The primary aim of the present study was to evaluate the effect of the genotype of vitamin K epoxide reductase complex 1 (VKORC1) on warfarin dose requirements in Japanese pediatric patients. Forty-eight pediatric patients (0.42-19.25 years old) in whom stable anticoagulation was achieved by warfarin were enrolled in this study, and the polymorphic alleles of VKORC1 and CYP2C9 were determined for each subject. The relative impact of covariates on the anticoagulant effect of warfarin was evaluated by multiple regression analysis. It was found that VKORC1 genotype and age were major factors affecting the relationship between the weight-normalized warfarin dose and the therapeutic prothrombin time-international normalized ratio (PT-INR). Because only one patient had the CYP2C9*3 allele, we could not evaluate the effect of CYP2C9 polymorphisms on the anticoagulant effect of warfarin. In contrast, the anticoagulant effect of warfarin in patients with the VKORC1 1173CT or 1173CC genotype was 52.3% of that in patients with the 1173TT genotype. In addition, the anticoagulant effect of warfarin was shown to increase by 10.5% per year in Japanese pediatric patients. In conclusion, genotyping of VKORC1 will be useful in establishing individual anticoagulant therapy with warfarin, and it should be noted that a higher weight-normalized dose of warfarin is required in younger pediatric patients.

What's already known about this topic? The noninvasive prenatal testing from maternal blood can be confounded by maternal conditions that lead to structural variants/copy number variations in the genome. What does this study add? This study provides further evidence that the grossly ‘abnormal’ and ‘non‐reportable’ noninvasive prenatal testing result due to global genomic changes was attributable to a maternal uterine leiomyoma, in an otherwise normal fetus. The possibility of such adventitious findings is something about which physicians ordering noninvasive prenatal testing for their patients may want to offer pre‐test counseling. © 2015 John Wiley & Sons, Ltd.

We evaluated the pharmacokinetics of routinely administered bosentan in 46 Japanese pediatric patients with pulmonary arterial hypertension. Plasma samples were taken twice at times corresponding to the peak and trough concentrations following repetitive oral administration. The population pharmacokinetic parameters of bosentan were estimated by use of the NONMEM program, in which a one-compartment model with repetitive bolus dosing was parameterized in terms of the oral clearance (CL/F) and elimination rate constant (k). Polymorphisms of CYP3A5, SLCO1B1, SLCO1B3, and SLCO2B1 had no significant effect on the disposition of bosentan. In addition, the pharmacokinetics of bosentan was not altered by heart failure or coadministration of sildenafil. In contrast, weight (WT)-normalized values of CL/F were correlated negatively with age (AGE). The final population mean values of CL/F and k were estimated to be 0.409 · (1 - 0.0377 · (AGE - 3.81)) · WT L/h and 0.175 h(-1), respectively.

Carvedilol is a b-adrenoceptor antagonist, clinically used to treat chronic heart failure as well as hypertension, angina pectoris, and cardiac arrhythmias.1) Orally administered carvedilol undergoes stereoselective first-pass metabolism, and the maximal plasma concentration of R-enantiomer with low b-blocking activity is approximately 2-fold higher than that of S-enantiomer with high b-blocking activity.2) Carvedilol is metabolized extensively via aliphatic sidechain oxidation, aromatic ring oxidation, and conjugation pathways.3) Oldham and Clarke 4) reported that oxidative activity for carvedilol is observed in cytochrome P450 (CYP) 2D6, 2C9, 3A4, and 1A2. In addition, Ohno et al. 5) reported that UDP-glucuronosyltransferase (UGT) 2B7, 2B4, and 1A1 are capable of catalyzing the glucuronidation of carvedilol. In the previous study, we examined the effect of CYP2D6*10, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, UGT2B7*3, and the C3435T mutation of MDR1 on the pharmacokinetics of carvedilol in 54 Japanese volunteers. 2,6) The oral clearance (CL/F) and also volume of distribution (V/F) of R-and S-carvedilol were significantly lower in subjects with the CYP2D6*10 allele than those with CYP2D6*1/*1, *1/*2, or *2/*2 genotype, indicating that the systemic clearance (CL) and/or bioavailability (F) of both enantiomers is significantly altered in Japanese with the CYP2D6*10 allele. On the other hand, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT2B7*2, UGT2B7*3, and the C3435T mutation of MDR1 did not affect the pharmacokinetics of R-and S-carvedilol in healthy Japanese. 2,6) Several pharmacokinetic studies have suggested that hepatic elimination of certain drugs via oxidative metabolism is impaired in patients with heart failure (HF) [7][8][9][10][11][12][13] ; that is, the CL/F value of prazosin after oral administration in HF patients was 46% of that in healthy subjects.7) It was also reported that the CL/F value of aminopyrine after oral administration in HF patients in the aminopyrine breath test was 24% of that in control subjects. 8) In addition, CL values of midazolam and quinidine (CYP3A4 substrates) after intravenous administration were decreased by 32% and 33% in HF patients, respectively. 9,10) The CL value of theophylline (CYP1A2 substrate) after intravenous administration was markedly decreased in HF patients. 11,12) Recently, population pharmacokinetic analysis has revealed that the CL/F value of mexiletine, which is mainly metabolized by CYP1A2 and CYP2D6, is reduced significantly in HF patients as compared with non-HF patients.13) However, it is still unclear whether the pharmacokinetics of R-and/or S-carvedilol is altered by HF. In the present study, therefore, we investigated the pharmacokinetics of R-and S-carvedilol in routinely treated Japanese patients with HF. MATERIALS AND METHODS Subjects and Study ProtocolTwenty-four Japanese patients with HF (16 men and 8 women) participated in this study. Their age was between 45 and 91 years old (70.5Ϯ11.3 years), and their body weight was between 36...

We successfully managed two cases of puerperal vulvovaginal hematoma by arterial embolization based on the evaluation of an enhanced CT scan. In conclusion, we suggest arterial embolization to be a viable option for first-line treatment in the management of vulvovaginal hematomas.