffeine on the kinetics of fluvoxamine and its major metabolite in plasma after a single oral dose of the drug.

The effects of caffeine on the kinetics of fluvoxamine (FLV) and its major metabolite fluvoxamino acid (FLA) in plasma, after a single oral dose of the drug, were studied in 12 healthy male volunteers. The subjects received caffeine 300 mg/d or placebo for 11 days in a double-blind randomized crossover manner, and on the eighth day they received a single oral 50-mg dose of FLV. Blood sampling and pharmacodynamic evaluation were conducted up to 72 hours after FLV dosing. Plasma concentrations of FLV and FLA were measured by high-performance liquid chromatography. Caffeine significantly decreased the plasma concentrations at 6 time points (P<0.05) and total area under the plasma concentration-time curve (156.5+/-51.7 vs. 118.9+/-38.2 ng/h/mL, P<0.01) of FLV. Plasma concentration and pharmacokinetic parameters of FLA were not affected by caffeine. Caffeine induced no significant change in the pharmacodynamic effects of FLV. The present study suggests that caffeine slightly induces the metabolism of FLV, probably mediated by CYP1A2.

Adult↗
PubMed2006

Monoamine oxidase A gene promoter polymorphism affects novelty seeking and reward dependence in healthy study participants.

It has been suggested that monoamine oxidase A plays an important role in the characterization of personality. Previous studies on the association between the polymorphism of variable number tandem repeat in the promoter region of the monoamine oxidase A gene and personality traits have, however, been unproductive. In the present study, the association between the monoamine oxidase A variable number tandem repeat polymorphism and personality traits assessed by the Temperament and Character Inventory was examined in 324 Japanese volunteers without psychiatric disorders. The low activity allele with three repeats (allele 3) and high activity allele with four repeats (allele 4) were determined by a polymerase chain reaction method. The carriers of allele 3 in males and the homozygotes of allele 3 in females were classified as the low activity group, the heterozygotes of alleles 3 and 4 in females as the medium activity group, and the carriers of allele 4 in males and the homozygotes of allele 4 in females as the high activity group. One-way analysis of variance showed that the scores of novelty seeking (P=0.006) and reward dependence (P=0.013) were significantly higher in the high activity group than in the low activity group. Multiple regression analysis demonstrated that the excess in the high activity allele was significantly associated with higher scores of novelty seeking (P=0.004) and reward dependence (P=0.003). The present study thus suggests that the monoamine oxidase A variable number tandem repeat polymorphism affects novelty seeking and reward dependence in healthy study participants.

Adult↗
PubMed2005

A three-factor model of the MADRS in major depressive disorder.

Major Depressive Disorder (MDD) may be composed of some symptom clusters with distinct neurochemical disturbances, suggesting the importance of the factor analysis of depressive symptoms; however, the results of previous studies using the Montgomery-Asberg Depression Rating Scale (MADRS) have been inconsistent. In the present study, factor analysis of the MADRS was performed in 132 Japanese patients (range 23-74 years, mean 47.6 years) with MDD without any psychiatric comorbidity. The principal component analysis with Varimax rotation identified three factors, accounting for 61% of the total variance: The first factor, labeled dysphoria, included pessimistic thoughts, suicidal thoughts, and reported sadness; the second factor, labeled retardation, included lassitude, inability to feel, apparent sadness, and concentration difficulties; and the third factor, labeled vegetative symptoms, included reduced sleep, reduced appetite, and inner tension. The score of the vegetative factor showed a significant positive correlation with age and was significantly higher in females than in males. This study suggests that the symptoms of MDD, as assessed by the MADRS, cluster into three factors (dysphoria, retardation, and vegetative symptoms).

Adult↗
PubMed2005

Interaction study between enoxacin and fluvoxamine.

