Physiologically based pharmacokinetic modeling of the inhibitory effect of dapagliflozin on intestinal and renal SGLT / 药学学报

This study establishes and optimizes the physiologically based pharmacokinetics (PBPK) model for dapagliflozin, predicts the drug distribution into relevant tissues, and calculates the inhibitory effect on the sodium-glucose cotransporters (SGLTs) in the intestine and renal proximal tubule. Based on literature data, a PBPK model for oral administration in healthy adults was established and the predicted blood concentration-time curve characteristics, the main pharmacokinetic parameters (PK), and drug excretion in urine were compared with the published data. To verify and optimize the model and verify the accuracy of the tissue distribution and concentration predictions, a pharmacodynamics model (PD) was established. Urine glucose excretion (UGE) was simulated at the corresponding times. The characteristics of the drug-time curve predicted by the model are similar to those of the measured curve, and the ratio of the main PK parameters to the measured values is within a two-fold range; the accuracy of the established PBPK model is good. The maximal inhibition obtained with 10 mg of dapagliflozin on the duodenum and jejunum segment sodium-glucose co-transporter 1 (SGLT1s) was 1.6%-4.7%, and the inhibition rate of the sodium-glucose co-transporter 2 (SGLT2s) in the proximal tubule of the kidney was as high as 99.9%. At a dose of 10 mg, dapagliflozin delayed intestinal glucose absorption while occupying most of the sites (99.9%) of the renal sodium-glucose cotransporter 2 and inhibiting its glucose reabsorption. This physiological-pharmacokinetic model for dapagliflozin in healthy adults can provide meaningful guidance for exploring pharmacological mechanisms and potential toxicity of gliflozin by simulating drug distribution in different tissues.

Effect of procyanidine on the function and expression of miR-221 in human umbilical vein endothelial cells / 解放军医学杂志

Objective To study the effect ofprocyanidine (PC) on the proliferation and migration of human umbilical vein endothelial cells (HUVECs),determine the expression changes of miR-221,and to investigate the mechanism involved.Methods HUVECs were cultured in vitro and treated with PC (5,25,50,75,100μg/ml) for 24 hours,and a PC concentration of 50μg/ml was screened by CCK-8 assay for the follow up experiment,then the cell proliferation activity was detected by the wound healing assay.The expression of miR-221 in HUVECs was detected by real-time quantitative PCR;MiR-221 target genes were predicted in miRWalk database,and the target genes were analyzed by GO and KEGG pathway.Results Compared with the control group,the HUVECs treated with PC for 24h,their proliferation activity in PC 5μg/ml group did not change obviously (P＞0.05),and in PC 25,50,75 and 100μg/ml groups decreased in a concentration dependent manner (P＜0.01).Compared with the control group,the migration ability of PC 50μg/ml group decreased markedly (P＜0.01).Compared with the control group,the expression of miR-221 increased after treatment with PC 50μg/ml (P＜0.01).Go analysis indicated that the target genes of miR-221 were mainly related to cell proliferation,migration,gene translation and so on.The target genes related to cell proliferation and migration were ADAM17,KIT,PDGFD and so on.KEGG pathway analysis showed that the target genes of miR-221 enriched 5 signal pathways,such as FoxO,PI3K-Akt and so on.Conclusions Low concentration of PC has no effect on the proliferation activity of HUVECs.A certain concentration of PC can inhibit the proliferation and migration of HUVECs,of which the mechanism may be involved with the up-regulation of miR-221 and FoxO,PI3K-Akt and other signaling pathways.

