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Although standing plantar perception training (SPPT) may improve standing postural stability, the underlying neural mechanisms remain unclear. The authors investigated the relationship between regional cortical responses to SPPT using a balance pad and training outcomes in 32 older participants (mean ± SD:72.2 ± 6.0, range:60–87). Regional cortical activity was measured in the bilateral supplementary motor area, primary sensorimotor area, and parietal association area using near-infrared spectroscopy. Postural sway changes were compared before and after SPPT. Changes in two-point plantar discrimination and regional cortical activity during SPPT, associated with standing postural stability improvements, were examined using multiple regression and indicated improved standing postural stability after SPPT (p

Background:There are no universal tools to predict the necessity of high-dose opioid use for cancer-related pain. Early recognition and interventions for intractable cancer pain could minimize the distress of palliative patients., Objective:We sought to identify the clinical factors associated with high-dose opioid use in advanced cancer patients to recognize palliative patients who would develop intractable cancer pain, as early as possible., Setting/Subjects:Among 385 in-hospital cancer patients from April 1, 2014 to July 31, 2019, who were referred to the palliative care team for cancer-related pain, clinical factors significantly correlated to high-dose opioid use were retrospectively analyzed., Measurements:We conducted a multiple logistic regression analysis to identify variables significantly related to high-dose opioid use (>120 mg/day oral morphine equivalent dose)., Results:Independent factors of high-dose opioid use included younger age (odds ratio [OR] 0.965, 95% confidence interval [CI] 0.944-0.986, p = 0.001), respiratory cancers (OR 1.882, 95% CI 1.069-3.312, p < 0.001), and opioid switch (OR 2.869, 95% CI 1.497-5.497, p = 0.001). The percentage of correct classifications of the regression equation was 86.9%., Conclusions:Younger age, respiratory cancers, and opioid switch were related to high-dose opioid use. Our findings may help palliative caregivers to deal with intractable cancer pain in palliative patients, and thus relieve their distress.

Purpose: The purpose of this study is to compare the steady-state plasma levels of HAL between Japanese, Koreans and Swedes who were treated with HAL monotherapy per os. Method: The steady-state plasma levels of haloperidol (HAL) in 75 Japanese, 120 Korean, and 50 Swedish psychiatric patients treated orally with HAL were compared. Results: Significantly higher doses of HAL were used in the Koreans (mean dose = 21 mg/day) than in the Japanese (15 mg/day) or Swedes (9 mg/day) (one-way analysis of variance (ANOVA) (p

We previously reported that a decrease in the melanin content of mouse melanoma cells (B16 cells) treated with δ-tocotrienol was the result of a decrease in the level of tyrosinase activity and protein. Use of δ-tocotrienol as a whitening agent, may therefore have side effects. In the present study, we examined whether δ-tocotrienol caused side effects (the release of lysosomes from and a decrease in the cholesterol content of cells). We also examined the release of melanosomes (lysosome-related organella). Neither of lysosomes nor melanosomes were released from cells treated with δ-tocotrienol, since βglucuronidase (melanosomal and lysosomal enzyme) activity, melanin content (melanosomal marker), and tyrosinase (melanosomal enzyme) activity did not increase in the cell culture medium. Although mevalonate pyrophosphate decarboxylase (MPD; an enzyme of cholesterol biosynthesis) was significantly reduced in the cells treated with δ-tocotrienol, cholesterol content was not. Thus, δ-tocotrienol might be useful as a therapeutic or preventive drug for hyperpigmentation and as a component of whitening and/or lightening cosmetics not causing severe side effect (reduction of cholesterol content and release of lysosomes/melanosomes), although δ-tocotrienol cause a decrease of MPD.

The objective of this study was to evaluate genetic and pharmacokinetic factors affecting the initial pharmacotherapeutic effect of paroxetine (PAX) in Japanese patients with panic disorder (PD). Plasma concentration of PAX was determined by high performance liquid chromatography. Serotonin transporter gene-linked polymorphic region (5-HTTLPR) variants were determined by polymerase chain reaction techniques. PD severity was assessed using the Panic and Agoraphobia Scale (PAS). Multiple regression analysis revealed that the plasma concentration of PAX, 5-HTTLPR genotype, and comorbid physical illness were significant factors affecting the initial pharmacotherapeutic effect of PAX in PD and indicated that these factors accounted for 52.4% (R 2 = 0.524) of the variability in the percent reduction in PAS score. The final model was described by the following equation (P = 0.001): percent reduction in PAS score (%) = 68.5 − 1.2 × [plasma concentration of PAX (ng/ml)] − 33.0 × (L/S = 1, S/S = 0) − 21.8 × (with comorbid physical illness = 1, without comorbid physical illness = 0). The high plasma concentration of PAX, the L/S genotype of 5-HTTLPR, and comorbid physical illness might be associated with a poor response to the initial phase of pharmacotherapy of PD with PAX.