Authors examined a possible interaction between enoxacin, an inhibitor of cytochrome P4501A2, and fluvoxamine (FLV), a substrate for this enzyme. Ten healthy male volunteers received enoxacin 200 mg/d or placebo for 11 days in a double-blind randomized crossover manner, and on the eighth day they received a single oral 50-mg dose of FLV. Blood samplings and pharmacodynamic evaluation were conducted up to 72 hours after FLV dosing. Plasma concentrations of FLV and its active metabolite fluvoxamino acid (FLA) were measured by high-performance liquid chromatography. Enoxacin significantly increased the plasma concentrations at 2 hours (placebo versus enoxacin, mean+/-SD: 4.4+/-2.4 vs 7.0+/-4.1 ng/mL, P<0.05) and 3 hours (7.4+/-2.7 vs 11.2+/-3.8 ng/mL, P<0.01) and the Cmax (10.2+/-2.9 vs 11.6+/-4.0 ng/mL, P<0.05) of FLV. Plasma concentration and pharmacokinetic parameters of FLA were not affected by enoxacin. Enoxacin significantly (P<0.05) increased the scores of the Stanford Sleepiness Scale from 0.5 to 4 hours, suggesting that enoxacin increased the sleepiness produced by FLV. The present study suggests that enoxacin slightly inhibits the metabolism of FLV, and enoxacin should be combined with FLV with caution.

Adult↗
PubMed2005

Inhibition of the metabolism of brotizolam by erythromycin in humans: in vivo evidence for the involvement of CYP3A4 in brotizolam metabolism.

AIMS: To obtain in vivo evidence for the involvement of cytochrome P450 (CYP) 3A4 in the metabolism of brotizolam. METHODS: Fourteen healthy male volunteers received erythromycin 1200 mg day(-1) or placebo for 7 days in a double-blind randomized crossover manner. On the 6th day they received a single oral 0.5-mg dose of brotizolam, and blood samplings were performed for 24 h. RESULTS: Erythromycin treatment significantly increased the peak plasma concentration (P < 0.05), total area under the plasma concentration-time curve (P < 0.01), and elimination half-life (P < 0.01) of brotizolam. CONCLUSIONS: The present study provides in vivo evidence for the involvement of CYP3A4 in brotizolam metabolism.

Administration, Oral↗
PubMed2004

Single oral dose pharmacokinetics of quazepam is influenced by CYP2C19 activity.

The effects of cytochrome P450 (CYP)2C19 activity and cigarette smoking on the single oral dose pharmacokinetics of quazepam were studied in 20 healthy Japanese volunteers. Twelve subjects were extensive metabolizers (EMs), and 8 subjects were poor metabolizers (PMs) by CYP2C19 as determined by the PCR-based genotyping. Nine subjects were smokers (>10 cigarettes/d), and 11 subjects were nonsmokers. The subjects received a single oral 20-mg dose of quazepam, and blood samplings and evaluation of psychomotor function were conducted up to 72 hours after dosing. Plasma concentrations of quazepam and its active metabolite 2-oxoquazepam (OQ) were measured by HPLC. There were significant differences between EMs and PMs in the peak plasma concentration (mean +/- SD: 34.5 +/- 16.6 versus 66.2 +/- 19.2 ng/mL, P < 0.01) and total area under the plasma concentration-time curve (490.1 +/- 277.5 vs 812.1 +/- 267.2 ng x h/mL, P < 0.05) of quazepam. The pharmacokinetic parameters of OQ and pharmacodynamic parameters were not different between the 2 groups. Smoking status did not affect the pharmacokinetic parameters of quazepam and OQ or pharmacodynamic parameters. The present study suggests that the single oral dose pharmacokinetics of quazepam are influenced by CYP2C19 activity but not by cigarette smoking.

Adult↗
PubMed2004

Effects of various factors on steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone: lack of impact of MDR-1 genotypes.

