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Biomedical subjects

K Otani

Publications and source records attributed to K Otani.

At least 109 records · Page 6Linked to original sources
PubMed1997

Single-dose pharmacokinetics and pharmacodynamics of oral triazolam in relation to cytochrome P4502C19 (CYP2C19) activity.

Previous studies have suggested that triazolam is at least partly metabolized by cytochrome P4503A4 (CYP3A4). However, no study has examined the relationship between the metabolism of triazolam and CYP2C19, which is involved in the metabolism of diazepam. Therefore, the single-dose pharmacokinetics and pharmacodynamics of oral triazolam were studied in relation to the CYP2C19 status assessed by the S-mephenytoin 4-hydroxylation capacity in 12 healthy male volunteers, consisting of seven extensive metabolizers (EMs) and five poor metabolizers (PMs) of S-mephenytoin 4-hydroxylation. Each subject was administered a single oral dose of 0.5 mg of triazolam, and blood was sampled up to 12 hours after the dosing. Psychomotor function was assessed by the Digit-Symbol Substitution test, Visual Analogue Scale, and Udvalg for Kliniske Undersøgelser (UKU) scale. Plasma triazolam concentrations were measured by high-performance liquid chromatography. There were no significant differences in plasma concentrations from 20 minutes to 6 hours after the dosing nor in pharmacokinetic parameters of triazolam between the EM and PM groups. No significant difference was found in psychomotor function between the EM and PM groups. These results suggest that CYP2C19 is not involved in the metabolism of triazolam and that CYP2C19 status is not a pharmacodynamic determinant of this triazolobenzodiazepine.

Adjuvants, Anesthesia↗
PubMed1997

Effects of thioridazine, an inhibitor of CYP2D6, on the steady-state plasma concentrations of the enantiomers of mianserin and its active metabolite, desmethylmianserin, in depressed Japanese patients.

The antidepressant mianserin is administered as a racemate of the S(+)- and R(-)-enantiomers. Previous in-vitro studies have suggested that CYP2D6 is involved in the stereoselective metabolism of mianserin and its active metabolite, desmethylmianserin. To determine a role for CYP2D6 in vivo, the effects of thioridazine, an inhibitor of CYP2D6, on the steady-state plasma concentrations of the enantiomers of mianserin and desmethylmianserin were examined in 13 depressed Japanese patients. All patients were taking 30 mg of racemic mianserin at bedtime for 8-50 days. Thioridazine (40 mg/day) was coadministered for 1 week, and blood samplings were performed before and after thioridazine coadministration, 12 h after bedtime dosing. Plasma concentrations of the enantiomers of mianserin and desmethylmianserin were measured by HPLC, and the CYP2D6 genotype was determined by allele-specific PCR analysis. Thioridazine significantly increased plasma concentration of S(+)-mianserin (mean SD: 78.2 +/- 35.0 vs. 150.8 +/- 48.7 nM, P < 0.001), but not R(-)-mianserin (39.8 +/- 21.2 vs. 39.5 +/- 20.6 nM, NS). Thioridazine also significantly increased plasma concentrations of both S-desmethylmianserin (11.9 +/- 2.8 vs. 24.4 +/- 10.7 nM, P < 0.01) and R-desmethylmianserin (42.6 +/- 28.4 vs. 115.6 +/- 36.9 nM, P < 0.001). One patient homozygous for the defective allele CYP2D6*5 had the second highest and highest plasma concentrations of S(+)-mianserin and R-desmethylmianserin, respectively, before thioridazine coadministration, and exhibited little increase in plasma concentration of the drugs after thioridazine coadministration. These results suggest that thioridazine specifically inhibits the metabolism of S(+)-mianserin and R-desmethylmianserin, probably through inhibition of CYP2D6, but not R(-)-mianserin.

Antidepressive Agents, Second-Generation↗
PubMed1997

Zonisamide monotherapy in newly diagnosed infantile spasms.