We examined the effect of δ-tocotrienol on melanin content in mouse melanoma B16 cells. Melanin content was significantly reduced in cells treated with 50 and 100 μM δ-tocotrienol, but not 10 μM δ-tocotrienol. The activity and amount of tyrosinase also significantly decreased in cells treated with 10, 50, and 100 μM δ-tocotrienol. Furthermore, the mRNA level of tyrosinase as measured using realtime PCR was significantly decreased compared to controls in cells treated with 100 μM δ-tocotrienol, but not 10 or 50 μM δ-tocotrienol. These results indicated that at first δ-tocotrienol caused tyrosinase degradation, and then caused a further decrease in the tyrosinase protein level via both tyrosinase degradation and a decrease in the mRNA level of tyrosinase. We conclude that the decrease of melanin content in the cells by δ-tocotrienol was the result of the decrease of the protein level of tyrosinase (tyrosinase degradation is more important than the decrease of mRNA).

Recently, it has been questioned whether mevalonate pyrophosphate decarboxylase (MPD) is predominantly located in the peroxisomes or cytosol. We previously reported that a small amount of MPD in the liver of rats fed a CP diet (5% cholestyramine and 0.1% pravastatin) existed in the peroxisomes, although MPD is predominantly located in the cytosol in the liver of rats fed normal chow and a CP diet for 12 days. In the present study, we examined the subcellular distribution of MPD in mouse melanoma cells (B16 and B16F10) treated with or without lovastatin, using digitonin permeabilization and immunoblotting. In permeabilized B16 by digitonin after treatment with or without lovastatin, 95% and 5%, or 98% and 2% of MPD existed in the cytosol and membrane/organelle (M/O) fraction, respectively. Using B16F10 under the same conditions, 80% and 20%, or 91% and 9% of MPD existed in the cytosol and M/O fraction, respectively. These results indicated that MPD was predominantly located in the cytosol in both mouse melanoma cells treated with or without lovastatin.

Recently, it has been questioned whether mevalonate pyrophosphate decarboxylase (MPD) is predominantly located in the peroxisomes or cytosol. We previously reported that MPD was predominantly present in the cytosol of rat hepatocytes, normal rat kidney cells, or mouse melanoma cells. In the present study, we examined whether MPD was predominantly present in the cytosol of HepG2 (human hepatoma) cells and Cos7 (monkey kidney) cells using digitonin permeabilization. In HepG2 cells permeabilized with digitonin, 90%and 10%of MPD existed in the cytosol and membrane/organelle (M/O) fraction, respectively, while in Cos7 cells permeabilized with digitonin, 20% and 80% of MPD existed in the cytosol and M/O fraction, respectively. These data suggest that the difference in subcellular distribution of MPD is due to the cell type.

Selective serotonin reuptake inhibitors are thought to interact with serotonergic neurons and be effective for treatment of panic disorder. In the present study, the authors investigated an association between plasma concentrations of paroxetine in patients with panic disorder and clinical response to initial treatment with paroxetine. Subjects were 21 unrelated Japanese patients who fulfilled DSM-IV-TR criteria for a diagnosis of panic disorder (6 males, 15 females, mean age 35.9 +/- 11.3 years). Subjects were administered 10 mg/day of paroxetine for 2 weeks as initial treatment. Improvement of the symptoms of the disorder was assessed with the Panic and Agoraphobia Scale (PAS). In the range of plasma levels >20 ng/mL, none of the subjects showed the reduction ratio in PAS score >0.2. The subjects whose plasma concentrations of paroxetine were less than 20 ng/mL had a significantly higher mean reduction ratio in PAS score than the subjects whose plasma concentrations of paroxetine were >20 ng/mL. Multiple regression analysis showed that the plasma concentration of paroxetine was the only significant factor and accounted for 28.0% of the variability in the reduction ratio of PAS score of the subjects. The final model of correlation was: reduction ratio in PAS score = 0.423 - 0.009 x (plasma concentrations of paroxetine) (R = 0.529, P = 0.014, coefficient of determination (R2) = 0.280). Assuming that the reduction ratio in PAS score was 0.2 in the equation above, plasma concentration of paroxetine is calculated to be about 25 ng/mL, which is suggested to be the upper end of the therapeutic window for the initial phase of the treatment with paroxetine for panic disorder.

