Biomedical subjects

Koichi Otani

Publications and source records attributed to Koichi Otani.

At least 37 records · Page 2Linked to original sources

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 the CYP 2D6 genotype and cigarette smoking on the steady-state plasma concentrations of fluvoxamine and its major metabolite fluvoxamino acid in Japanese depressed patients.

The effects of the cytochrome P450 (CYP) 2D6 genotype and cigarette smoking on the steady-state plasma concentrations (C(ss)) of fluvoxamine (FLV) and its demethylated metabolite fluvoxamino acid (FLA) were studied in 49 Japanese depressed patients receiving FLV 200 mg/d. The C(ss) of FLV and FLA were measured by HPLC, and the wild-type allele (*1) and two mutated alleles causing absent (*5) or decreased (*10) CYP 2D6 activity were identified by PCR methods. The patients were divided into three genotype groups by the number of mutated alleles: 12 cases with no (*1/*1), 27 cases with one (*1/*5 and *1/*10), and 10 cases with two (*5/*10 and *10/*10) mutated alleles. The means +/- SD of the C(ss) of FLV and FLA and the FLA/FLV ratio of all patients were 169.1 +/- 147.5 ng/mL, 83.9 +/- 52.7 ng/mL, and 0.71 +/- 0.50, respectively. The C(ss) of FLV and FLA were not significantly different among the three genotype groups. However, the FLA/FLV ratio was significantly lower in the patients with one (P < 0.05) and two (P < 0.01) mutated alleles than in those with no mutated allele. There was no significant difference between nonsmokers (n = 34) and smokers (n = 15) in these values. In the stepwise multiple regression, the C(ss) of FLA (P < 0.05) and FLA/FLV ratio (P < 0.001) showed significant negative correlations with the number of mutated alleles, and the FLA/FLV ratio was significantly (P < 0.05) lower in women than in men. The present study suggests that the CYP 2D6 genotype and cigarette smoking have no major impact on the C(ss) of FLV and FLA, though CYP 2D6 is involved in the demethylation of FLV.

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

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↗

PubMed2003

High-performance liquid chromatographic determination of fluvoxamine and fluvoxamino acid in human plasma.

A high-performance liquid chromatographic (HPLC) method has been developed for the simultaneous determination of fluvoxamine and its major metabolite fluvoxamino acid in plasma. Fluvoxamine and fluvoxamino acid in plasma were extracted using a C18 bonded-solid phase cartridge, followed by C4 reversed-phase HPLC separation.Fluvoxamine, fluvoxamino acid and moperone as an internal standard were detected by ultraviolet absorbance at 254 nm. It was possible to determine both fluvoxamine and fluvoxamino acid in the concentration range of 25.0-200.0 ng/mL, respectively. The detection limits of both fluvoxamine and fluvoxamino acid were 10.0 ng/mL, respectively. The mean recoveries of fluvoxamine and fluvoxamino acid added to plasma were more than 94.0% and 96.5%, with a coefficient of variation of less than 7.6% and 8.2%, respectively. This method has been used for the simultaneous determination of steady-state plasma concentration (Css) of fluvoxamine and fluvoxamino acid in depressive patients treated with 200 mg of oral fluvoxamine dosed as 100 mg twice-daily. The Css values of fluvoxamine and fluvoxamino acid in twelve Japanese patients were showed individual variations, which were in the range of 48.3-532.9 ng/ml and 35.6-307.1 ng/ml, respectively.

Amino Acids↗

PubMed2003

[Cytochrome P450 3A4 and Benzodiazepines].

Cytochrome P450(CYP)3A4 is one of the CYP enzymes catalyzing oxidative metabolism, and involved in the metabolism of many drugs. Among benzodiazepines, alprazolam, triazolam, brotizolam and midazolam are mainly metabolished by CYP3A4, and quazepam, diazepam and flunitrazepam are partly metabolised by this enzyme. Azole antifungals, macrolide antibiotics, calcium antagonists and grapefruit juice inhibit CYP3A4 activity, while antiepileptics and rifampicin induce the activity. The drugs affecting CYP3A4 activity inhibit or induce the metabolism of the benzodiazepines metabolised by this enzyme, and induce side effects or reduce therapeutic effects of these drugs. Therefore, the combination of the two groups of drugs should be avoided, and if it is unavoidable the dose of benzodiazepines should be adjusted.

