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Biomedical subjects

S Kaneko

Publications and source records attributed to S Kaneko.

At least 343 records · Page 19Linked to original sources
PubMed1997

Biphasic effects of carbamazepine on the dopaminergic system in rat striatum and hippocampus.

To clarify the effects of carbamazepine (CBZ) on dopamine (DA) release and their metabolism, the extracellular and total levels of DA, its metabolites (DOPAC and HVA) and precursor, 3,4-dihydroxyphenylalanine (DOPA) in the striatum and hippocampus were studied. DA re-uptake and DOPA accumulation in the striatum and hippocampus, and monoamine oxidase (MAO) activities were also determined. After acute and chronic administrations of CBZ, the plasma concentration of CBZ associated with therapeutic activity increased the extracellular and total levels of all substances determined, whereas supratherapeutic concentration of CBZ decreased extracellular and total levels of all substances. Neither therapeutic nor supratherapeutic concentrations of CBZ affected MAO-A nor -B activities, nor DA re-uptake. DOPA accumulation caused by NSD1015 was inhibited by therapeutic and supratherapeutic concentrations of CBZ. These results suggest that a therapeutic concentration of CBZ enhances DA turnover, whereas a supratherapeutic concentration of CBZ inhibits DA turnover. These effects of CBZ on dopaminergic systems may be, at least partially, involved in the mechanisms of action of CBZ.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1997

Effects of non-toxic and toxic concentrations of phenytoin on monoamines levels in rat brain.

To clarify the mechanisms of the antiepileptic activity of phenytoin (PHI), the effects of PHT on extracellular and total levels of monoamines (dopamine and serotonin), in rat striatum and hippocampus were studied. The plasma concentrations of PHT associated with therapeutic activity did not affect striatal and hippocampal extracellular levels of monoamines, whereas supratherapeutic concentrations of PHT decreased striatal and hippocampal extracellular levels of monoamines, in a concentration dependent manner. Toxic concentrations of PHT produced generalized seizures 'paradoxical intoxication' and an initial drastic decrease in striatal and hippocampal extracellular levels of monoamines before seizure onset, whereas the extracellular monoamines levels increased after seizures. In addition, the therapeutic concentrations of PHT did not affect monoamine turnover, whereas supratherapeutic concentrations of PHT inhibited monoamine turnover. These results suggest that monoaminergic transmission may not be involved in the antiepileptic mechanism of action of PHT, and that dysfunction of monoaminergic transmission can produce generalized tonic-clonic convulsions. Thus, the present study suggests that 'Paradoxical Intoxication' induced by toxic concentrations of PHT, at least partially, can be mediated by hypo-monoaminergic function in the brain.

Animals↗
PubMed1997

Characterization of the gene for pyruvate,orthophosphate dikinase from rice, a C3 plant, and a comparison of structure and expression between C3 and C4 genes for this protein.

To investigate the molecular changes that might have occurred in genes for pyruvate,orthophosphate dikinase (PPDK) during the evolution of C4 plants from C3 plants, we isolated a full-length cDNA and the corresponding gene for a C4-like PPDK from rice, a C3 gramineous plant and compared their structures and promoter activities to those of the corresponding gene from maize, a C4 gramineous plant. As in maize, there are at least two ppdk genes in rice and one of them was very similar to the maize C4-type ppdk. The deduced amino acid sequence of the rice PPDK was 88% homologous to the maize C4-type PPDK in the mature peptide region and 56% homologous in the transit peptide region. The C4-like ppdk in rice contained 21 exons, which were interrupted by twenty introns, and the positions of the introns were essentially the same as those in the gene from maize, with the except in that the gene from rice had two extra introns. Such extra introns were also found in the C4-type ppdk from a dicot, Flaveria, at the same positions. These results strongly suggest that the two introns were present in an ancestral gene before the divergence of monocot and dicot plants. The C4-like ppdk in rice contained two functionally independent promoters had generated a larger transcript with the transit peptide region and a smaller transcript without this region. The unusual dual-promoter system for transcription has been conserved in the C4-type ppdk gene from maize, indicating that the dual-promoter system is a common feature of ppdk genes in both C3 and C4 plants. The patterns of expression of the two transcripts in rice were different: the larger transcript was expressed exclusively in green leaves at a low level whereas the smaller transcript was expressed in some reproductive organs at a high level. Essentially the same patterns of expression were observed in maize, but the level of expression of the larger transcript in maize green leaves was much higher than that in green leaves of rice. The promoter activities of the rice and maize genes for PPDK were examined directly in a transient expression assay in maize mesophyll protoplasts after electroporation with promoter::beta-glucuronidase chimeric genes. The rice promoter for the smaller transcript was very active in the protoplasts but the rice promoter for the larger transcript had relatively low activity. By contrast, both promoters of the maize gene had high activity. Taken together, these results demonstrate that the rice C4-like ppdk is very similar to the maize C4-type ppdk, not only in terms of primary structure but also in terms of the regulation of expression, with the exception that the strength of the maize promoter for the larger transcript is higher. The results strongly suggest that the genetic alterations required to give rise to the C4-type ppdk gene were relatively limited.