The authors investigated the impact of the CYP2D6 genotypes on the plasma concentration of paroxetine (PAX) in 55 Japanese psychiatric patients. They were administered 10 to 40 mg/day (24+/-10.0 mg/day) of PAX and maintained at the same daily dose for at least two weeks to obtain the steady-state concentrations. The plasma levels of PAX were 15.8+/-15.0, 47.4+/-32.0, 101.2+/-59.9 and 177.5+/-123.6 ng/ml at the daily dose of 10, 20, 30 and 40 mg, respectively, which suggested dose dependent kinetics of PAX. The allele frequencies of the CYP2D65, CYP2D610 and CYP2D641 were 1.8%, 41.8% and 1.8%, respectively. Significantly higher PAX concentrations were observed in the patients having one functional allele compared with those with two functional alleles (150.9+/-20.6 vs. 243.6+/-25.2 ng/ml mg(-1) kg(-1), p0.05, Newman-Keuls multiple comparison test) or no functional (243.6+/-25.2 vs. 76.7+/-6.1 ng/ml mg(-1) kg(-1), p0.05, Newman-Keuls multiple comparison test) in the subjects with 30 mg/day of paroxetine. The same trend of findings as in the subjects treated with 30 mg/day were observed in the subjects with 40 mg/day of PAX. The present results suggest that having one non-functional allele is the marker for high plasma concentration of PAX when relatively high daily dose of PAX is administered.

加齢に伴う体力の低下は、高齢者の日常生活における様々な行動に影響を及ぼす。体力や健康を維持していくことは、高齢者の日常生活の質を左右すると言える。高齢者が生きがいを持ち心豊かに生活していけるためには、自立した生活を長く維持することが重要であり、超高齢社会を目前にした我が国において、健康寿命の確立は大きな課題となっている。我が国における寝たきりの原因は、脳卒中に次いで転倒などによる骨折が多い。転倒による骨折を予防するため、骨粗鬆症の予防や転倒予防教室、高齢者の体力トレーニングなどへの関心は高まっているが、実際には高齢者の日常生活の中に十分活かされているとは言い難い。高齢者の体力や健康レベルには、生活歴や生活習慣病によって個人差が大きく、身体能力の維持・増進に必要な要因を評価していくことが重要と考える。本研究では、地域在住高齢者の生活活動力の特徴を明らかにすることを目的に、Ｙ県内在住の65歳以上の高齢者（男性34名；平均年齢74.91±5.3歳、女性30名；平均年齢75.47±6.68歳）を対象に生活活動力（握力・立ち上がり・ジグザグ歩行・開眼片足立ちなどの9項目）の測定、骨密度の測定、生活習慣アンケート調査を実施した。生活活動力測定では、年齢と立ち上がり起立動作とジグザグ歩行との間にはr=.63とに高い相関が見られた。また、最大握力が強いほど、立ち上がり起立動作およびジグザグ歩行に要する時間は短く、開眼片足立ち時間は長かった。また、骨疾患の既往の有無での生活活動力の違いについて分析してみると、男性では骨密度で、女性では開眼片足立ちで有意な差が見られた。このことから、最大握力の値は高齢者の体力の指標となることが示唆された。更に、男性では骨密度が骨折のリスクの指標となり、女性では生活活動力の開眼片足立ち時間の長さが転倒・骨折のリスクの指標となることが示唆された。, Our physical strength declines as we get old. Therefore, it is very important for the elderly people to be strong enough to maintain their abilities of daily living. In Japan where the aging of the society is progressing rapidly,improving the health of the elderly is the challenge we have to face. The primary disease in Japan that makes patients bedridden is the stroke, and the fractures caused by falling to prevent osteoporosis and the fractures caused by falling are being held. However, the difference of the physical strength and health condition among the old people is so large due to their work experience and living habits that it is inevitable to assess each person of his or her physical strength. This study aims at clarifying the abilities of living activities and their traits among the elderly people living in Y Prefecture. A total of 64 people aged more than 65 years old (34 men: average age 74.91±5.3, women: average age 75.47±6.68) were tested their physical strength in the eight fields, including grasping power, standing test, walking in a zigzag, balance on one leg with their eyes open. We also measured their bone density. We asked them to fill out the questionnaire to know their living habits. Our study shows that abilities of standing and walking in zigzag has a strong correlation with their age (r=0.63). It also reveals that the stronger their grasping power is, the more quickly they can stand up and walk in a zigzag, and the longer they can balance on one leg. The male elderly with a bone disease shows low-level bone density and the female with the disease can not balance on one leg as long as those without the disease. Our findings suggest that the grasping power can be used as a fundamental indicator to know the physical strength of the elderly people.