PURPOSE: We determined the short-term efficacy of zonisamide (ZNS) monotherapy in newly diagnosed patients with infantile spasms (IS). METHODS: Eleven hospitals participated in this open, prospective trial. ZNS 3-10 mg/kg/day was administered as the second-choice drug to 11 newly diagnosed patients with IS (cryptogenic 3, symptomatic 8) who failed to respond to high-dose vitamin B6. RESULTS: Four infants with symptomatic IS had cessation of spasms and disappearance of the hypsarrhythmia. In these responders, the spasms ceased after a few days (1-5 days) of treatment at a dose of ZNS 4-5 mg/kg/day which produced plasma ZNS concentrations ranging from 5.2 to 16.3 microg/ml (mean 9.8 microg/ml). There were two relapses (50%) 4-6 weeks after cessation of seizures, however. Relapse was predicted by effects of ZNS on EEG; the 2 infants in whom an abnormal EEG persisted had relapses, whereas the 2 whose EEG normalized remained seizure-free (follow-up 20 and 26 months). No adverse reactions were noted. CONCLUSIONS: ZNS may be effective in the initial treatment of selected patients with IS.

Adrenocorticotropic Hormone↗
PubMed1997

Birth trends, survival improvements, and aging.

"Decompositions of a change in the proportion of aged persons on the basis of the stable population theory [have] emphasized the contribution of fertility change. This study confirmed that cohort survival improvements largely contributed to changes in the proportion of aged persons and the average age since the late 1970s. Particularly, the cohort survival effects for those belonging to the age group 65+ at the time concerned was great." The geographical focus is on Japan.

Adult↗
PubMed1996

Suppression of antigen-induced arthritis in rabbits by ex vivo gene therapy.

Gene therapy offers a novel approach to treating human joint diseases such as rheumatoid arthritis. In the present study, we have used the retrovirus, MFG-IRAP, to transfer the human IL-1 receptor antagonist protein (IRAP) gene to rabbits' knees and have assessed its impact on inflammatory and chondrodestructive aspects of the acute phase of antigen-induced arthritis in these joints. Surprisingly, intra-articular expression of IRAP was three- to fivefold higher in arthritic knees than in nonarthritic knees, accumulating to levels of over 20 ng/knee in the highest expressing joints. This level of expression produced a marked chondroprotective effect but a milder anti-inflammatory one. Both the increased cartilage matrix catabolism and the inhibition of matrix synthesis that occur in antigen-induced arthritis were abrogated in the presence of the IRAP gene; the latter effect was particularly strong. Of the indices of inflammation that were examined, only leukocyte influx into the joint space was inhibited, and this effect declined with time. Concentrations of rabbit IL-1 were reduced by the IRAP gene, suggesting inhibition of an autocrine induction loop. These data demonstrate that the course of arthritic disease in the rabbit knee can be altered by genetic manipulation, thus encouraging the further development of gene treatments for human joint diseases.

Animals↗
PubMed1996

Simple and selective assay of 4-hydroxymephenytoin in human urine using solid-phase extraction and high-performance liquid chromatography with electrochemical detection and its preliminary application to phenotyping test.

A simple and selective HPLC method for the determination of 4-hydroxymephenytoin (4-OH-M) in human urine, using a controlled potential coulometric detector equipped with a dual working electrode cell of fully porous graphite, has been developed. After acid hydrolysis of urine, 4-OH-M and the internal standard (I.S.), 5-hydroxy-1-tetralone, were extracted from urine by means of a Bond Elut Certify LRC column. The extracts were chromatographed on a reversed-phase mu Bondapak C18 column using methanol-50 mM KH2PO4 (pH 4.0) (30:70, v/v) as the mobile phase at a flow-rate of 1.0 ml/min. Electrochemical detection at applied potential of 800 mV resulted in a limit of quantitation of 0.76 micrograms/ml. The method showed a satisfactory sensitivity, precision, accuracy, recovery and selectivity. The present method was applied to the phenotyping test in thirteen Japanese healthy volunteers who received an oral 100-mg racemic mephenytoin. The phenotypes determined by the present method were found to be in agreement with those obtained with the reported customary assay based on gas chromatography.

Adult↗
PubMed1996

Possible inhibitory effect of diazepam on the metabolism of zotepine, an antipsychotic drug.

