PubMed Health⌕ Search

Biomedical subjects

Yoshimasa Inoue

Publications and source records attributed to Yoshimasa Inoue.

At least 37 records · Page 2Linked to original sources
PubMed2003

Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia.

Augmentation with low-dose fluvoxamine (50-100 mg/day) to antipsychotic treatment may improve the negative symptoms in schizophrenic patients, but involves a risk of drug-drug interaction. We studied the effects of fluvoxamine on plasma concentrations of haloperidol and reduced haloperidol, and their clinical symptoms, in haloperidol treated patients. Twelve schizophrenic inpatients with prevailingly negative symptoms receiving haloperidol 6 mg/day were additionally treated with incremental doses of fluvoxamine for 6 weeks (25, 75 and 150 mg/day for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the three fluvoxamine doses. Geometric mean of haloperidol concentrations during coadministration of fluvoxamine 25, 75 and 150 mg/day were 120% (95%CI; 114-127%), 139% (95%CI; 130-149%), and 160% (95%CI; 142-178%) of those before fluvoxamine coadministration, respectively. We found positive correlations between increase in plasma haloperidol concentrations and plasma fluvoxamine concentrations. Scores in negative symptoms were significantly reduced after fluvoxamine coadministration, whereas no changes were observed in the other psychiatric symptoms or any subgrouped side effects. Therefore, this study indicates that fluvoxamine increases plasma haloperidol concentrations in a dose-dependent manner. However, relatively small elevations in haloperidol concentration did not lead to the development of extrapyramidal symptoms under the conditions of this study.

Adult↗
PubMed2003

Structure--activity relationships of azasugar-based MMP/ADAM inhibitors.

In order to investigate structure-activity relationships of azasugar series toward metalloproteinases, we synthesized and evaluated several azasugar-based compounds. As a result, it was found that 4-phenoxybenzene derivative 3 having 2R,3R,4R,5S-configurations exhibited most potent inhibitory activities against matrix metalloproteinase-1, -3 and -9 and TACE.

ADAM Proteins↗
PubMed2003

Design, synthesis and evaluation of novel azasugar-based MMP/ADAM inhibitors.

In order to verify whether azasugar would be a useful scaffold for inhibitory activity against metalloproteinases, we synthesized some azasugar-based compounds. As a result, it is clarified that azasugar moiety could function as successful inhibitor of matrix metalloproteinase-1, -3 and -9 and TACE.

ADAM Proteins↗
PubMed2003

Determination of a new atypical antipsychotic agent perospirone and its metabolite in human plasma by automated column-switching high-performance liquid chromatography.

A simple and sensitive column-switching high-performance liquid chromatographic (HPLC) method with fluorescence detection is described for the quantification of perospirone, a serotonin and dopamine antagonist, and its metabolite ID-15036 in human plasma. The test compounds were extracted from 2 ml of plasma using chloroform-hexane (30:70, v/v) and the extract was injected into a column I (TSK-PW precolumn, 10 micro m, 35 x 4.6 mm I.D.) for clean-up and column II (C(18) STR ODS-II analytical column, 5 micro m, 150 x 4.6 mm I.D.) for separation. The peak was detected using a fluorescence detector set at Ex 315 nm and Em 405 nm, and the total time for a chromatographic separation was approximately 30 min. The method was validated for the concentration range from 0.1 to 100 ng/ml. Mean recoveries were 97% for perospirone and 96% for ID-15036. Intra- and inter-day relative standard deviations were less than 2.8 and 5.3% for perospirone and 2.4 and 4.4% for ID-15036, respectively, at the concentration range from 0.3 to 30 ng/ml. This method shows good specificity with respect to commonly prescribed psychotropic drugs, and it could be successfully applied for pharmacokinetic studies and therapeutic drug monitoring.

Administration, Oral↗
PubMed2003

Effects of concomitant fluvoxamine on the metabolism of alprazolam in Japanese psychiatric patients: interaction with CYP2C19 mutated alleles.

