Notes

Engagement of ADGRV1 Gene in Familial Forms of Hereditary Generalized Epilepsy.
The common alleles of HLA were -A*0201, -B*5101, and -C*0304 which were carried by three patients (60%) for each allele. The patient with CBZ-induced DRESS syndrome carried the HLA-A* 3101 allele. One patient with CBZ-induced SJS and one patient with VPA-induced SJS carried the HLA-B*1511 allele. No patients carried the HLA-B*1502 allele, which is a known risk allele of AED-induced SCARs. Further investigation of the three common alleles found in the five AED-induced SCARs patients is needed. We demonstrated the usefulness of LAT for confirming the culprit drug. Copyright © 2019 Translational and Clinical Pharmacology.Although sciences and technology have progressed rapidly, de novo drug development has been a costly and time-consuming process over the past decades. In view of these circumstances, 'drug repurposing' (or 'drug repositioning') has appeared as an alternative tool to accelerate drug development process by seeking new indications for already approved drugs rather than discovering de novo drug compounds, nowadays accounting for 30% of newly marked drugs in the U.S. In the meantime, the explosive and large-scale growth of molecular, genomic and phenotypic data of pharmacological compounds is enabling the development of new area of drug repurposing called computational drug repurposing. This review provides an overview of recent progress in the area of computational drug repurposing. Navoximod First, it summarizes available repositioning strategies, followed by computational methods commonly used. Then, it describes validation techniques for repurposing studies. Finally, it concludes by discussing the remaining challenges in computational repurposing. Copyright © 2019 Translational and Clinical Pharmacology.This tutorial introduces the mathematical skills required to obtain exact and approximate solutions for reversible reactions and provides graphical insights to help understand the pharmacokinetics of reversible metabolism. The matrix method provides an easy way to derive the exact solution for the amount of each species as a function of time. The plots of the exact solutions reveal some characteristic features of the pharmacokinetic profiles of the reversible metabolism. We also describe two approximation approaches, steady-state approximation, and equilibrium approximation, to simplify the solutions. The skills and knowledge acquired through this tutorial will provide a basis for understanding more complex reversible reaction systems. Copyright © 2019 Seungil Cho and Young-Ran Yoon.The analytical solution for multi-compartment models with a non-zero initial condition is complex because of the inter-compartmental transfer. An elegant solution and its implementation in the 'wnl' R package can be useful in solving examples of textbooks and developing software of therapeutic drug monitoring, pharmacokinetic simulation, and parameter estimation. This solution uses Laplace transformation, convolution, matrix inversion, and the fact that the general solution of an inhomogeneous ordinary differential equation is the sum of a homogenous and a particular solution, together. Copyright © 2019 David Z. D'Argenio and Kyun-Seop Bae.Apixaban, an inhibitor of direct factor Xa, is used for the treatment of venous thromboembolic events or prevention of stroke. Unlike many other anticoagulant agents, it does not need periodic monitoring. However, monitoring is still required to determine the risk of bleeding due to overdose or surgery. Usually, apixaban concentrations are indirectly quantified using an anti-factor Xa assay. However, this method has a relatively narrow analytical concentration range, poor selectivity, and requires an external calibrator. Therefore, the goal of current study was to establish an analytical method for determining plasma levels of apixaban using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). To this end, apixaban was separated using 2.5 mM ammonium formate (pH 3.0) (A) and 100% methanol containing 0.1% formic acid (B) using the gradient method with a Thermo hypersil GOLD column. The mass detector condition was optimized using the electrospray ionization (ESI) positive mode for apixaban quantification. The developed method showed sufficient linearity (coefficient of determination [r2 ≥ 0.997]) at calibration curve ranges. The percentage (%) changes in accuracy, precision, and all stability tests were within 15% of the nominal concentration. Apixaban concentration in plasma from healthy volunteers was quantified using the developed method. The mean maximum plasma concentration (Cmax) was 371.57 ng/mL, and the median time to achieve the Cmax (Tmax) was 4 h after administration of 10 mg apixaban alone. Although the results showed low extraction efficiency (~16%), the reproducibility (% change was within 15% of nominal concentration) was reliable. Therefore, the developed method could be used for clinical pharmacokinetic studies. Copyright © 2019 Translational and Clinical Pharmacology.Characterizing the time course of baseline or pre-drug blood pressure is important in acquiring unbiased estimates of antihypertensive drug effect. In this study, we recruited 23 healthy male volunteers and measured systolic (SBP) and diastolic blood pressure (DBP) over 24 hours on an hourly basis. Using a non-linear mixed effects model, circadian rhythm observed in blood pressure measurements was described by incorporating two cosine functions with periods 24 and 12 hours. A mixture model was applied to identify subgroups exhibiting qualitatively different circadian rhythms. Our results suggested that 78% of the study population, defined as 'dippers', demonstrated a typical circadian profile with a morning rise and a nocturnal dip. The remaining 22% of the subjects defined as 'non-dippers', however, were not adequately described using the typical profile and demonstrated an elevation of blood pressure during night-time. Covariate search identified weight as being positively correlated with mesor of SBP. Visual predictive checks using 1,000 simulated datasets were performed for model validation. Observations were in agreement with predicted values in 'dippers', but deviated slightly in 'non-dippers'. Our work is expected to serve as a useful reference in assessing systematic intra-day blood pressure fluctuations and antihypertensive effects as well as assessing drug safety of incrementally modified drugs. Copyright © 2019 Translational and Clinical Pharmacology.
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