Amino Acid Sequence↗
PubMed1997

Inhibition of Ca2+ channel current by mu- and kappa-opioid receptors coexpressed in Xenopus oocytes: desensitization dependence on Ca2+ channel alpha 1 subunits.

1. Desensitization of mu- and kappa-opioid receptor-mediated inhibition of voltage-dependent Ca2+ channels was studied in a Xenopus oocyte translation system. 2. In the oocytes coexpressing kappa-opioid receptors with N- or Q-type Ca2+ channel alpha 1 and beta subunits, the kappa-agonist, U50488H, inhibited both neuronal Ca2+ channel current responses in a pertussis toxin-sensitive manner and the inhibition was reduced by prolonged agonist exposure. 3. More than 10 min was required to halve the inhibition of Q-type channels by the kappa-agonist. However, the half-life for the inhibition of N-type channels was only 6 +/- 1 min. In addition, in the oocytes coexpressing mu-opioid receptors with N-type or Q-type channels, the uncoupling rate of the mu-receptor-mediated inhibition of N-channels was also faster than that of Q-type channels. 4. In the oocytes coexpressing both mu- and kappa-receptors with N-type channels, stimulation of either receptor resulted in a cross-desensitization of the subsequent response to the other agonist. Treatment of oocytes with either H-8 (100 microM), staurosporine (400 nM), okadaic acid (200 nM), phorbol myristate acetate (5 nM) or forskolin (50 microM) plus phosphodiesterase inhibitor did not affect either the desensitization or the agonist-evoked inhibition of Ca2+ channels. 5. These results suggest that the rate of rapid desensitization is dependent on the alpha 1 subtype of the neuronal Ca2+ channel, and that a common phosphorylation-independent mechanism underlies the heterologous desensitization between opioid receptor subtypes.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1997

Characterization of T cells specific for an epitope of human 60-kD heat shock protein (hsp) in patients with Behcet's disease (BD) in Japan.

BD is prevalent in the area of the Silk Route. It has been shown that hsp are involved in the T cell activation in patients with BD in the UK, where this disease has developed sporadically. We have thus examined whether the T cell response to the hsp-derived peptides may be induced in patients with BD in Japan, an east pole of the Silk Route. As with patients in the UK, the human 60-kD hsp peptide 336-351 also yielded vigorous proliferation of T cells in Japanese patients with BD, but neither in normal subjects nor in patients with rheumatoid arthritis (RA); there was significant association between proliferation by this peptide and the presence of ocular lesion, but not any other symptoms of BD. To clarify whether the peptide stimulates T cells as a polyclonal activator, a specific antigen or a superantigen-like substance, we analysed T cell receptor (TCR) usage of responding T cells by means of MoAbs specific for TCR Vbeta subfamily and polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP)-based technique. We found that T cells with certain TCR Vbeta subfamilies (including Vbeta5.2-3, 8, 13.6, 18, 21.3) were increased in circulation and responded to the hsp peptide in an antigen-specific fashion. In addition, TCR Vbeta gene-amplified products of freshly isolated T cells of patients with BD formed several bands in the PCR-SSCP analysis; some of them became prominent after stimulation with the peptide. This suggests that T cells in patients with this disease have already been expanded oligoclonally in vivo, which may be a result of stimulation by triggering antigens, including the hsp peptide. In addition, hsp peptide stimulation induced proinflammatory cytokine mRNA expression in peripheral blood mononuclear cells, including IL-8, tumour necrosis factor-alpha (TNF-alpha) and TNF-beta in eight out of eight patients studied. Taken together, the results suggest that hsp antigen may play a role in the pathogenesis of BD, not only in the area of the Silk Route, but also outside the Silk Route area.