Anti-Anxiety Agents↗

PubMed2003

Morphology of the inner structure of the hippocampal formation in Alzheimer disease.

BACKGROUND AND PURPOSE: To our knowledge, inner structural alterations of the hippocampus have never been demonstrated because of the lack of contrast between the hippocampus proper and the superficial medullary lamina. We sought to demonstrate the anatomic details of the inner hippocampus and to elucidate its alterations in Alzheimer disease (AD) in vivo. METHODS: We obtained multishot diffusion- and T2-weighted MR images in 14 healthy control subjects and 26 patients with mild or moderate AD (diagnosis based on Mini-Mental Status Examination scores). We measured the width of the subiculum, CA1 and CA3-4, and the height of CA3-4 on coronal images. RESULTS: The subiculum and hippocampus proper were demonstrated as whirlpool-shaped hyperintense areas, and the superficial medullary lamina was visible as a hypointense structure along the inner margin of the hippocampus proper. Regarding the width of the subiculum and CA1, intergroup analysis revealed significant differences between the control and mild or moderate AD groups. In the width of CA3-4, we found no significant difference between the control and mild AD groups; however, differences between the control and moderate AD groups and between the mild and moderate AD groups were significant. In the height of CA3-4, we observed no significant differences between groups. CONCLUSION: We clearly visualized the inner structure of the hippocampal formation by using multishot diffusion-weighted imaging. The subiculum and CA1 are the most vulnerable regions in AD, and atrophy of these structures was evident in both mild and moderate AD.

Aged↗

PubMed2002

Occipital hypoperfusion in a patient with psychogenic visual disturbance.

A patient with bilateral diminished visual acuity and blurred vision was given the diagnosis of psychogenic visual disturbance after extensive psychiatric and ophthalmological examinations. Single photon emission computed tomography with Tc-99m-ethylcysteinate dimer demonstrated remarkably reduced regional cerebral blood flow (rCBF) in the bilateral occipital lobes. More specifically, rCBF was reduced in the visual association areas, but not in the primary visual areas. These findings suggest that functional suppression of the visual association area is associated with the development of psychogenic visual disturbance.

Adult↗

PubMed2002

Therapeutic effects of bromperidol on the five dimensions of schizophrenic symptoms.

Therapeutic profiles of bromperidol and their relationship with plasma drug concentration and prolactin response were investigated in 30 acutely exacerbated schizophrenic patients treated with randomly allocated fixed-doses of bromperidol (6, 12 or 18 mg/day) for 3 weeks. The mean values (+/- S.D.) of percentage improvement at 3 weeks in total Brief Psychiatric Rating Scale (BPRS) and five subgrouped symptoms were 59.8+/-29.2% for total, 64.6+/-37.5% for positive, 73.3+/-33.7% for excitement, 80.2+/-45.5% for cognitive, 43.1+/-46.5% for negative and 49.6+/-46.8% for anxiety-depression symptoms, respectively. Twenty (67%) of 30 patients were responders defined as having 50% or more symptom reduction significantly greater in responders than those in nonresponders after 2 weeks. Mean plasma bromperidol concentration in patients with 50% or more reduction in positive symptoms was significantly higher than in the others (8.2+/-4.7 vs. 4.1+/-1.8 ng/ml, P< .05). Percentage improvement in total BPRS at 1 and 2 weeks were correlated well with that at 3 weeks. These findings suggest that an early improvement in positive and anxiety-depression symptoms results in favorable outcome of total response to bromperidol treatment. Plasma drug monitoring may have a limited predictive value for improvement in positive symptoms.

Adult↗

PubMed2002

Improvement of both psychotic symptoms and Parkinsonism in a case of dementia with Lewy bodies by the combination therapy of risperidone and L-DOPA.

A 69-year-old female of dementia with Lewy bodies (DLB) with fluctuating cognitive impairment, visual and auditory hallucinations, persecutory delusions and Parkinsonism was treated by the combination of 1 mg/day risperidone and 300-750 mg/day L-DOPA. By this combination therapy, both the psychotic symptoms and Parkinsonism improved, while cognitive function did not deteriorate. This report suggests that the combination therapy of risperidone and L-DOPA may be worth considering in the special cases of DLB.