OBJECTIVES: Administration of fluvoxamine (FLV) with concomitant benzodiazepines is common in clinical situations. We studied the effects of the coadministration of FLV on plasma concentrations of alprazolam (ALP). We also studied the effects of CYP2C19(*)2 or CYP2C19(*)3 on these drug interactions. METHODS: The subjects were 23 Japanese outpatients all concomitantly treated with FLV either before or after monotherapy with ALP. We measured the plasma concentrations of ALP and FLV using a column-switching, high-performance liquid chromatographic method with ultraviolet detection. The CYP2C19(*)2 or CYP2C19(*)3 alleles were identified using a polymerase chain reaction analysis. RESULTS: Coadministration with FLV produced significant, on average 58%, increases in the plasma concentrations of ALP ( P<0.001). There were, however, wide variations in the interactive effects of the coadministration of FLV on the plasma concentrations of ALP. While there were some subjects who had greater increases in plasma ALP concentrations, more than 100%, in response to the coadministration of FLV among the subjects with no mutated or one mutated allele, there are no subjects who had increases in plasma ALP concentrations of more than 50% among the subjects with two mutated alleles. The differences of these variances among the three genotype groups reached a level of significance ( P<0.05). CONCLUSION: Coadministration of FLV significantly increased the plasma concentrations of ALP compared with ALP monotherapy. Wide variations were observed in the drug interactions, with the CYP2C19 genotype possibly being related to these interactions.

Adult↗
PubMed2003

Synthesis and structure-activity relationships of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids as HB-EGF shedding inhibitors.

HB-EGF Shedding inhibitors have been expected to become effective medicines for skin diseases caused by the proliferation of keratinocytes. In order to discover novel HB-EGF shedding inhibitors and clarify their structure-activity relationships, 5,6,7,8-tetrahydronaphthylidine-based hydroxamic acid and 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids have been synthesized. Among the synthesized compounds, the ethoxyethoxy derivative 3o and the methoxypropoxy derivative 3p exhibited much more potent HB-EGF shedding inhibitory activity than CGS 27023A. The structural modification of 5,6,7,8-tetrahydropyrido[3,4-b]pyrazine-based hydroxamic acids enabled us to establish the following structure-activity relationships; the existence of the hydroxamic acid, the sulfonamide, and the phenyl moieties are crucial for a potent HB-EGF shedding inhibitory activity, and the stereochemistry of the alpha carbon of hydroxamic acid is also important. In addition, from the comparison of their HB-EGF shedding inhibitory activities with their MMPs inhibitory activities, we found that the S1' pocket of the responsible enzyme for HB-EGF shedding is deep unlike that of MMP-1.

Epidermal Growth Factor↗
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

Poor reliability of therapeutic drug monitoring data for haloperidol and bromperidol using enzyme immunoassay.

Therapeutic drug monitoring (TDM) services for plasma concentrations of haloperidol and bromperidol using enzyme immunoassay (EIA) methods are available in Japan, whereas high-performance liquid chromatographic (HPLC) methods are preferred in other countries. To compare these methods, we took 54 plasma samples for haloperidol and 91 plasma samples for bromperidol from schizophrenic patients receiving haloperidol or bromperidol, and the samples were measured using both commercial EIA and HPLC methods. Significant linear correlations were found between the two methods in determining haloperidol (EIA = 1.351 x HPLC + 1.39; r = 0.934, P < 0.001) and bromperidol (EIA = 1.420 x HPLC + 0.712; r = 0.956, P < 0.001) concentrations, but plasma concentrations using the EIA kits were approximately 92% (95% CI; 53-131%) and 62% (54-70%) higher than those using HPLC for haloperidol and bromperidol, respectively. Mean (and range) plasma concentrations of reduced metabolites were 54% (30-92%) and 55% (29-111%) of those of haloperidol and bromperidol, respectively. The present study suggests that reduced metabolites are included to a considerable degree in TDM data using the EIA kits. Therefore, some limitation of TDM data of haloperidol and bromperidol using the EIA kits, ie, high precision but poor accuracy, should be kept in mind.

