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Histidine phosphorylation (pHis) was first reported in 1962. There are few studies on pHis because of the thermal and acidic instability of pHis and the lack of specific methods to detect it. pHis has two isomers of 1-phosphate histidine (1-pHis) and 3-phosphate histidine (3-pHis). pHis antibodies have been developed recently and have promoted research in this field. In this study, we established a CCl4-induced liver fibrosis model in C57 mice and a TGF-β1-induced HSC activation model in LX-2 cells, to study the role of histidine phosphorylation. The expression of histidine kinases NME1 and NME2 was increased, histidine phosphatase PGAM5 and PHPT1 was unchanged, and 1-pHis and 3-pHis were increased in the in vivo and in vitro models. The expression of LHPP was decreased in the in vivo model but not in the in vitro model. To further study the role of NME1, NME2, and histidine phosphorylation in HSC activation, we silenced NME1 or NME2 and administered TGF-β1 in LX-2 cells. The results showed silencing NME1 or NME2 decreased TGF-β1-induced pHis levels and the expression of α-SMA and COL1A1, indicating the activation of HSC was suppressed. Then, we found the inhibitory effect on HSC activation is due to reduced phosphorylation of Smad2 and Smad3. In summary, our studies indicate that NME1 and NME2 are involved in TGF-β1-induced HSC activation and CCl4-induced liver fibrosis, which may be mediated by histidine phosphorylation.

On account of the potential inhibition of OATP1B1 (organic anion transporting polypeptide) by angiotensin II receptor blockers (ARBs) and the effects of SLCO1B1 (solute carrier organic anion transporter family member) polymorphism, the aim of current study is to assess the impact of ARBs on the pharmacokinetics (PK) and pharmacodynamics (PD) of repaglinide in Chinese healthy volunteers with different SLCO1B1 genotypes. The in vitro study was conducted on irbesartan, valsartan, olmesartan, and losartan by using HEK293 cells transfected with OATP1B1. Data on drug interactions between repaglinide and irbesartan from 21 healthy Chinese-Han male volunteers were collected and analyzed. IC50 from in vitro study suggested irbesartan was the most potent inhibitor of OATP1B1 transporter. Clinical data from single dose of repaglinide indicated SLCO1B1 c.521 T>C polymorphism influenced the PK and PD of repaglinide in healthy Chinese-Han male volunteers. In subjects with SLCO1B1 c.521 TT genotype, irbesartan comedication increased the exposure of repaglinide. In details, the peak plasma concentration [Cmax] increased 84% (P = 0.003) and the area under the curve of plasma concentration 0–8 h [AUC0–8] increased 34% (P = 0.004), while the minimum blood glucose concentration [Cmin] decreased 33.8% (P = 0.005). No significant change was observed in repaglinide exposure in subjects with SLCO1B1 c.521 TC genotype in presence or absence of irbesartan. SLCO1B1 c.521 T>C polymorphism affects the PK of repaglinide in Chinese population. Irbesartan increased repaglinide exposure in subjects with SLCO1B1 c.521 TT genotype, but not SLCO1B1 c.521 TC genotype.

Purpose: SET and MYND domain-containing protein2 (SMYD2), a histone lysine methyltransferases, is a candidate human oncogene in multiple tumors. However, the expression dynamics of SMYD2 in hepatocellular carcinoma (HCC) and its clinical/prognostic significance are unclear. Methods: The SMYD2 expression profile was examined by quantitative real-time polymerase chain reaction (qRT-PCR), and immunohistochemistry (IHC) in HCC tissues and matched adjacent non-tumorous tissues. SMYD2 was silenced in HCC cell lines to determine its role in tumor proliferation and cell cycle progression, and the possible mechanism. Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model were used to analyze the data. Results: The SMYD2 expression in HCC tissues were significantly up-regulated at both mRNA and protein levels as compared with the matched adjacent non-tumorous tissues. By IHC, positive expression of SMYD2 was examined in 122/163 (74.85%) of HCC and in 10/59 (16.95%) of tumor-adjacent tissues. Positive expression of SMYD2 was correlated with tumor size, vascular invasion, differentiation and TNM stage (P < 0.05). In univariate survival analysis, a significant association between positive expression of SMYD2 and shortened patients' survival was found (P < 0.05). Importantly, SMYD2 expression together with vascular invasion (P < 0.05) provided significant independent prognostic parameters in multivariate analysis. Functionally, SMYD2 silenced markedly inhibited cell proliferation and cell cycle progression in SMMC-7721 cell. Conclusions: Our findings provide evidences that positive expression of SMYD2 in HCC may be important in the acquisition of an aggressive phenotype, and it is an independent biomarker for poor prognosis of patients with HCC.