AIMS: An in vitro study has suggested that risperidone is a substrate of P-glycoprotein, which is coded by MDR-1 gene. Thus, we studied the effects of major polymorphisms of the MDR-1 gene on plasma drug concentrations. METHODS: Subjects were 85 schizophrenic patients receiving 3 mg twice daily of risperidone. Sample collections were conducted 12 h after the bedtime dosing. Plasma concentrations of risperidone and 9-hydroxyrisperidone were quantified using LC/MS/MS. MDR-1 genotypes (C3435T and G2677T/A) and CYP2D6 genotypes were identified using PCR-RFLP methods. RESULTS: There was no difference in geometric mean (95% CI) of steady-state plasma concentration of risperidone between C3435T genotypes [C/C, C/T, T/T; 2.06 (1.63, 6.47), 2.96 (3.10, 7.91), 2.28 (1.81, 8.04) ng ml(-1), P = 0.759] or G2677T/A genotypes [G/G, G/T or A, T or A/T or A; 1.62 (0.08, 6.07), 2.64 (3.25, 7.10), 2.71 (2.77, 8.72) ng ml(-1), P = 0.625] or 9-hydroxyrisperidone between C3435T genotypes [38.3 (33.7, 50.1), 34.9 (32.9, 42.0), 35.7 (31.7, 42.3) ng ml(-1), P = 0.715] or G2677T/A genotypes [40.6 (33.0, 51.8), 35.0 (33.3, 42.4), 36.1 (32.8, 47.2) ng ml(-1), P = 0.601]. Multiple regression analyses including CYP2D6 genotypes, sex, and age revealed that steady-state plasma concentration of risperidone correlated with the number of mutated alleles for CYP2D6 (standardized partial correlation coefficients (beta) = 0.540, P < 0.001) and those of 9-hydroxyrisperidone (standardized beta = 0.244, P = 0.038) and active moiety (standardized beta = 0.257, P = 0.027) correlated with age. CONCLUSIONS: These findings suggest that the MDR-1 variants are not associated with steady-state plasma concentration of risperidone or 9-hydroxyrisperidone, but CYP2D6 genotypes and age are determinants of these concentrations.

Adolescent↗
PubMed2003

Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome.

Our previous study has suggested that the TaqI A polymorphism of dopamine D2 receptor gene (DRD2) is associated with the predisposition to neuroleptic malignant syndrome (NMS). However, the specificity of this polymorphism as a predictor of NMS dose not seem to be sufficient enough. Meanwhile, it has been shown that the non-carriers of Del allele of the -141C Ins/Del polymorphism in the promoter region of DRD2 have lower dopamine D2 receptor in the brain than the carriers. In addition, dopamine D3 receptor gene has a Ser(9)Gly polymorphism, which may alter the receptor function. The present study examined the association between these three polymorphisms and the development of NMS to investigate if a combination of these polymorphisms could increase the specificity as markers for NMS. The subjects were 17 psychiatric patients who had developed NMS (13 patients with schizophrenia, 3 with major depression, and 1 with dementia of the Alzheimer's type) and 163 schizophrenic patients who had never developed this syndrome. The frequency of the A1 allele was significantly (P = 0.012) higher in the patients who had developed NMS (59%) than in the patients who had not (35%). The proportion of the A1 carriers was significantly (P = 0.003) higher in the patients with NMS (16/17: 94%) than in those without the syndrome (93/163: 57%). However, no significant differences were found in the allele and genotype frequencies of the other two polymorphisms between the two groups. The present study suggests that only the TaqI A polymorphism is at least partly useful as a predictor of NMS, but the -141 C Ins/Del and Ser(9)Gly polymorphisms are not.

Adult↗
PubMed2003

Combination of dopamine D2 receptor gene polymorphisms as a possible predictor of treatment-resistance to dopamine antagonists in schizophrenic patients.

Both the A1 allele carriers of TaqI A and Del allele noncarriers of -141C Ins/Del for dopamine D(2) receptor (DRD(2)) gene polymorphisms have been reported to have a lowered DRD(2) density. The present study aimed to examine whether the combinations of these two DRD(2) gene polymorphisms predict treatment response to antidopaminergic agents in schizophrenic patients. Subjects consisted of 49 acutely exacerbated schizophrenic inpatients treated with bromperidol (30 cases, mean dose+/-S.D.: 11.4+/-4.8 mg/day) or nemonapride (19 cases, 18 mg/day). Clinical symptoms were evaluated using Brief Psychiatric Rating Scale (BPRS) before and 3 weeks after the treatment. DRD(2) genotypes were determined using a polymerase chain reaction method. The A1 noncarriers with a Del allele showed poorer percentage improvement in anxiety-depression symptom after 3-week treatment (n=9, 7.3+/-42.9%) than A1 carriers without Del alleles (n=25, 62.4+/-38.0%) or A1 noncarriers without Del alleles (n=10, 65.4+/-29.2%). However, these preliminary results should be replicated in further research with a larger number of the subjects in each haplotype subgroup.