We investigated the effect of CYP2D6 genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 88 Japanese schizophrenic inpatients being treated with HAL. Some subjects carrying CYP2D6*5 allele (CYP2D6*1/CYP2D6*5, CYP2D6*5/CYP2D6*10) showed extremely high concentrations of both HAL and RHAL, and the groups with CYP2D6*5 allele seemed to have higher plasma concentrations of HAL (1.14+/-0.69 ng/ml/mg) and RHAL (1.10+/-1.05 ng/ml/mg) than the other groups. Among those without CYP2D6*5 allele, there were no significant differences in plasma concentrations of HAL and RHAL between those without CYP2D6*10 allele (HAL=0.68+/-0.31 ng/ml/mg, RHAL=0.28+/-0.37 ng/ml/mg), those with one CYP2D6*10 (HAL=0.70+/-0.23 ng/ml/mg, RHAL=0.31+/-0.16 ng/ml/mg) and those with two CYP2D6*10 alleles (HAL=0.69+/-0.14 ng/ml/mg, RHAL=0.40+/-0.09 ng/ml/mg), although there was a tendency of higher plasma concentration of RHAL in those with two CYP2D6*10 alleles. At a lower daily dosage of HAL (

We investigated the effect of the CYP2C19 and CYP2D6 genotypes on the metabolism of amitriptyline (AT) in Japanese psychiatric patients. Steady-state concentrations of AT and its metabolites (nortriptyline [NT], trans-10-hydroxy-nortriptyline [EHNT], cis-10-hydroxy-nortriptyline [ZHNT], trans-10-hydroxy-amitriptyline [EHAT], and cis-10-hydroxy-amitriptyline [ZHAT]) in 50 patients were determined by high-performance liquid chromatography. Significantly higher plasma concentrations of AT corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 were observed (no mutated alleles vs. two mutated alleles: 36.0 +/- 18.2 vs. 64.0 +/- 25.2 ng/mL/mg/kg, p = 0.025). A significantly higher AT/NT ratio was seen in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 (no mutated alleles vs. two mutated alleles: 1.27 +/- 0.59 vs. 3.40 +/- 1.02, p = 0.001). A trend for higher NT/EHNT ratio in the subjects with two mutated alleles of CYP2D6 than in those with no mutated alleles of CYP2D6 was observed (no mutated alleles vs. two mutated alleles: 0.73 +/- 0.39 vs. 1.31 +/- 0.81, p = 0.068). A trend for higher plasma concentrations of total hydroxylated metabolites of AT (EHAT + ZHAT) corrected for dose and body weight in the subjects with two mutated alleles of CYP2C19 than in those with no mutated alleles of CYP2C19 was found (no mutated alleles vs. two mutated alleles: 9.5 +/- 5.8 vs. 17.8 +/- 8.9, p = 0.051). Therefore, the genotype of CYP2C19 is one of the important determinants of the plasma concentrations of AT and the capacity to desmethylate AT. Mother compound AT is shunted via hydroxylation pathways from AT to EHAT and ZHAT in the subjects with homozygotes of mutated alleles of CYP2C19 in order to compensate for the decreased capacity to desmethylate AT.

In this study, the authors investigated the relationship between the metabolism of clomipramine (C) and the genotypes of cytochrome P450 (CYP) CYP2C19 and CYP2D6. Fifty-one Japanese patients (18 men and 33 women) were administered 10 to 250 mg/day of C by mouth and maintained on the same daily dose of C for at least 2 weeks to obtain steady-state concentrations. Plasma levels of C and its metabolites N-desmethylclomipramine (DC), 8-hydroxyclomipramine, and 8-hydroxy-N-desmethylclomipramine (HDC) were determined by high-performance liquid chromatography. The allele frequencies of CYP2C19*2, CYP2C19*3, CYP2D6*5, and CYP2D6*10 were 27.5%, 12.8%, 2.9%, and 43.1%, respectively. Subjects who were homozygous for mutated alleles of CYP2C19 showed approximately 75% higher concentrations of C corrected by dose and body weight compared with those who were homozygous for wild-type alleles. Also, subjects who were homozygous for mutated alleles of CYP2C19 showed an approximately 68% higher value of C/DC compared with those who were homozygous for wild-type alleles. No significant difference in the ratio of DC/HDC was observed between subjects who were homozygous for mutated alleles of CYP2D6 and those who were homozygous for wild-type alleles. These results suggest that genotyping CYP2C19 is useful for grossly predicting the risk of getting high plasma concentrations of C and the low individual capacity to demethylate C because there is marked interindividual variability within each genotype. However, the genotyping of CYP2D6 is not useful for predicting the individual capacity to hydroxylate DC.