Aged↗

PubMed2002

Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients.

The presence of the long (l) variant of the serotonin (5-hydroxytryptamine: 5-HT) transporter gene-linked polymorphic region (5-HTTLPR) is reported to be associated with a more favorable and faster antidepressant effect of selective serotonin reuptake inhibitors in Caucasians. The frequency of the l allele is lower in Japanese than in Caucasians; therefore, the antidepressant effect of fluvoxamine can be not as good in Japanese as in Caucasians. The authors investigated whether 5-HTTLPR was associated with the antidepressant response to fluvoxamine in 66 Japanese patients with major depressive disorder in a protocolized-dosing 6-week study. The short (s) allele frequency was significantly higher in the responsive individuals than in the nonresponsive ones (P = .010). The present study suggests that fluvoxamine is not less effective in depressive patients carrying the s allele than in the ones carrying the l allele and it is not less effective in Japanese than in Caucasians.

Adult↗

PubMed2002

Comparison of prolactin concentrations between haloperidol and bromperidol treatments in schizophrenic patients.

The antipsychotic drug, bromperidol, is a close structural analogue of haloperidol. These two drugs also have similarities in metabolic pathways and pharmacological properties. In the present study, the prolactin concentrations in plasma during bromperidol versus haloperidol treatments were compared in the same individuals. The subjects were 22 schizophrenic inpatients, who first received bromperidol 12 mg/day for at least 2 weeks followed by haloperidol 12 mg/day. The prolactin concentration in plasma during bromperidol treatment (median and range; 24 and 7-93 ng/ml, respectively) was significantly (P< .01) lower than during haloperidol treatment (32 and 8-102 ng/ml), although the difference was small. The mean (+/- S.D.) plasma concentration of bromperidol was significantly lower than that of haloperidol (20.8+/-8.0 vs. 28.0+/-13.1 nmol/l, P<.05). Prolactin concentrations during both treatment phases correlated well in individuals (r's=.813, P<.001), while no correlation was observed between plasma concentrations of haloperidol and bromperidol (r=.053, ns). These findings suggest that slightly higher prolactin concentration does not necessarily lead to increased risk of hyperprolactinemia during bromperidol treatment compared with haloperidol treatment. In addition, it is suggested that both drugs show similar pharmacodynamic response despite the difference in pharmacokinetics in the same individuals.

Adult↗

PubMed2002

Neuroleptic malignant syndrome complicated by massive intestinal bleeding in a patient with chronic renal failure.

A patient with chronic renal failure (CRF) developed neuroleptic malignant syndrome (NMS) after administration of risperidone and levomepromazine. In addition to the typical symptoms of NMS, massive intestinal bleeding was observed during the episode. This report suggests that NMS in a patient with CRF may be complicated by intestinal bleeding and needs special caution for this complication.

Adult↗

PubMed2002

Monoamine oxidase: A gene polymorphism, tryptophan hydroxylase gene polymorphism and antidepressant response to fluvoxamine in Japanese patients with major depressive disorder.

Monoamine oxidase A (MAOA) and tryptophan hydroxylase (TPH) are the staple enzymes in the metabolism of serotonin (5-HT). The genetic polymorphisms of these two enzymes might individually alter the production, release, reuptake or degradation of 5-HT during the treatment of selective serotonin reuptake inhibitors (SSRIs), leading to the individual differences in the antidepressant effects of SSRIs. The authors investigated whether a functional polymorphism in the MAOA gene promoter (MAOA-VNTR) and a TPH gene polymorphism in intron 7 (TPH-A218C) were associated with the antidepressant response to fluvoxamine in 66 Japanese patients with major depressive disorder during a 6-week study with a specific dosage plan. Fifty-four patients completed the study. The present study fails to demonstrate that the genetic polymorphisms of MAOA-VNTR and TPH-A218C affect the antidepressant effect of fluvoxamine in Japanese patients with major depressive disorder.

Adult↗

PubMed2002

The characteristics of side-effects of bromperidol in schizophrenic patients.

