How to handle a missed or delayed dose of lacosamide in pediatric patients with epilepsy? a mode-informed individual dosing.

This study aims to investigate the effects on the pharmacokinetic (PK) of lacosamide (LCM), and to guide the individual dosing regimens for children and ones with poor medication adherence. Population PK research was performed based on 164 plasma samples of 113 pediatric patients aged from 1.75 to 14.42 years old. The PK characteristic of LCM was developed by a one-compartment model with first-order elimination. The typical value of apparent clearance (CL) and apparent volume of distribution (Vd) was 1.91 L·h-1 and 56.53 L respectively. In the final model, the variability of CL was significantly associated with the body surface area (BSA) and elevated uric acid (UA) level. In contrast, the impact of some prevalent anti-seizure medicines, such as valproic acid, levetiracetam, oxcarbazepine, lamotrigine, and perampanel, and gene polymorphisms of Cytochrome P450 (CYP)2C19, ATP-binding cassette (ABC)B1, and ABCC2 had no clinical significance on the PK parameters of LCM. BSA-based dosing regimen of LCM was provided according to Monte Carlo simulation approach; while the dosage should reduce half in patients with an UA level of more than 400 µmol·L-1 comparing with an UA level of 100 µmol·L-1. Individualize remedial doses of about 0.5- to 1.5-fold of regular doses were recommended in six common scenarios of missed or delayed doses, that depended on the delayed time. In current study, the population PK model of LCM in children with epilepsy was developed successfully. The BSA-based dosing regimen and individualized remedial strategy were recommended to guarantee the precise administration of LCM.

Erratum to: The Role of CARD9 in Metabolic Diseases.

The article "The Role of CARD9 in Metabolic Diseases", written by Cheng TIAN, Ya-li TUO, Yi LU, Chuan-rui XU, Ming XIANG, was originally published electronically on the publisher's internet portal on May 2020 without open access. With the author(s)' decision to opt for Open Choice, the copyright of the article is changed to © The Author(s) 2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ ), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.The original article has been corrected.

The Role of CARD9 in Metabolic Diseases.

Caspase recruitment domain containing protein 9 (CARD9) is an adaptor protein that plays a critical role in pattern recognition receptors (PRRs)-mediated activation of NF-?B and mitogen-activated protein kinase (MAPK). This elicits initiation of the pro-inflammatory cytokines and leads to inflammatory responses, which has been recognized as a critical contributor to chronic inflammation. Current researches demonstrate that CARD9 is strongly associated with metabolic diseases, such as obesity, insulin resistance, atherosclerosis and so on. In this review, we summarize CARD9 signaling pathway and the role of CARD9 in metabolic diseases.

PID1, a new tumor-promoting gene in insulin resistance mediated acceleration of hepatocellular carcinoma development and progression / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effect of phosphotyrosine interaction domain containing 1 (PID1, NYGGF4) on promotion of IR and HCC, and explore its underlying mechanisms. METHODS Lentivirus were used to mediate the knockdown of PID1 in HFD induced IR mouse model as well as ob/ob mice. Intraperitoneal glucose and insulin tolerance were performed 4 weeks after lentivirus injection. Hydrodynamics-based transfection was applied to inducethe liver specific overexpression of PID1. Flow cytometry was exerted to detect the proportion and function of immune cells. qRT-PCR and Western blot were used to detect the expression of downstream pathways of PID1.Immunoprecipitation was used to determine the receptor of PID1. Chromatin immunoprecipitation (ChIP) was operated to measure the modification of H3K4me3 of PID1 promoter. RESULTS PID1 restriction improved insulin resistance, hyperglycemia and fatty liver. Conversely, hepatic knockdown of PID1 attenuated liver xenografted tumor growth. Moreover, PID1 liver- specific protooncogenes via hydrodynamics- based transfection established a primary hepatocellular carcinoma mouse model, induced an immunosuppressive environment, with the reduction of CD3 +, CD4 +, CD8 +T cells, retarded maturation of dendritic cells (DCs), pronounced differentiation of regulatory T cells (Tregs), and recruitment of MDSC. In addition, PID1 overexpression activated proliferation related genes, promoted anti- inflammatory genes, suppressed pro-inflammatory genes, induced glycolysis and lipid metabolism genes to facilitate tumorigenesis in liver. Importantly, PID1 exerted its tumor-promoting function through binding to epidermal growth factor receptor (EGFR) and activation of downstream MAPK pathway. As such, PID1 exist trimethylation of histone H3 at lysine 4 (H3K4me3) modification and IR up-regulated the expression of PID1 by activation the H3K4me3 modification. CONCLUSION PID1 is a new gene that exerts both liver cancer-promoting and insulin resistance inducing function. IR accelerates liver cancer development and progression partially dependent on the activation of PID1.

Effects of methionine enkephalin on immune enhancement by reducing myeloid derived suppressor cells and reprogramming liver metabolism in colon cancer mice / 中国药理学与毒理学杂志

OBJECTIVE To investigate enhanced immune function of methionine encephalin (MENK) and its anti-tumor mechanism in CT26 colon cancer mouse model. METHODS 3×106 CT26 cells were implanted subcutaneously in BALB/c mice. Four days after, MENK was peritoneally administrated at the concentration of 20 mg·kg-1 for 14 d. The percentage of MDSCs in bone marrow, spleen, blood, tumor and liver were detected by flow cytometry. Non- esterified fatty acid (NEFA), triglycerides (TG) and total cholesterol (T-CHO) in liver homogenate were tested by a NEFA test kit, a TG test kit and a T- CHO test kit respectively. qRT- PCR and Western blot were used to measure mRNA and protein levels of inflammation-, glycometabolsim- and lipometabolsim-associated indexes in liver. RESULTS MENK decreased percentages of MDSCs in bone marrow, spleen, blood and tumor in colon cancer mice. MENK-treated mice displayed elevated ratio of CD4+T and CD8+T cells in spleen as well as increased T and B lymphocytes proliferation. Meanwhile, MENK also ameliorated liver damage reflected by lower levels of GPT and GOT in serum and reduced risks of cancer- associated index including inflammation, high lipid and high glucose. Furthermore, MENK lowered down the levels of NEFA, TG and T- CHO in liver homogenate. MENK treatment decreased expression of p- STAT3, increased expression of p-AKT, IRS1 and Glut4 at protein level as well as reduced lipogenesis-associated genes and elevated glycolysis-associated genes in liver of tumor bearing mice. Also, abated expression of genes associated with MDSCs generation (M-CSF, GM-CSF, IL-6, IL-1β) and migration (S100A9, KC) was observed within shrunken subcutaneous tumor by MENK intervention. CONCLUSION MENK has the ability to strength immune function against colon cancer by reducing MDSCs and improving liver metabolism.