Recent evidence shows that resveratrol (RSV) may ameliorate high-glucose-induced cardiac oxidative stress, mitochondrial dysfunction and myocardial fibrosis in diabetes. However, the mechanisms by which RSV regulates mitochondrial function in diabetic cardiomyopathy have not been fully elucidated. Mitochondrial dysfunction contributes to cardiac dysfunction in diabetic patients, which is associated with dysregulation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). In this study we examined whether resveratrol alleviated cardiac dysfunction in diabetes by improving mitochondrial function via SIRT1-mediated PGC-1α deacetylation. T2DM was induced in rats by a high-fat diet combined with STZ injection. Diabetic rats were orally administered RSV (50 mg·kg–1·d–1) for 16 weeks. RSV administration significantly attenuated diabetes-induced cardiac dysfunction and hypertrophy evidenced by increasing ejection fraction (EF%), fraction shortening (FS%), ratio of early diastolic peak velocity (E velocity) and late diastolic peak velocity (A velocity) of the LV inflow (E/A ratio) and reducing expression levels of pro-hypertrophic markers ANP, BNP and β-MHC. Furthermore, manganese superoxide dismutase (SOD) activity, ATP content, mitochondrial DNA copy number, mitochondrial membrane potential and the expression of nuclear respiration factor (NRF) were all significantly increased in diabetic hearts by RSV administration, whereas the levels of malondialdehvde (MDA) and uncoupling protein 2 (UCP2) were significantly decreased. Moreover, RSV administration significantly activated SIRT1 expression and increased PGC-1α deacetylation. H9c2 cells cultured in a high glucose (HG, 30 mmol/L) condition were used for further analyzing the role of SIRT1/PGC-1α pathway in RSV regulation of mitochondrial function. RSV (20 μmol/L) caused similar beneficial effects in HG-treated H9c2 cells in vitro as in diabetic rats, but these protective effects were abolished by addition of a SIRT1 inhibitor sirtinol (25 μmol/L) or by SIRT1 siRNA transfection. In H9c2 cells, RSV-induced PGC-1α deacetylation was dependent on SIRT1, which was also abolished by a SIRT1 inhibitor and SIRT1 siRNA transfection. Our results demonstrate that resveratrol attenuates cardiac injury in diabetic rats through regulation of mitochondrial function, which is mediated partly through SIRT1 activation and increased PGC-1α deacetylation.

Telmisartan is an angiotensin receptor blocker used for the treatment of hypertension. The effects of gender and uridine diphosphate-glycosytransferase 1A1 (UGT1A1) genetic polymorphisms (rs4124874, rs4148323, and rs6742078) on telmisartan plasma concentration and blood pressure in Chinese patients with hypertension have been reported previously. In this study, we aimed to develop a population pharmacokinetic (PopPK) model to quantify the effects of gender and UGT1A1 polymorphisms on the pharmacokinetics of telmisartan. Population pharmacokinetic analyses were performed using data collected prospectively from 58 Chinese patients with mild to moderate essential hypertension (aged 45–72 years; 36 men, 22 women) receiving 80 mg/day telmisartan orally for 4 weeks. Blood samples were collected in heparinized tubes at 0, 0.5, 1, and 6 h on day 28 after telmisartan administration. The plasma concentrations and UGT1A1 genetic variants were determined by high-performance liquid chromatography–mass spectrometry and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, respectively. A two-compartment pharmacokinetic structural model with first-order elimination and absorption best described the pharmacokinetic characteristics of telmisartan. Gender and triglyceride influenced the apparent oral clearance (CL) of telmisartan. UGT1A1 (rs4124874) affected the bioavailability (F1) of telmisartan. Lower CL and bioavailability resulted in higher plasma concentrations being observed in female subjects with UGT1A1 CC or CA genotype and high triglyceride. A PopPK model of telmisartan was established to confirm that UGT1A1 genotype, gender and triglyceride can affect the pharmacokinetics of telmisartan in Chinese patients with hypertension. Our findings can provide relevant pharmacokinetic parameters for further study of telmisartan.

Background Oxymatrine (OM), a quinolizidine alkaloid extracted from a herb Sophorae Flavescentis Radix, has been used to treat liver fibrotic diseases. However, the mechanism of its anti-fibrosis effects is still unclear. TGF-β/Smad signaling and miR-195 have been proved to paly an important role in hepatic stellate cells (HSCs) activation and liver fibrosis. In this study, we investigated whether OM could inhibit HSCs activation through TGF-β1/miR-195/Smads signaling or not. Methods First, the effects of OM on HSC-T6 in different concentrations and time points were tested by MTT assay. We choose three appropriate concentrations of OM as treatment concentrations in following experiment. By Quantitative Real-time PCR and Western Blot, then we investigated the effect of OM on miR-195, Smad7 and α-SMA’s expressions to prove the correlation between OM and the TGF-β1/miR-195/Smads signaling. Last, miR-195 mimic and INF-γ were used to investigate the relation between miR-195 and OM in HSC activation. Results Our results showed that the proliferation of HSC was significantly inhibited when OM concentration was higher than 200 μg/mL after 24 h, 100 μg/mL after 48 h and 10 μg/mL after 72 h. The IC50 of OM after 24, 48 and 72 h were 539, 454, 387 μg/mL respectively. OM could down-regulate miR-195 and α-SMA (P