The authors studied the interactive effects of the coadministration of haloperidol and chlorpromazine on plasma concentrations of haloperidol and reduced haloperidol. The subjects were 43 Japanese male schizophrenic inpatients who were concomitantly treated with chlorpromazine before or after monotherapy with haloperidol. Coadministration of chlorpromazine produced significant increases in the plasma concentrations of haloperidol (P < 0.01) and reduced haloperidol (P < 0.001) by an average of 28.5% +/- 83.3% and 160.8% +/- 288.9%, respectively. However, there were marked interindividual variations in the interactive effects of chlorpromazine. The authors analyzed the importance of five CYP2D6 genotypes, *1/ *1, *1/ *10, *10/ *10, *1/*5, and *5/*10 on the percentage of change in plasma concentrations of haloperidol and reduced haloperidol. Patients with the CYP2D6*5 allele (n = 4) showed a significantly smaller increase in plasma concentrations of haloperidol (P < 0.05) and a slightly smaller increase in those of reduced haloperidol (P = 0.074) in response to the coadministration of chlorpromazine compared than those with the CYP2D6*1/*1 genotype (n = 8). Those with the CYP2D6*1/*1 genotype (n = 8) showed a trend toward greater increases in plasma concentrations of haloperidol than those with other genotypes (P = 0.087).

Background Melatonin is a hormone that is metabolized by cytochrome P450 (CYP) 1A2 to its main primary metabolite 6-hydroxymelatonin. We therefore evaluated the utility of oral melatonin as a marker of hepatic CYP1A2 activity. Methods Twenty-five milligrams of melatonin was given at 9:30 am to 12 healthy Swedish volunteers, who had previously been phenotyped for CYP1A2 with caffeine. Melatonin and conjugated 6-hydroxymelatonin were analyzed by liquid chromatography–mass spectrometry in blood samples taken between 0.5 and 6.5 hours after drug intake. Serum concentrations of melatonin and conjugated 6-hydroxymelatonin, or their ratio at different time points, and the apparent melatonin clearance were tested for correlation with caffeine clearance. Results We found a significant correlation between apparent clearance of melatonin and caffeine clearance with a Spearman rank correlation coefficient (Rs) of 0.75 (P = .005). The melatonin concentration 1.5 hours after administration also closely correlated with the caffeine clearance (Rs = −0.62; P = .03). Inclusion of conjugated 6-hydroxymelatonin gave no closer correlations. Conclusion Melatonin might be developed as an alternative to caffeine as a probe drug for CYP1A2 phenotyping. Clinical Pharmacology & Therapeutics (2001) 70, 10–16; doi: 10.1067/mcp.2001.116512

The authors investigated the impact of the CYP2D6 genotype on steady-state concentrations of nortriptyline (NT) and its metabolites, trans-10-hydroxynortriptyline (EHNT) and cis-10-hydroxynortriptyline in a Japanese population of psychiatric patients. Forty-one patients (20 men and 21 women) were orally administered nortriptyline hydrochloride. The allele frequencies of the CYP2D6*5 and CYP2D6*10 were 4.9% and 34.1%, respectively. Significant differences in NT concentrations corrected for dose and weight were observed between the subjects with no mutated alleles and those with one mutated allele (mean +/- SD for no mutated alleles vs. one mutated allele: 70.3 +/- 25.4 vs. 98.4 +/- 36.6 ng/mL x mg(-1) x kg(-1); t = 2.54, dcf = 33, p < 0.05) and between the subjects with no mutated alleles and two mutated alleles (no mutated alleles vs. two mutated alleles: 70.3 +/- 25.4 vs. 147 +/- 31.1 ng/mL x mg(-1) x kg(-1); t = 5.87, df = 19, p < 0.0001). Also, a significant difference in the NT/EHNT ratio, which is representative of the hydroxylation ratio of NT, was observed between the subjects with no mutated alleles and those with two mutated alleles (no mutated alleles vs. two mutated alleles: 0.82 +/- 0.30 vs. 2.71 +/- 0.84; t = 7.86, df = 19, p < 0.0001). Multiple regression analysis showed that the number of mutated alleles of CYP2D6, which was the only significant factor, accounted for 41% and 48% of the variability in log(NT corrected for dose and weight) and log(NT/EHNT), respectively.