Adult↗
PubMed2003

Histamine H1-receptor antagonists, promethazine and homochlorcyclizine, increase the steady-state plasma concentrations of haloperidol and reduced haloperidol.

The effects of histamine H1-receptor antagonists, promethazine and homochlorcyclizine, both of which are inhibitors of CYP2D6, on the steady-state plasma concentrations (Css) of haloperidol and reduced haloperidol were studied in 23 schizophrenic inpatients receiving haloperidol, 12 to 36 mg/d, for 2 to 29 weeks. Promethazine, 150 mg/d, in 11 patients and homochlorcyclizine, 60 mg/d, in the others were coadministered for at least 1 week. Blood sampling was performed before and during coadministration of promethazine or homochlorcyclizine and 1 week after the discontinuation, together with clinical assessments by Brief Psychiatric Rating Scale (BPRS) and Udvalg for kliniske undersogelser (UKU) side effect rating scale. The Css (mean +/- SD) of haloperidol and reduced haloperidol during promethazine coadministration (27.6 +/- 24.9 and 8.6 +/- 13.2 ng/mL) were significantly higher than those before the coadministration (12.7 +/- 10.8 and 5.0 +/- 6.0 ng/mL; P < 0.01) or 1 week after the discontinuation (15.6 +/- 14.8 and 5.8 +/- 7.9 ng/mL; P < 0.05). The Css of haloperidol and reduced haloperidol during homochlorcyclizine coadministration (14.9 +/- 8.1 and 6.4 +/- 5.4 ng/mL) were also significantly higher than those before the coadministration (10.9 +/- 7.2 and 3.8 +/- 3.6 ng/mL; P < 0.01) or 1 week after the discontinuation (12.9 +/- 7.4 and 4.8 +/- 4.1 ng/mL; P < 0.05). No change in BPRS or UKU score was found throughout the study. Thus, the current study suggests that coadministration of clinical doses of promethazine and homochlorcyclizine increases the Css of haloperidol and reduced haloperidol via the inhibitory effects on the CYP2D6-catalyzed metabolism of haloperidol and reduced haloperidol.

Adult↗
PubMed2003

Effects of various CYP2D6 genotypes on the steady-state plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, in Japanese patients with schizophrenia.

The effects of various CYP2D6 genotypes on the steady-state plasma concentrations (Css) of risperidone and its active metabolite, 9-hydroxyrisperidone, were studied in 85 Japanese schizophrenic patients (27 men and 58 women) treated with 6 mg/d risperidone for at least 2 weeks. Plasma concentrations of risperidone and 9-hydroxyrisperidone were measured using liquid chromatography-tandem mass spectrometry. The patients had the following CYP2D6 genotypes: wild-type (wt)/wt (40 patients), CYP2D6*10 (*10)/wt ( 28), CYP2D6*5 (*5)/wt ( 8), *10/*10 ( 5), *5/*10 ( 3), and CYP2D6*4/CYP2D6*14 ( 1), respectively. The Css values of risperidone and 9-hydroxyrisperidone were corrected to the median body weight of 58 kg. The medians (ranges) of the Css of risperidone in the aforementioned genotype groups were 2.2 (0.37-35.7), 6.4 (2.1-26.5), 12.3 (4.7-39.5), 19.4 (13.4-26.4), 64.0 (41.6-68.8), and 91.8 nmol/L. Those values for risperidone-to-9-hydroxyrisperidone ratio were 0.03 (0.01-0.33), 0.06 (0.03-0.19), 0.14 (0.07-0.29), 0.28 (0.25-0.38), 0.48 (0.38-0.58), and 2.35, respectively. The Css of risperidone was significantly (P < 0.05 or P < 0.001) different among the four genotype groups (wt/wt, *10/wt, *5/wt, and *10/*10), except between the *5/wt and *10/*10 groups. Also, the risperidone-to-9-hydroxyrisperidone ratio significantly (P < 0.005 or P < 0.001) differed among these genotype groups. No significant differences were found in the Css of 9-hydroxyrisperidone and the active moiety (the Css of risperidone plus 9-hydroxyrisperidone) among these genotype groups. This study confirms previous findings that the CYP2D6 status affects the Css of risperidone via its strong regulation of 9-hydroxylation of risperidone. However, similar active moiety of risperidone among different genotype groups suggests that the determination of the CYP2D6 genotype has little importance for clinical situations.