Effects of smoking and cytochrome P450 2C19 (CYP2C19) status on the single dose kinetics of zotepine and pharmacokinetic interaction between zotepine and diazepam were investigated. In 14 healthy volunteers, the pharmacokinetics of zotepine after a single oral 25 mg dose were compared between eight smokers and six non-smokers, or between seven extensive metabolizers (EMs) and seven poor metabolizers (PMs) of S-mephenytoin. There was no significant difference in any pharmacokinetic parameters between smokers and non-smokers, or between the EM and PM groups. In 17 patients treated with zotepine 80-340 mg/day, intra-individual changes in plasma concentrations of zotepine caused by coadministration of diazepam 10 mg/day for 2 weeks were examined. Plasma concentrations of zotepine were significantly increased after coadministration of diazepam (P < 0.05). Consequently, it is suggested that neither smoking nor CYP2C19 status affects the metabolism of zotepine. The elevation in plasma concentrations of zotepine after coadministration of diazepam may be a result of competitive inhibition of zotepine metabolism by diazepam via other isoenzyme than CYP2C19, e.g., CYP3A4.

Adult↗
PubMed1996

A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans: in vivo evidence for the involvement of CYP3A4 in alprazolam metabolism.

OBJECTIVE: To assess the possible involvement of CYP3A4 in the metabolism of alprazolam in vivo. METHOD: Twelve healthy male volunteers were randomly allocated to one of the two different treatment sequences, placebo-erythromycin or erythromycin-placebo, with an at least 6-week washout period between the two trial phases. Each volunteer received 400 mg erythromycin or matched placebo given orally three times a day for 10 days and an oral dose (0.8 mg) of alprazolam on the posttreatment day 8. Plasma concentration of alprazolam was measured up to 48 hours after the administration, and psychomotor function was assessed at each time of blood samplings with use of the Digit Symbol Substitution Test, visual analog scale, and Udvalg for kliniske undersøgelser side effect rating scale. RESULTS: Erythromycin significantly (p < 0.001) increased the area under the plasma concentration-time curves (200 +/- 43 versus 322 +/- 49 ng . hr/ml from 0 to 48 hours and 229 +/- 52 versus 566 +/- 161 ng . hr/ml from 0 hour to infinity), decreased the apparent oral clearance (1.02 +/- 0.31 versus 0.41 +/- 0.12 ml/min/kg), and prolonged the elimination half-life (16.0 +/- 4.5 versus 40.3 +/- 14.4 hours) of alprazolam. However, any psychomotor function variables did not differ significantly between the erythromycin and placebo trial phases. CONCLUSION: This study suggests that erythromycin, an inhibitor of CYP3A4, inhibits the metabolism of alprazolam, providing an in vivo evidence for the involvement of CYP3A4 in its metabolism. However, the kinetic change of alprazolam by erythromycin does not result in the pharmacodynamic change of this triazolobenzodiazepine, at least after single dosing.

Administration, Oral↗
PubMed1996

No interaction between desipramine and bromperidol.

1. The authors studied the effects of coadministration of desipramine, which is a substrate of CYP2D6, on plasma concentrations of bromperidol and its reduced metabolite (reduced bromperidol). Clinical changes were also evaluated by the CGI and UKU. 2. The subjects were 13 schizophrenic inpatients receiving bromperidol 12.24 mg/day for 1.20 weeks. Desipramine 50 mg/day was coadministered for 1 week, and blood samplings and clinical ratings were performed before and after the coadministration. 3. Plasma concentrations of bromperidol and reduced bromperidol were measured by a HPLC method. 4. Desipramine coadministration did not affect plasma concentration of bromperidol (9.6 +/- 4.5 vs. 9.6 +/- 2.8 ng/ml) nor that of reduced bromperidol (2.8 +/- 2.5 vs. 2.8 +/- 2.1 ng/ml). 5. There was no significant change in the CGI scores nor UKU scores after desipramine coadministration. 6. The present study thus suggests that there is no interaction between desipramine and bromperidol.

Adult↗
PubMed1996

Plasma prolactin concentration and psychopathology of schizophrenia.

1. The correlation between plasma prolactin concentration and psychopathology, as assessed by the BPRS, was studied in 56 unmedicated schizophrenic patients (28 males, 28 females). 2. There was no significant correlation between plasma prolactin concentration and total BPRS score or each item score. 3. No significant correlation was found when the BPRS items were classified into five clusters, i.e., positive, excitement, cognitive, negative, and anxiety-depression symptoms. 4. When males and females were analyzed separately, no significant correlation was found except a weak negative correlation (rs = -0.388, p < 0.05) for hostility score in females. 5. The present study suggests that plasma prolactin concentration does not reflect psychopathology of schizophrenia.