We investigated the effect of cytochrome P450 (CYP2D6) genotypes on plasma levels of haloperidol (HAL) and reduced haloperidol (RHAL) in 47 Japanese male schizophrenic inpatients being treated with HAL. Mutation-specific polymerase chain reaction (PCR) analysis was used to detect CYP2D6*10 as the C188C1T mutation in exon 1. A long-PCR analysis method was used to detect CYP2D6*5. Allele frequencies of CYP2D6*5 and CYP2D6*10 were 4.3% and 34.0%, respectively. Plasma concentrations of HAL and RHAL were measured using high-performance liquid chromatography. The ranges of the plasma concentration of HAL and RHAL corrected to the dose were 0.28-1.60 (mean +/- SD, 0.66+/-0.25, n = 47) ng/mL/mg and 0.03-3.00 (mean+/-SD, 0.36+/-0.46, n = 47) ng/mL, respectively. Plasma RHAL/HAL ratios (R/H ratios) ranged from 0.06 to 1.88 (mean +/- SD, 0.48+/-0.32, n = 47). The analysis was performed among the four genotype groups: CYP2D6*1/CYP2D6*1 (n = 11), CYP2D6*1/CYP2D6*10 (n = 11), CYP2D6*10/CYP2D6*10 (n = 6) and those who have CYP2D6*5 allele (CYP2D6*1/ CYP2D6*5 or CYP2D6*5/CYP2D6*10 (n = 4). We observed significant tendency in effects of CYP2D6 genotypes on plasma concentration of HAL and significant effects on plasma concentration of RHAL, and R/H ratio. These results we obtained suggested that the plasma concentration of HAL and RHAL were determined partly by CYP2D6 polymorphic activity.

We analyzed therapeutic drug monitoring (TDM) data from 231 schizophrenic inpatients (137 men, 94 women) and investigated interindividual differences of plasma haloperidol (HAL) concentrations and drug/drug interactions between HAL and various concomitant drugs. Plasma HAL concentrations were determined by an enzyme immunoassay (EIA) method. Plasma HAL concentrations per daily dose of HAL per body weight (HAL C/D ratio) demonstrated an approximately 11-fold interindividual variation. The patient subjects who received carbamazepine (CBZ) concomitantly had a mean HAL C/D ratio that was 37% lower than that of the patient subjects without CBZ. The patient subjects treated with concomitant phenobarbital (PB) also showed a mean HAL C/D ratio that was 22% lower than those without PB. We concluded that careful evaluation of HAL TDM data and consideration of the impact of concomitant medication such as CBZ or PB that might influence the metabolism of HAL is necessary in daily clinical settings to avoid insufficient clinical response because of lowered concentrations of HAL or adverse effects because of high concentrations of HAL.

The clinical significance of monitoring the plasma levels of amitriptyline and its metabolites in prediction of the clinical outcome of depressive episode was investigated in 49 inpatients. Discriminant analysis of drug concentrations (at two weeks after initiation of drug treatment) and clinical outcome revealed that increasing the plasma levels of amitriptyline, cis-isomers of hydroxylated metabolites (Z-10-hydroxyamitriptyline and Z-10-hydroxynortriptyline) predicted a better clinical outcome, while increasing of plasma levels of nortriptyline and trans-isomers of hydroxylated metabolites (E-10-hydroxyamitriptyline and E-10-hydroxynortriptyline) were shown to predict a poor clinical outcome in the depressive episode of the subjects, and that clinical outcome of approximately 73% of the subjects could be correctly predicted.

We measured the concentrations in plasma of amitriptyline and its metabolites, nortriptyline and geometric isomers of 10-hydroxynortriptyline and 10-hydroxyamitriptyline, in 73 Japanese psychiatric patients receiving amitriptyline hydrochloride (Tryptanol; Banyu Pharmaceutical Co. Ltd., Tokyo, Japan) by high-performance liquid chromatography. Although there were large interindividual variations of total drug concentrations and concentrations of parent or intermediate metabolic compounds in plasma, significant positive correlations were observed between these drug concentrations and daily doses of amitriptyline hydrochloride (milligrams per kilogram of body weight). The metabolic ratios for both hydroxylation and desmethylation varied substantially with approximately 8- to 19-fold interindividual variations. Frequency distribution histograms and probit analyses of these parameters identified neither definite poor hydroxylators nor poor desmethylators of amitriptyline.