Adult↗
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

The modifier subunit of glutamate cysteine ligase (GCLM) is a molecular target for amelioration of cisplatin resistance in lung cancer.

It is unclear whether a subunit of glutamate cysteine ligase [a modifier subunit (GCLM) and a catalytic subunit (GCLC)] is an effective target for ameliorating cisplatin (CDDP)-resistance. We inhibited each subunit of GCL mRNA using a specific ribozyme (M-Rz and C-Rz) in the pulmonary adenocarcinoma cell line A549. GCL activity was suppressed by the ribozyme. CDDP-resistance was more effectively ameliorated when GCLM rather than GCLC was inhibited. GCLM is a potentially more effective pharmacologic target for ameliorating CDDP-resistance in non-small cell lung cancer than GCLC.

Antineoplastic Agents↗
PubMed2002

Interleukin 18 (IL-18) in synergy with IL-2 induces lethal lung injury in mice: a potential role for cytokines, chemokines, and natural killer cells in the pathogenesis of interstitial pneumonia.

Interleukin 18 (IL-18) was discovered as an interferon-gamma (IFN-gamma)-inducing factor and plays important roles in natural killer (NK) cell activation. IL-18 also induces proinflammatory cytokines; chemokines; helper T-cell 2 (T(H)2) cytokines (eg, IL-4, IL-13); and immunoglobulin E (Ig-E) and IgG1 production. The combination of IL-18 plus IL-2 or IL-12 up-regulates IFN-gamma gene expression and NK cytotoxicity and has synergistic antitumor activity in vivo and in vitro. Here it is reported that daily administration of IL-18 with IL-2, but not of IL-18 or IL-2 alone, induces lethal lung injury in normal mice, but not in IL-18 receptor alpha (IL-1 receptor-related protein)-deficient (IL-18 receptor alpha(-/-)) mice. Marked interstitial infiltration of lymphocytes, composed mainly of NK cells, was found in the lungs of IL-18/IL-2-treated mice. Increased cytokine and chemokine levels were observed in the sera and lungs of IL-18/IL-2-treated mice. Administration of IL-18/IL-2 was also lethal to mice treated with a metalloproteinase inhibitor, which inhibited tumor necrosis factor-alpha and Fas-ligand release. While IFN-gamma(-/-) mice were partially resistant to the treatment, IL-4(-/-), IL-13(-/-), IL-4/IL-13(-/-), and Stat6(-/-) mice were sensitive to IL-18/IL-2, indicating that these genes were not involved in the host response. The lethal effect by IL-18/IL-2 was completely eliminated in severe combined immunodeficient mice pretreated with antiasialo-GM1 antibody and normal mice pretreated with anti-NK1.1 but not with anti-CD4 or anti-CD8, monoclonal antibody. These results suggest that specific cytokines, chemokines, and NK cells are involved in the pathogenesis of interstitial pneumonia. These results suggest that the clinical use of this interleukin may result in unexpected physiological consequences.

Animals↗
PubMed2002

New type of metalloproteinase inhibitor: design and synthesis of new phosphonamide-based hydroxamic acids.

A series of phosphonamide-based hydroxamate derivatives were synthesized, and the inhibitory activities were evaluated against various metalloproteinases in order to clarify its selectivity profile. Among the four diastereomeric isomers resulting from the chirality at the C-3 and P atoms, the compound with a (R,R)-configuration both at the C-3 position and the phosphorus atom was found to be potently active, while the other diastereomeric isomers were almost inactive. A number of (R,R)-compounds synthesized here exhibited broad spectrum activities with nanomolar K(i) values against MMP-1, -3, -9, and TACE and also showed nanomolar IC(50) values against HB-EGF shedding in a cell-based inhibition assay. The modeling study using X-ray structure of MMP-3 suggested the possible binding mode of the phosphonamide-based inhibitors.