Analysis on Inpatient Health Expenditures of Renal Cell Carcinoma in a Grade-A Tertiary Hospital in Beijing / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Renal cell carcinoma (RCC) is the most common type of malignant renal tumors with a growing incidence in the recent years. This study aimed to investigate the influencing factors and variation trend of hospitalization expenditures among RCC patients in a single-centered hospital in Beijing during 5 consecutive years and to find the major cost items and fluctuation tendency of inpatient medical expenditures.</p><p><b>METHODS</b>The information of medical expenditures among RCC patients in a Grade-A tertiary hospital during the years 2012-2016 was investigated to find the main cost items and changes affecting the medical cost structure. Gray correlation method was adopted in quantitative analysis to analyze the composition of medical expenditures, and the variation of hospitalization expense structure during the five years was studied by analyzing the degree of structural variation.</p><p><b>RESULTS</b>The cost item constitution of the hospitalization expenditures among RCC patients was relatively stable in the sample hospital during the past five years. To be specific, drug costs accounted for the largest proportion of medical expenditures each year, with the highest of 37.81% in 2012, and showed a slowly declining tendency in the coming years. The cost item with the highest correlation degree was drug costs, with the value of 1.0000; followed by the costs of surgeries, 0.8423. Furthermore, drug costs shared the largest proportion (40.95%) of structural variation, followed by the costs of surgeries (18.35%).</p><p><b>CONCLUSIONS</b>Drug costs are the major influencing factors of the hospitalization expenditures among RCC patients. Thus, reasonable control on excessive drugs as well as the standardization of the diagnosis and treatment behaviors is conducive in reducing medical expenditures as well as easing patients' economic burdens. Besides, the positive growth on surgery costs suggests that the labor value of medical staffs has been gradually recognized.</p>

Antitumer effect of supernatant from co-culture of human embryonic stem cells and breast cancer cells on MDA-MB-231 cells in vitro / 药学学报

This study was designed to investigate the inhibitory effect of supernatant from co-culture of human embryonic stem cells and tumor MDA-MB-231 cells on the breast cancer. The direct co-culture system of human embryonic stem cells H9 and breast cancer MDA-MB-231 cells was established, and the supernatant was tested in the inhibition of MDA-MB-231 cells. The inhibitory effects were examined in tumor cell morphology using microscope, cell proliferation with MTT assay, and cell apoptosis using the Hoechst staining and flow cytometry. Transwell assay was used to detect the migration and invasion of tumor cells. The results suggest that the supernatant significantly inhibited the proliferation, invasion and migration, and promoted cell apoptosis of MDA-MB-231 cells. However, the supernatant of H9 cells alone had little effect on MDA-MB-231 cells. Therefore, we conclude that the supernatant of co-culture cells had an inhibitory effect on tumor cells in vitro.

Case of bilateral Testicular Tumors subsequently diagnosed as Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

21-hydroxylase deficiency [21-OHD] caused congenital adrenal hyperplasia [CAH] is a group of autosomal recessive genetic disorders resulting from mutations in genes involved with cortisol [CO] synthesis in the adrenal glands. Testicular adrenal rest tumors [TARTs] are rarely the presenting symptoms of CAH. Here, we describe a case of simple virilizing CAH with TARTs, in a 15-year-old boy. The patient showed physical signs of precocious puberty. The levels of blood adrenocorticotropic hormone [ACTH], urinary 17-ketone steroids [17-KS], dehydroepiandrosterone sulfate [DHEA-S], and serum progesterone [PRGE] were elevated, whereas those of follicle-stimulating hormone [FSH], luteinizing hormone [LH], and CO were reduced. Computed tomography [CT] of the adrenal glands and magnetic resonance imaging [MRI] of the testes showed a soft tissue density [more pronounced on the right side] and an irregularly swollen mass [more pronounced on the left side], respectively. Pathological examination of a specimen of the mass indicated polygonal/circular eosinophilic cytoplasm, cord-like arrangement of interstitial cells, and lipid pigment in the cytoplasm. Immunohistochemistry results precluded a diagnosis of Leydig cell tumors. DNA sequencing revealed a hackneyed homozygous mutation, I2g, on intron 2 of the CYP21A2 gene. The patient's symptoms improved after a three-month of dexamethasone therapy. Recent radiographic data showed reduced hyperplastic adrenal nodules and testicular tumors. A diagnosis of TART should be considered and prioritized in CAH patients with testicular tumors. Replacement therapy using a sufficient amount of dexamethasone in this case helps combat TART