The Effect of Yokukansan, a Traditional Herbal Preparation Used for the Behavioral and Psychological Symptoms of Dementia, on the Drug-Metabolizing Enzyme Activities in Healthy Male Volunteers.

The concomitant use of herb and prescription medications is increasing globally. Herb-drug interactions are therefore a clinically important problem. Yokukansan (YKS), a Japanese traditional herbal medicine, is one of the most frequently used herbal medicines. It is effective for treating the behavioral and psychological symptoms of dementia. We investigated the potential effects of YKS on drug-metabolizing enzyme activities in humans. An open-label repeat-dose study was conducted in 26 healthy Japanese male volunteers (age: 22.7±2.3 years) with no history of smoking. An 8-h urine sample was collected after a 150-mg dose of caffeine and a 30-mg dose of dextromethorphan before and after the administration of YKS (2.5 g, twice a day for 1 week). The activities of cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, xanthine oxidase (XO) and N-acetyltransferase 2 (NAT2) were assessed based on the urinary metabolic indices of caffeine and dextromethorphan, and the urinary excretion ratio of 6ß-hydroxycortisol to cortisol. There were no statistically significant differences in the activities of the examined enzymes before or after the 7-d administration of YKS. Although further studies assessing the influence of YKS on the pharmacokinetics and pharmacodynamics of the substrates of the drug-metabolizing enzymes are needed to verify the present results, YKS is unlikely that a pharmacokinetic interaction will occur with concomitantly administered medications that are predominantly metabolized by the CYP1A2, CYP2D6, CYP3A, XO and NAT2.

Sex differences in the effect of cytochrome P450 2C19 polymorphisms on the risk of diabetic retinopathy: a retrospective longitudinal study in Japanese patients with type 2 diabetes.

Cytochrome P450 2C19 (CYP2C19) is expressed in human endothelial cells and catalyzes the biosynthesis of vasoprotective epoxyeicosatrienoic acids and 19-hydroxyeicosatetraenoic acid from arachidonic acid. This study investigated the association between CYP2C19 polymorphisms and an increased risk of diabetic retinopathy (DR). A clinic-based retrospective longitudinal analysis was carried out that included 383 Japanese patients with type 2 diabetes mellitus. Compared with male extensive metabolizers, female intermediate metabolizers [adjusted odds ratio (OR), 2.43; 95% confidence interval (95% CI), 1.17-5.06] and poor metabolizers (OR, 7.49; 95% CI, 2.64-21.26) were at a significantly higher risk of developing DR. Furthermore, the CYP2C19 poor metabolizer genotype was found to be an independent risk factor for DR only in women when patients were stratified by sex (OR, 4.18; 95% CI, 1.42-12.26). This is the first report showing the interactive effect of sex and CYP2C19 polymorphisms on microvascular disease in humans, although further investigations are needed to verify these findings.

Glutathione S-transferase K1 genotype and overweight status in schizophrenia patients: A pilot study.

Elevated oxidative stress in mitochondria and mitochondrial dysfunction are associated with weight gain in schizophrenia (SCZ) patients. Glutathione S-transferase kappa 1 (GSTK1) protects cells against exogenous and endogenous oxidative stress in the mitochondria. This exploratory study investigated the possible effects of a common GSTK1 polymorphism (rs1917760, G-1308T) on the risk for overweight status among 329 SCZ patients and 305 age- and gender-matched controls and on the GSTK1 mRNA level in peripheral blood mononuclear cells among 14 SCZ patients. The GSTK1 T/T genotype was associated with having a higher BMI value among SCZ male patients, whereas this genotype tended to be associated with a lower BMI value among female patients. Conversely, these associations were not observed among the controls. The GSTK1 T/T genotype was associated with decreased GSTK1 mRNA level among SCZ patients. The GSTK1 T/T genotype may be a novel risk factor for the prediction of overweight status in SCZ male patients, although the results of this pilot study should be verified by a larger study.

Possible association between moderate intellectual disability and weight gain in valproic acid-treated patients with epilepsy.

BACKGROUND: Although patients with moderate intellectual disability (ID) are known to have higher rates of being overweight and obese than those without ID, there are no current data regarding the relationship between ID and weight gain in epilepsy patients treated with valproic acid (VPA). PATIENTS AND METHODS: The possible association between moderate ID and an overweight status at the time of initiation of VPA therapy (baseline) was investigated using a logistic regression analysis in 143 patients with epilepsy. Among the 119 nonoverweight patients at baseline, the longitudinal association between moderate ID and the weight status during VPA therapy was retrospectively examined using a Cox hazards regression analysis and the generalized estimating equations approach, while also paying careful attention to associations with other patient characteristics. RESULTS: The proportion of patients with moderate ID was 52.4% among the 143 study subjects. The presence of moderate ID was not associated with an overweight status at baseline (P=0.762). Among the nonoverweight patients at baseline, 16 subjects were newly diagnosed as being overweight during treatment with VPA (3.6±2.1 years). The presence of moderate ID was significantly associated with the incidence of an overweight status after starting VPA therapy (adjusted hazard ratio =6.72, P=0.007). The patient age at baseline and treatment with co-administered carbamazepine, clobazam, and zonisamide significantly influenced the degree of weight fluctuation during VPA therapy among the patients with moderate ID (P<0.001, P<0.001, P=0.002, and P=0.028, respectively), whereas only patient age at baseline affected this parameter among the patients without moderate ID (P=0.022). CONCLUSION: The present findings suggest that the weight status should be carefully monitored in VPA-treated patients with moderate ID, especially those receiving other co-administered antiepileptic drugs that facilitate weight gain, such as carbamazepine.

Possible associations between antioxidant enzyme polymorphisms and metabolic abnormalities in patients with schizophrenia.

BACKGROUND: This study investigated the possible association between common and potentially functional polymorphisms of antioxidant enzymes and metabolic abnormalities in patients with schizophrenia. METHODS: The possible associations of the glutathione S-transferase (GST) M1 null and GSTT1 null genotypes, and the superoxide dismutase 2 (SOD2) Val16Ala polymorphism with the risks of being overweight and having metabolic syndrome were examined using a logistic regression analysis in 154 schizophrenic Japanese patients and 203 controls. RESULTS: Among smokers with schizophrenia, the risks of being overweight and having decreased high-density lipoprotein cholesterol were significantly higher in those with the GSTM1 null genotype than in those with the present genotype (odds ratio 3.20 and 3.15, P=0.03 and P=0.04, respectively), while among nonsmokers with schizophrenia, the risk of an abnormal waist circumference was lower in those with the GSTM1 null genotype (odds ratio 0.34, P=0.04). The risk of a decreased high-density lipoprotein cholesterol level was significantly higher in patients with the combined GSTM1 null and GSTT1 present genotypes than in those with the present genotypes of both genes (odds ratio 3.60, P<0.01). The SOD2 Val16Ala polymorphism was not associated with risk of metabolic abnormalities in either group. CONCLUSION: The present study suggests that the GSTM1 null genotype, in combination with smoking status or GSTT1 genotype, might be associated with the metabolic abnormalities in patients with schizophrenia.