Adult↗
PubMed1997

Rescue by cytokines of apoptotic cell death induced by IL-2 deprivation of human antigen-specific T cell clones.

The control of cell survival and cell death is of central importance in tissues with high cell turnover such as the lymphoid system. We have examined the effect of cytokines on IL-2 deprivation-induced apoptosis of human antigen-specific T helper clones with different cytokine production profiles. We found that IL-2, interferon-alpha (IFN-alpha), and IFN-beta inhibited IL-2 deprivation apoptosis in Th0, Th1, and Th2 clones. We also found that IL-2 protects T cell clones from IL-2 deprivation apoptosis accompanying active proliferation and enhanced expression of P53, Rb and Bcl-xL proteins. In contrast, IFN-alpha/beta rescued T cell clones from apoptosis without active proliferation, and expression of apoptosis-associated proteins tested so far was unaffected. This may be due to the fact that T cells treated with IL-2 contained those located in S + G2/M phases of the cell cycle, whereas the vast majority of T cells treated with IFN-alpha/beta were located in G0/G1 phase. IFN-alpha/beta specifically induced tyrosine phosphorylation and translocation into nucleus of signal transducers and activators of transcription (STAT) 2 protein in the T cell clones. In addition, over-expression of STAT2 by transfection of the cDNA prevented apoptosis of the T cell clones. Our present study shows that IFN-alpha and -beta mediate anti-apoptotic effect through other pathways than that of IL-2 in growth factor deprivation apoptosis.

Animals↗
PubMed1997

Therapeutic effects of preferential induction of mite-specific T helper 0 clones.

The predominance of Th2 cytokine-secreting pattern in allergic asthma has been known as a cause and an accelerating factor, and Th1 suppresses these allergic phenomena, but the role of Th0 clones is obscure. Because Th1/Th2 differentiation has been determined by cytokine environment, we investigated how mite-specific helper T cells stimulated in different cytokine environments actually influenced IgE and IgG4 synthesis, which are known to be regulatory immunoglobulins for allergic response. Th0 clones, which were mainly established in the presence of IL-12, provided a great deal of help for IgG4 and IgG1 synthesis, but did not provide help for IgE synthesis, whereas Th2 clones helped IgE synthesis prominently, and IgG4 and IgG1 synthesis marginally. These characteristics of Th0 clones were also true for Th0 clones obtained from patients who were successfully treated with desensitization therapy. Furthermore, the differences in helper activity between Th0 and Th2 clones were not ascribed solely to soluble factors. These data indicate that IgE and IgG4 synthesis is differentially regulated by antigen-specific T cells, and that conversion or selection from Th2 to Th0 by the addition of IL-12 may exhibit therapeutic effects.

Adult↗
PubMed1997

Effects of adenosine receptor subtypes on hippocampal extracellular serotonin level and serotonin reuptake activity.

To clarify the effects of adenosine receptor subtypes (A1, A2, and A3) on hippocampal serotoninergic function, hippocampal extracellular serotonin (5-HT) levels were determined by in vivo microdialysis in freely moving rats under various conditions. Both adenosine and an adenosine A1 receptor agonist, 2-chloro-N6-cyclopentyladenosine, decreased extracellular 5-HT levels, whereas an adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (CPT), and caffeine increased these levels. A selective A2A receptor agonist (CGS-21680), an adenosine A2 receptor agonist (PD-125944), an adenosine A2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), and an adenosine A3 receptor agonist, N6-2-(4-aminophenyl)ethyladenosine (APNEA), did not affect extracellular 5-HT levels. When the adenosine A1 receptor was blocked by CPT, the hippocampal extracellular 5-HT level was increased by adenosine, CGS-21680, and PD-125944, and decreased by caffeine, DMPX, and APNEA. When both adenosine A1 and A2 receptors were blocked by CPT and DMPX, the extracellular 5-HT level was decreased by adenosine, caffeine, and APNEA. The hippocampal extracellular 5-HT level was not affected by administration of APNEA alone, but was decreased by this agent when the adenosine A1 receptor was blocked, irrespective of whether the adenosine A2 receptor was functional. These inhibitory effects of adenosine, caffeine, and APNEA on extracellular 5-HT levels, during both adenosine A1 and A2 receptor blockade, were inhibited by selective 5-HT reuptake inhibitors. These results indicate that the stimulatory effects of the adenosine A2 receptor and the inhibitory effects of the A3 receptor on hippocampal extracellular 5-HT levels are masked by the inhibitory effects of the adenosine A1 receptor.