Adult↗
PubMed2003

Effects of itraconazole on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug.

The effects of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the plasma kinetics of quazepam and its two active metabolites after a single oral dose of the drug were studied. Ten healthy male volunteers received itraconazole 100 mg/d or placebo for 14 days in a double-blind randomized crossover manner, and on the fourth day of the treatment they received a single oral 20-mg dose of quazepam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 240 h after quazepam dosing. Itraconazole treatment did not change the plasma kinetics of quazepam but significantly decreased the peak plasma concentration and area under the plasma concentration-time curve of 2-oxoquazepam and N-desalkyl-2-oxoquazepam. Itraconazole treatment did not affect either of the psychomotor function parameters. The present study thus suggests that CYP 3A4 is partly involved in the metabolism of quazepam.

Administration, Oral↗
PubMed2003

Significant dose effect of carbamazepine on reduction of steady-state plasma concentration of haloperidol in schizophrenic patients.

A reduction in haloperidol concentration induced by carbamazepine coadministration has been consistently reported. However, the degree of this reduction is very different among individuals treated with various doses of carbamazepine. Thus, we investigated dose effect of carbamazepine on the steady-state plasma concentration of haloperidol. Eleven excited schizophrenic inpatients, despite receiving haloperidol 12 mg/d, were treated with incremental doses of carbamazepine for 6 weeks (100, 300, 600 mg/d for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the 3 carbamazepine doses. Mean haloperidol concentrations during coadministration of carbamazepine 100, 300, and 600 mg/d were 75%, 39%, and 15%, respectively, of corresponding variables before carbamazepine coadministration. Negative linear correlations were observed between dose or plasma concentration of carbamazepine and the degree of reduction in haloperidol concentration. Mean carbamazepine dose and plasma carbamazepine concentrations at 50% reduction of haloperidol concentration were 240 mg/d and 3.5 microg/mL, respectively. Scores in total and excitement symptoms were significantly reduced after carbamazepine coadministration, whereas no changes were observed in other clinical symptoms or any of the subgroup side effects. Therefore, this study indicates that carbamazepine decreases plasma haloperidol concentration in a dose-dependent or concentration-dependent manner, and that reduction in haloperidol concentration is apparent even at subtherapeutic dose of carbamazepine.

Adult↗
PubMed2003

Interaction study between fluvoxamine and quazepam.

It has been reported that fluvoxamine, an inhibitor of various cytochrome P450 enzymes, markedly inhibits the metabolism of several drugs. The purpose of the present study was to examine a possible interaction between fluvoxamine and quazepam. Twelve healthy male volunteers received fluvoxamine 50 mg/day or placebo for 14 days in a double-blind randomized crossover manner, and on the 4th day they received a single oral 20-mg dose of quazepam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test and Stanford Sleepiness Scale were conducted up to 240 hours after quazepam dosing. Plasma concentrations of quazepam and its active metabolites 2-oxoquazepam (OQ) and N-desalkyl-2-oxoquazepam (DOQ) were measured by high-performance liquid chromatography (HPLC). Fluvoxamine did not change plasma concentrations of quazepam but significantly decreased those of OQ from 6 to 12 hours and those of DOQ from 3 to 48 hours. The AUC ratio of OQ to quazepam was significantly lower in the fluvoxamine phase. Fluvoxamine did not affect psychomotor function at most of the time points. The present study suggests that fluvoxamine slightly inhibits the metabolism of quazepam to OQ, but this interaction appears to have minimal clinical significance.

Adult↗