Adolescent↗
PubMed1996

Growth suppression in children receiving acetazolamide with antiepileptic drugs.

To clarify the effect of the clinical dosage of acetazolamide on growth in children with epilepsy or febrile convulsion, the standard scores of height and weight in 17 subjects receiving acetazolamide as an adjunct to unchanged monotherapy of antiepileptic drug were compared longitudinally through four phases: before antiepileptic drug administration, with monotherapy of antiepileptic drug, with acetazolamide in addition to monotherapy, and after acetazolamide discontinuation. The standard scores of both height and weight in the subjects were significantly reduced during the phase of acetazolamide administration. During this period, serum concentrations of potassium and total CO2 decreased while that of chloride increased, suggesting the existence of metabolic acidosis in the subjects. For both height and weight, there was no correlation between the degree of standard score reduction during acetazolamide administration and age at the time of acetazolamide initiation, duration of acetazolamide administration, dosages of acetazolamide, and variety of antiepileptic drugs concomitantly administered with acetazolamide. We speculate that metabolic acidosis induced by acetazolamide suppressed the growth of the subjects and that there were large individual differences in the susceptibility to acetazolamide for growth suppression among patients receiving acetazolamide.

Acetazolamide↗
PubMed1996

Carbamazepine augmentation therapy in three patients with trazodone-resistant unipolar depression.

In three patients with trazodone-resistant unipolar depression, carbamazepine 400 mg/day was co-administered for 4 weeks. They all showed favourable responses; two non-delusional patients completely or almost recovered, while one delusional patient showed considerable improvement in depressive symptoms other than delusions of guilt. Plasma concentrations of trazodone and its active metabolite m-chlorophenylpiperazine (m-CPP) were decreased, while the m-CPP/trazodone ratio was increased in all cases. The present report suggests that carbamazepine augments antidepressant effects of trazodone by an enhancement of serotonin function.

Aged↗
PubMed1996

Dermabrasion using an ultrasonic surgical aspirator.

We used an ultrasonic surgical aspirator on the epidermal surface to perform dermabrasion instead of the conventional motor-driven grinder. It was determined on histologic examination that it is possible to fragment the epidermis with greater selectively using the ultrasonic surgical aspirator. Abrasion also can be performed safely on spotty lesions and intricate, problematic regions with the ultrasonic surgical aspirator. We feel that the ultrasonic surgical aspirator is a promising device for use in dermabrasion.

Adult↗
PubMed1996

Effects of carbamazepine coadministration on plasma concentrations of trazodone and its active metabolite, m-chlorophenylpiperazine.

Effects of carbamazepine coadministration on plasma concentrations of trazodone and its active metabolite, m-chlorophenylpiperazine (m-CPP) were studied in six depressed patients treated with trazodone. The daily dose of trazodone was 150 mg in three cases and 300 mg in three cases. Carbamazepine, 400 mg/day, was coadministered for 4 weeks, and blood samples were taken before carbamazepine addition and at weekly intervals after the addition. Carbamazepine significantly (p < 0.01) decreased plasma concentrations of not only trazodone but also m-CPP at each week. On the average, plasma concentrations of trazodone and m-CPP at 4 weeks were 24 and 40% of the corresponding precarbamazepine values. This study thus suggests that carbamazepine coadministration decreases plasma concentrations of trazodone and m-CPP by inducing the metabolism of these compounds.

Anticonvulsants↗
PubMed1996

A method for rapid determination of zotepine by gas chromatography-mass spectrometry.

A rapid and sensitive method using solid-phase extraction and gas chromatography-mass spectrometry (GC-MS) has been developed for the determination of zotepine (ZTP), an atypical neuroleptic, in human plasma. The detection limit of ZTP was 1 microgram/L. Standard curves over the concentration range from 2.5 to 100 micrograms/L had a good linearity. Intraassay variability ranged from 2.2 to 3.3% and interassay variability from 3.5 to 6.6% at the concentration range of 5-75 micrograms/L. Our preliminary data of single-dose kinetics of ZTP by using this method suggested that the peak time and elimination half-life was much longer than previously reported, and that there appeared to be a second peak after 10-12 h of ZTP administration, indicating the possibility of the presence of enterohepatic recirculation.

Antipsychotic Agents↗