Animals↗
PubMed1997

Cloning and functional analysis of rat cyclin D2 promoter: multiple prolactin-responsive elements.

Structure and function of the promoter region of rat cyclin D2 gene were investigated by cloning, sequence analysis and DNA mobility shift assay using nuclear extracts of prolactin-stimulated Nb2 cells. The results show that the expression of rat cyclin D2 gene is not dependent on the TATA-box but is stimulated by multiple transcription factors induced by prolactin at an immediate-early stage of the cell cycle.

Amino Acid Sequence↗
PubMed1997

The CYP2D6 genotype and plasma concentrations of mianserin enantiomers in relation to therapeutic response to mianserin in depressed Japanese patients.

The relationship between therapeutic response to racemic mianserin and steady-state plasma concentrations of S(+)- and R(-)-mianserin was studied in 26 Japanese patients with major depression. The daily dose of mianserin was 30 mg, and the duration of treatment was 3 weeks. Regarding S-mianserin, the proportion of responders (final Montgomery-Asberg Depression Rating Scale score of 10 or less) was significantly higher in the plasma concentration range of 10 to 23 ng/mL than outside (10 of 11 vs. 3 of 15, p = 0.0005). Such a plasma concentration difference between responders and nonresponders was not found for R-mianserin. In 15 patients, the relationships between the CYP2D6 genotype, determined by allele-specific polymerase chain reaction analysis and Escherichia coli RI restriction fragment length polymorphism, plasma concentrations of the enantiomers, and the therapeutic response were studied. Five patients were homozygous for the wild type (wt) allele (wt/wt), nine were heterozygous for the CYP2D6Ch (Ch) allele causing decreased CYP2D6 activity (Ch/wt), and one patient was heterozygous for the Ch allele and the defect allele CYP2D6D (D) (Ch/D). The Ch/wt group showed significantly higher plasma concentrations of S-mianserin (mean +/- SD: 15 +/- 6 vs. 8 +/- 1 ng/mL, p = 0.007) and proportion of responders (8 of 9 vs. 1 of 5, p = 0.023) than the wt/wt group. The patient with the Ch/D genotype had the highest plasma concentration of S-mianserin (37 ng/mL) and a poor response. No significant relationship was found between the CYP2D6 genotype and plasma concentration of R-mianserin. The study presented here thus suggests that the CYP2D6 genotype plays a major role in controlling plasma concentration of the S-enantiomer of mianserin, which contributes to a major extent to the antidepressant effect during mianserin treatment.

Adult↗
PubMed1997

Relationship between single oral dose pharmacokinetics of alprazolam and triazolam.

The relationship between the single oral dose pharmacokinetics of alprazolam and triazolam was studied in 10 healthy male volunteers. Each subject took single oral doses of alprazolam 0.8 mg and triazolam 0.5 mg with at least a 2 week interval between each dose. Blood samplings were performed up to 48 h after alprazolam dosing and up to 12 h after triazolam dosing. Plasma concentrations of both drugs were measured by high-performance liquid chromatography. The means +/- standard deviation of the peak plasma concentration, the total area under the plasma concentration-time curve and the elimination half-life of alprazolam were 11.3 +/- 3.1 ng/ml, 232.4 +/- 59.2 ng/h/ml and 16.5 +/- 4.6 h, respectively, and those of triazolam were 3.2 +/- 1.0 ng/ml, 11.8 +/- 5.2 ng/h/ml and 2.5 +/- 1.1 h, respectively. There was no significant correlation between the two drugs in any pharmacokinetic parameters (r = 0.35, 0.25 and 0.50). The present study thus suggests that the single oral dose pharmacokinetics of alprazolam and triazolam do not correlate well in individuals.

Adult↗
PubMed1997

Carbamazepine toxicity induced by clarithromycin coadministration in psychiatric patients.

Seven psychiatric inpatients receiving carbamazepine 600 mg/day were coadministered clarithromycin 400 mg/day for 5 days to treat atypical pneumonia. Blood samples were taken after clarithromycin coadministration and at 1 and 4 weeks after its discontinuation. Plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide were measured using high-performance liquid chromatography. During clarithromycin coadministration, four out of the seven patients developed moderate-to-severe toxic symptoms of carbamazepine, such as drowsiness, dizziness, and ataxia, which resolved within 5 days after clarithromycin discontinuation. In these four patients, plasma carbamazepine concentrations after clarithromycin coadministration were approximately twice as high as those after its discontinuation. In the seven patients, the mean plasma concentration of carbamazepine, but not of carbamazepine-10,11-epoxide, after clarithromycin coadministration was significantly (p < 0.01) higher than those at 1 and 4 weeks after its discontinuation. The present report suggests that clarithromycin coadministration induces increased plasma carbamazepine concentrations, which may result in carbamazepine toxicity. Therefore, care should be given to prescribing clarithromycin for patients receiving carbamazepine.