The impact of genetic polymorphism of CYP1A2 that are related to the induction of the isozyme on the plasma levels of haloperidol (HAL) in 40 male smokers with schizophrenia was investigated. A point mutation from C to A in intron 1 at position 734 and a point mutation from G to A at position -2964 in the 5'-flanking region of CYP1A2 were identified by polymerase chain-reaction-restricted fragment length polymorphism method. Regarding C/A polymorphism in intron 1 at position 734, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight among the subjects with A/A (n = 21), A/C (n = 14) and C/C (n = 5) genotypes (one-way analysis of variance: 63.1 +/- 18.5, 47.8 +/- 12.5 and 50.8 +/- 15.1 ng/ml/mg/kg, respectively, F(2,37) = 2.556, P = .09). Regarding G/A polymorphism at position -2964 in the 5'-flanking region, no significant difference was found in the plasma concentrations of HAL corrected for dose and weight between subjects with G/G (n = 24) and G/A (n = 15) (two-tailed t test: G/G and G/A = 51.2 +/- 16.6 and 59.0 +/- 17.6 ng/ml/mg/kg, respectively, df = 28, P = .22). The present study suggests that the genotyping of CYP1A2 cannot predict the steady state plasma levels of HAL in male smoking schizophrenics.

Melatonin has recently garnered interest as a possible treatment for sleep disorders, and this has created a desire for appropriate pharmacokinetic studies. No method has yet been published that can measure the concentrations of both melatonin and its main metabolite, 6-hydroxymelatonin, in plasma or serum. Therefore, a liquid chromatography-mass spectrometry (LC/MS) method including enzymatic hydrolysis and one-step liquid-liquid extraction was developed for this purpose. The mean extraction recovery was 59% for melatonin and 42% for 6-hydroxymelatonin. The mean precision of the method as calculated from the interassay coefficient of variation of quality control samples at high and low concentrations was 18% for 6-hydroxymelatonin and 15% for melatonin. The inaccuracy was always less than 2%. The limit of detection was approximately 2 ng/mL for 6-hydroxymelatonin (signal/noise ratio = 4) and less than 2 ng/mL for melatonin (signal/noise ratio at 2 ng/mL = 10). The method was applied to the analysis of plasma from a healthy volunteer who had received a single oral dose of 25 mg melatonin.

The authors we investigated the relationship between plasma levels of haloperidol (HAL) and the number of CYP2D6*10 (*10) alleles in 66 Japanese inpatients with schizophrenia (male = 61, female = 5) on HAL. Plasma HAL level was determined by an enzyme immunoassay method. Daily dose of HAL was 1.5-36 (mean +/- SD = 12.3 +/- 7.6) mg or 0.02-0.49 (0.21 +/- 0.13) mg/kg body weight. Plasma HAL levels ranged from 1.4 to 47.4 (12.4 +/- 9.5) ng/mL. No significant difference in the plasma HAL levels was observed between the subjects with no, one, and two *10 alleles (one-way analysis of variance: 56.1 +/- 20.3, 61.0 +/- 20.3, and 63.3 +/- 20.3 ng/mL/mg/kg, respectively, F(2,63) = 0.65, p = 0.52). These results are not supportive of the previous report that plasma HAL levels can be predicted by the number of *10 alleles in Asian patients.

We investigated the impact of the genotype of CYP2D6 on the hydroxylation of desipramine in eighteen patients who were administered desipramine hydrochloride per os. Significantly higher plasma concentration of desipramine/daily dose of desipramine/body weight was observed in the subjects with two mutated alleles than in the subjects with either no mutated alleles or one mutated allele (two mutated alleles versus no mutated alleles=530.4+/-215.2 versus 118.1+/-63.9 ng/ml/mg/kg, t=5.68, P

