We performed a double‐blinded, genotype‐based stratification study to explore the pharmacokinetics and pharmacodynamics of amitriptyline according to CYP2C19 and CYP2D6 genotype in Korean subjects. Twenty‐four healthy adults were grouped by genotype of CYP2C19 and CYP2D6. After a single dose of 25 mg of amitriptyline, blood samples were collected and anticholinergic effects were measured. The extent of N‐demethylation of amitriptyline significantly decreased in subjects carrying two nonfunctional alleles of CYP2C19. The extent of hydroxylation of amitriptyline or nortriptyline was significantly reduced in subjects carrying two CYP2D6 decreased functional alleles compared with those with no or one decreased functional allele. The overall metabolic pathway of amitriptyline was more likely to be dominated by CYP2C19 than CYP2D6. The gene variations of CYP2C19 and CYP2D6 did not change the pharmacodynamic effect. The findings of this study will provide useful information on individualized drug treatment with amitriptyline considering both CYP2D6 and CYP2C19 gene variations.

We evaluated the prevalence, awareness, treatment and control of hypertension in Korean adults with diagnosed diabetes using nationally representative data. Among subjects aged ≥30 years who participated in the Fourth Korea National Health and Nutrition Examination Survey in 2007 and 2008, a total of 745 subjects (336 men and 409 women) with a previous diagnosis of diabetes mellitus were analyzed. The prevalence of hypertension in adults with diagnosed diabetes was 55.5%. The rates of awareness, treatment and control were 88.0, 94.2, and 30.8%, respectively. Compared with the general population, the prevalence of hypertension in adults with diagnosed diabetes was higher in all age groups in both genders. Factors independently associated with a high prevalence of hypertension included being male, increasing age, single, <9 years of education, the presence of chronic kidney disease risk, hypercholesterolemia (≥240 mg dl(-1)) and high body mass index (≥25 kg m(-2)). Regular medical screening was positively associated with hypertension control, whereas a high triglyceride level (≥150 mg dl(-1)) was inversely associated. A high prevalence and a low control rate of hypertension in adults with diagnosed diabetes suggest that stringent efforts are needed to control blood pressure in diabetic patients.

The downstream events and target genes of p53 in the process of senescence are not fully understood. Here, we report a novel function of the forkhead transcription factor Foxp3, which is a key player in mediating T-cell inhibitory functions, in p53-mediated cellular senescence. The overexpression of Foxp3 in mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas Foxp3 knockdown leads to escape from p53-mediated senescence in p53-expressing MEFs. Consistent with these results, Foxp3 expression resulted in the induction of senescence in epithelial cancer cells, including MCF7 and HCT116 cells. Foxp3 overexpression also increased the intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-l-cysteine rescued cells from Foxp3-expression-induced senescence. Furthermore, the elevated ROS levels that accompanied Foxp3 overexpression were paralleled by an increase in p21 expression. Knockdown of p21 in Foxp3-expressing MEFs abrogated the Foxp3-dependent increase in ROS levels, indicating that Foxp3 acts through the induction of p21 and the subsequent ROS elevation to trigger senescence. Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression, ROS production and p53-mediated senescence.

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