Aged↗
PubMed1997

Increases in plasma concentration of m-chlorophenylpiperazine, but not trazodone, with low-dose haloperidol.

Our previous study suggested that cytochrome P4502D6 (CYP2D6) is involved in the metabolism of trazodone and its active metabolite, m-chlorophenylpiperazine (m-CPP). The purpose of this study was to examine the degrees of increase in plasma concentrations of trazodone and m-CPP induced by haloperidol, which is an inhibitor of CYP2D6. The subjects were nine depressed inpatients receiving trazodone at bedtime (150 mg in seven patients and 300 mg in two) for 2-19 weeks. Haloperidol at 4 mg/day was coadministered for 1 week, and blood samplings were taken before and after the coadministration. Contrary to our expectation, haloperidol did not significantly increase the mean plasma trazodone concentration (810 +/- 382 vs. 856 +/- 357 ng/ml). However, haloperidol significantly increased (p < 0.01) the mean plasma m-CPP concentration (78 +/- 31 vs. 92 +/- 34 ng/ml).

Adult↗
PubMed1997

No effect of the anticholinergic drugs trihexyphenidyl and biperiden on the plasma concentrations of bromperidol and its reduced metabolite.

Effects of the anticholinergic drugs trihexyphenidyl and biperiden on plasma concentrations of bromperidol and its reduced metabolite were studied. Subjects comprised 20 schizophrenic inpatients taking bromperidol, 6-18 mg/ day for 1-9 weeks. Patients were randomly allocated to one of two treatment sequences: trihexyphenidyl-biperiden (n = 12) or biperiden-trihexyphenidyl (n = 8). Each sequence consisted of two 2-week phases, with no washout period between the two phases. The daily dose of trihexyphenidyl was 8 mg and that of biperiden 6 mg. Plasma concentrations of bromperidol and reduced bromperidol were measured using high-performance liquid chromatography (HPLC). There was no significant difference in plasma bromperidol or reduced bromperidol concentrations among baseline, trihexyphenidyl and biperiden phases: 7.3 +/- 3.7 versus 7.2 +/- 4.1 versus 7.0 +/- 4.3 ng/ml and 2.0 +/- 2.1 versus 2.2 +/- 2.1 versus 1.9 +/- 2.0 ng/ml, respectively. The present study thus suggests that neither trihexyphenidyl nor biperiden affects plasma concentrations of bromperidol and its reduced metabolite.

Adult↗
PubMed1997

Increased plasma concentrations of bromperidol and its reduced metabolite with levomepromazine, but not with thioridazine.

Bromperidol is a close structural analog of haloperidol. The authors studied the effects of levomepromazine and thioridazine, which are frequently added to other neuroleptics as sedatives, on plasma concentrations of bromperidol and its reduced metabolite. The subjects were 26 inpatients with schizophrenia receiving bromperidol, 12 to 24 mg/day, for 1 to 19 weeks. In 10 cases, 50 mg levomepromazine per day and in nine cases, 50 mg thioridazine per day were coadministered for 1 week. In seven cases, both drugs were coadministered with > or = 2-week intervals. Plasma concentrations of bromperidol and reduced bromperidol were measured by a high-performance liquid chromatographic method. Levomepromazine (n = 17) significantly (p < 0.001) increased plasma concentrations of bromperidol (7.3 +/- 4.1 versus 10.2 +/- 4.8 ng/ml) and reduced bromperidol (1.8 +/- 1.4 versus 4.5 +/- 3.3 ng/ml). Thioridazine (n = 16) did not significantly change plasma concentrations of bromperidol (9.1 +/- 5.7 versus 8.6 +/- 5.5 ng/ml), while those of reduced bromperidol could not be measured because of interfering peaks. The current study suggests that levomepromazine, but not thioridazine, increases plasma concentrations of bromperidol and reduced bromperidol by inhibiting the metabolism of these compounds.

Adult↗
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↗