The characteristics of the side-effects of bromperidol was investigated in 33 acutely exacerbated schizophrenic patients. The most frequently observed side-effects were extrapyramidal symptoms. Acute dystonia developed in 10 of 33 patients, and the mean age was significantly lower (P < 0.05) in patients with dystonia (27.3 +/- 6.2 years) than that in patients without dystonia (41.5 +/- 12.9 years). Plasma drug concentrations were not associated with side-effects. These findings suggest that acute dystonia is affected by age factor, and that daily dosage or monitoring of drug concentration is unlikely to be a useful marker for the prediction of side-effects during bromperidol treatment.

Adult↗

PubMed2002

No effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam.

To examine the involvement of cytochrome P450 3A4 in the metabolism of estazolam, the effect of itraconazole, a potent inhibitor of this enzyme, on the single oral dose pharmacokinetics and pharmacodynamics of estazolam was studied in a double-blind randomized crossover manner. Ten healthy male volunteers received itraconazole 100 mg/day or placebo orally for 7 days, and on the 4th day they received a single oral 4-mg dose of estazolam. Blood samplings and evaluation of psychomotor function by the Digit Symbol Substitution Test, Visual Analog Scale, and Stanford Sleepiness Scale were conducted up to 72 hours after estazolam dosing. There was no significant difference between the placebo and itraconazole phases for the peak plasma concentration, apparent oral clearance, and elimination half-life. Similarly, none of the psychomotor function parameters was significantly different between the two phases. The current study showed no significant effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of estazolam, suggesting that cytochrome P450 3A4 is not involved in the metabolism of estazolam to a major extent.

Administration, Oral↗

PubMed2002

Relationship between plasma concentrations of trazodone and its active metabolite, m-chlorophenylpiperazine, and its clinical effect in depressed patients.

Relationships between plasma concentrations of trazodone and m-chlorophenylpiperazine (m-CPP) and the clinical effects were studied in 26 patients (12 males and 14 females) with major depression during three weeks' treatment of 150 mg/d trazodone using an open-study design. Depressive symptoms were evaluated by Montgomery Asberg Depression Rating Scale (MADRS), and subjective side effects were assessed by UKU side effects rating scale (UKU) before treatment and at weekly intervals. Plasma concentrations of trazodone and m-CPP were measured by HPLC. There were significant linear relationships between the steady-state plasma concentration (Css) of trazodone and both the final MADRS score (rs = -0.529, P < 0.01) and the percent improvement at 3 weeks (r = 0.442, P < 0.05). Moreover, the proportion of responders (a final MADRS score of 10 or less) was significantly higher in the group with a trazodone concentration greater than 714 ng/mL (6/8 vs 3/18, P = 0.008). No significant correlation was found between UKU score and the Css for either compound nor between the UKU score and the ratio of m-CPP/trazodone. The current study suggests that a therapeutic response is dependent on the plasma concentration of trazodone but not m-CPP and that a plasma trazodone concentration of about 700 ng/mL may be a threshold for a good therapeutic response.

Adult↗

PubMed2002

Association between -1438G/A promoter polymorphism in the 5-HT(2A) receptor gene and fluvoxamine response in Japanese patients with major depressive disorder.

Genetic polymorphism of the serotonin 5-HT(2A) receptor seems to be associated with therapeutic response to selective serotonin reuptake inhibitors (SSRIs). The present study investigated whether a novel -1438G/A polymorphism in the promoter region of the 5-HT(2A )receptor gene is associated with therapeutic response to fluvoxamine (an SSRI) in 66 Japanese patients with major depressive disorder. Fluvoxamine (50 to 200 mg) was administered twice daily for 6 weeks. Fifty-four patients completed this study. The genotype distribution and the allele frequencies showed no significant difference between responders and non-responders. The time-course of the Montgomery-Asberg Depression Rating Scale scores showed no significant difference among -1438G/G, -1438G/A, and -1438A/A genotype groups. The results demonstrated that the -1438G/A promoter polymorphism in the 5-HT(2A) receptor gene was unlikely to have a major role in therapeutic response to fluvoxamine in Japanese patients with major depressive disorder.

Adult↗