The aim of this study was to compare the disposition of the tricyclic antidepressant clomipramine (C) in Japanese and Swedish patients receiving continuous treatment. Therapeutic drug monitoring data for C and the active metabolite N-desmethylclomipramine (DC) in Japanese patients receiving monotherapy (N = 12) and in those receiving C plus benzodiazepines (BZDs) (N = 96) as well as in Swedes receiving C monotherapy (N = 131) and in those receiving C plus BZDs (N = 43) were used. A population kinetic approach with Bayesian feedback was used to estimate the individual clearance values for C. The relationships between kinetic variables and covariates were evaluated by linear multiple regression. The median (25% and 75% quartiles, respectively) oral clearance of C was 12.7 L/hr (11.6, 30.6) in Japanese patients receiving C monotherapy, 18.1 L/hr (5.6, 31.8) in Japanese patients receiving C plus BZDs, 62.7 L/hr (40.0, 90.6) in Swedish patients receiving C monotherapy, and 56.5 L/hr (34.3, 74.1) in Swedish patients receiving C plus BZDs. When combining all populations in a linear multiple regression, clearance was correlated with ethnic group (p < 0.00001) and age (p < 0.0005), but it was uncorrelated with gender, body weight, and administration of BZDs. The C/DC plasma concentration ratios were 1.08 in Japanese patients receiving C monotherapy, 0.90 in Japanese patients receiving C plus BZDs, 0.51 in Swedish patients receiving C monotherapy, and 0.49 in Swedish patients receiving C plus BZDs. Thus, the lower oral clearance of C in Japanese patients compared with that in Swedish patients is not accounted for by the lower body weight in Japanese patients or by concomitant treatment with BZDs and is therefore likely to be a true ethnic difference. The higher C/DC ratio implicates a more pronounced serotonergic than noradrenergic effect in Japanese patients than in Swedish patients.

We measured the concentrations of clomipramine and its metabolites, N-desmethylclomipramine, 8-hydroxy-N-desmethylclomipramine, 8-hydroxyclomipramine by high-performance liquid chromatography in 108 Japanese psychiatric patients receiving clomipramine hydrochloride PO. The concentrations of the glucuronide conjugates of 8-hydroxyclomipramine and 8-hydroxy-N-desmethyl-clomipramine were assayed via enzymatic hydrolysis. Although there were large interindividual variations of concentrations of parent, intermediate metabolic compounds, and glucuronide conjugates, significant positive correlations were observed between these drug concentrations and daily doses of clomipramine hydrochloride (mg/kg body weight). Although the metabolic ratios for desmethylation, hydroxylation, and glucuronidation that were calculated from steady-state drug concentrations varied substantially with 36-, 14-, and 28-fold interindividual variations, respectively, apparent poor desmethylators, poor hydroxylators, or poor glucuronidators were not found.

σ-tocotrienolの引き起こす副作用(細胞からのリソソーム放出と細胞のcholesterol含有量減少)について検討した。また、メラノソーム(リソソームに関連した細胞小器官)の放出についても調べた。β-glucuronidase(メラノソームおよびリソソーム酵素)活性、melanin含有量(メラノソームマーカー)、tyrosinase(メラノソーム酵素)活性は、細胞培養培地において増加しなかったため、リソソーム、メラノソームのどちらも、σ-tocotrienolで処理した細胞からは放出されなかった。Mevalonate pyrophosphate decarboxylase(MPD、cholesterolの合成酵素)は、σ-tocotrienolで処理した細胞において有意に減少したが、cholesterol含有量は減少しなかった。σ-tocotrienolはMPDを引き起こすが、σ-tocotrienolは色素過剰の治療薬または予防薬として、また重症の副作用(cholesterol含有量の減少とリソソーム/メラノソームの放出)を引き起こさないホワイトニングおよび/または美白化粧品の成分として有用となる可能性が示唆された。

The impact of smoking on plasma haloperidol (HAL) concentrations was investigated in 66 Japanese male schizophrenic inpatients treated orally with HAL. The subjects consisted of 22 nonsmokers and 44 smokers each smoking ten cigarettes per day. Plasma concentrations of HAL were determined by an enzyme immunoassay method. There were significant positive correlations between the plasma HAL concentration and the daily dose of HAL per kg body weight (Y = 58.1X-0.01 (r = 0.86)). Smokers had significantly lower HAL concentrations per daily dose of HAL/kg body weight than nonsmokers (smokers vs. nonsmokers = 54.3+/-16.6 vs. 70.6+/-23.2 ng/mL/mg/kg). In doses less than 0.2 mg/kg of HAL, smokers showed significantly lower HAL concentrations per daily dose of HAL/kg body weight than nonsmokers (smokers vs. nonsmokers = 55.1+/-14.4 vs. 79.5+/-27.1 ng/mL/mg/kg), whereas no significant difference in HAL concentrations per daily dose of HAL/kg body weight was observed between smokers and nonsmokers when treated with more than 0.2 mg/kg (smokers vs. nonsmokers = 52.9+/-20.7 vs. 60.0+/-11.1 ng/mL/mg/kg). Our results indicate that smoking may induce the enzyme(s) metabolizing HAL, which results in lower plasma HAL concentrations in smokers than in nonsmokers, particularly at low doses of HAL.