Amides↗
PubMed2002

New strategy for antedrug application: development of metalloproteinase inhibitors as antipsoriatic drugs.

Phosphonamide-based inhibitors were synthesized and evaluated for the inhibitory activities against the shedding of epidermal growth factors, amphiregulin and heparin-binding EGF-like growth factor, that would participate in the development of psoriasis. All compounds exhibited excellent inhibitory activities for these EGF sheddings; however, they also inhibited matrix metalloproteinases (MMPs). To avoid adverse effects reported by the clinical development of MMP inhibitors, the antedrug concept was introduced. Among the phosphonamide inhibitors, the 2,2,2-trifluoroethyl ester 8d and 2,2-difluoroethyl ester 8c showed rapid decomposition in human plasma, which is an essential property for the antedrug. Topical applications of these compounds significantly suppressed TPA-induced epidermal hyperplasia in murin skin, a model of psoriasis. These results suggested that the phosphonamide-based inhibitors have a therapeutic potential for the treatment of psoriasis as an antedrug application.

Amphiregulin↗
PubMed2002

Evaluation of dextromethorphan N-demethylation activity as a biomarker for cytochrome P450 3A activity in man.

The present study evaluates the usefulness of dextromethorphan N-demethylation activity indices to reflect cytochrome P450 (CYP) 3A activity in man. Indices of dextromethorphan N-demethylation activity were categorized as N1=3-methoxymorphinan/dextromethorphan, N2=3-hydroxymorphinan/dextrorphan, N3=(3-methoxymorphinan + 3-hydroxymorphinan)/(dextromethorphan + dextrorphan). Two mg of midazolam were administered orally to 22 Japanese male volunteers, and midazolam clearance determined. Thirty mg of dextromethorphan were also orally administered to these volunteers and N1, N2 and N3 indices determined by 12 hr urine collection. Results showed N2 and N3 were highly correlated (r>0.99, P<0.001), and significantly correlated to oral midazolam clearance (r=0.45, P<0.05); suggesting that N2 and N3 are more suitable than N, when using dextromethorphan as an index of individual CYP3A activity.

Adult↗
PubMed2002

Lack of correlation between the steady-state plasma concentrations of haloperidol and risperidone.

Both haloperidol and risperidone have been widely used in the treatment of schizophrenia. Because of wider therapeutic spectrum of risperidone, switching from haloperidol to risperidone is recommended in patients who do not sufficiently respond to haloperidol. The present study investigated the correlation between the steady-state plasma concentrations of haloperidol and risperidone together with the effects of CYP2D6 status on the steady-state kinetics of both drugs. Subjects were 22 schizophrenic inpatients. Eleven patients first received risperidone 6 mg/day and then haloperidol 12 mg/day, while the remaining 11 patients received these two treatments in the opposite sequence. The steady-state plasma concentrations of risperidone, 9-hydroxyrisperidone, haloperidol, and reduced haloperidol were measured after the subjects had been on the treatment for at least 2 weeks, and CYP2D6 genotypes were identified in all subjects. Neither the correlation between the steady-state plasma concentrations of haloperidol and those of risperidone (r = 0.061, ns) nor the active moiety (sum of concentration of risperidone and 9-hydroxyrisperidone) of risperidone (r = 0.141, ns) was significant. The mean (+/- SD) plasma concentration of risperidone in patients with mutated allele(s)for CYP2D6 was significantly higher than those without mutated allele (1.5 +/- 0.7 vs. 8.5 +/- 11.0, p < 0.05), while such a tendency for haloperidol was not observed. The present study suggests that the steady-state plasma concentration of risperidone is not predicted from that of haloperidol in the same individual, probably because of the much greater involvement of CYP2D6 in the metabolism of risperidone than in that of haloperidol.

Adult↗