Aim: Iloperidone is an atypical antipsychotic drug that is mainly metabolized by CYP2D6, CYP3A4, and cytosolic enzymes. Previous studies show that extensive and poor metabolizers of CYP2D6 exhibit different plasma concentrations of iloperidone and its metabolites. The aim of this study was to develop a parent-metabolite population pharmacokinetic (PPK) model to quantify the effects of CYP2D6*10 allele on the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients. Methods: Seventy Chinese schizophrenia patients were enrolled, from whom limited blood samples were collected on d 15 (0 h) and d 28 (0, 4 and 12 h after drug administration). The plasma concentrations of iloperidone and its metabolites M1 (P-88) and M2 (P-95) were simultaneously detected using a validated HPLC-MS assay. CYP2D6*10 (rs1065852) genotyping was performed. A PPK model was developed based on data from the patients using the NONMEM software (version 7.2). A one-compartment model with first-order absorption and elimination was used to describe the pharmacokinetic data related to iloperidone and its metabolites. Results: Patients with the CYP2D6*10 T/T genotype had significantly higher concentrations of iloperidone and M1, and lower concentrations of M2 than the patients with C/C or C/T genotypes. The CYP2D6*10 genotype affected the elimination constants for transformation of iloperidone to the metabolites M1 (K23) and M2 (K24). The K23 value of the patients with T/T genotype was 1.34-fold as great as that of the patients with C/C or C/T genotype. The K24 value of the patients with C/T and T/T genotypes was 0.693- and 0.492-fold, respectively, as low as that of the patients with C/C genotype. Conclusion: CYP2D6*10 mutations affect the pharmacokinetics of iloperidone and its metabolites in Chinese schizophrenia patients, suggesting that the clinical doses of iloperidone for patients with CYP2D6*10 mutations need to be optimized.

MicroRNAs (miRNAs) are a family of non-coding RNA that are able to adjust the expression of many proteins, including ATP-binding cassette transporter and organic cation transporter. We sought to evaluate the effect of miR-511 on the regulation of OATP1B1 expression by free fatty acids. When using free fatty acids to stimulate Chang liver cells, we found that the expression of miR-511 increased significantly while the expression of OATP1B1 decreased. We also proved that SLCO1B1 is the target gene of miR-511 with a bioinformatics analysis and using the dual luciferase reporter assay. Furthermore, the expressions of SLCO1B1 and OATP1B1 decreased if transfecting Chang liver cells with miR-511, but did not increase when transfecting the inhibitors of miR-511 into steatosis cells. Our study indicates that miR-511 may play an important role in the regulation of OATP1B1 expression by free fatty acids.

New Onset Diabetes after Transplantation (NODAT) is defined as sustained hyperglycemia developing in patients without diabetes history before transplantation. A cohort study was performed to access the effects of tacrolimus on insulin secretion and insulin sensitivity and consequently in the development of NODAT in kidney transplant recipients. Then, we further investigated the association between NODAT and single-nucleotide polymorphisms of IRS-1 and IRS-2 in renal allograft recipients. One hundred and fifty-eight kidney transplant patients, receiving tacrolimus as the base immunosuppressant, were divided into two groups: with or without NODAT. Plasma levels of fasting insulin concentration (FINS) and C-peptide were determined by enhanced chemiluminescence immunoassay and ADVIA Centaur C peptide assay, respectively. The genotypes of Gly1057Asp in IRS-2 and Gly972Arg in IRS-1 were detected through polymerase chain reaction fragment length polymorphism in NODAT and non-NODAT patients. It was found that the concentrations of fasting plasma insulin and C-peptide in NODAT and non-NODAT patients treated with tacrolimus were higher than that in healthy volunteers (p 0.05). Fasting plasma insulin concentration in NODAT was significantly elevated compared with than that in non-NODAT group (p 0.05). But there are no statistical differences in fasting plasma C-peptide concentrations between NODAT and non-NODAT groups. The allele and genotype frequencies of IRS-2 Gly1057Asp and IRS-1 Gly972Arg in NODAT patients were not significantly different from non-NODAT patients (p 0.05). In conclusion, insulin resistance is the primary cause of tacrolimus-induced NODAT. The IRS-2 Gly1057Asp and IRS-1 Gly972Arg genotypes are not related to NODAT.

PURPOSE This study aimed to understand the effects of single nucleotide polymorphisms (SNPs) in UGT1A1, SLCO1B3, ABCB1, ABCC2, ABCG2, and ORM1 on the pharmacokinetics (PK) (plasma concentration) and pharmacodynamics (PD) (blood pressure) of telmisartan in Chinese patients. METHODS 58 Han Chinese patients (aged 45 - 72 years) with mild to moderate essential hypertension were included and received 80 mg/day telmisartan for 4 weeks. The plasma concentration and genetic variants were determined by LC/MS/MS and MALDI-TOF mass spectrometry, respectively. Multivariable linear analysis was used to examine the relationships between PK/PD and genetic variants. RESULTS Females showed a significantly higher AUClast than males (n = 22, 4,879.48 ± 3,449.33 h×ng/mL vs. n = 36, 2,715.59 ± 2,223.77 h×ng/mL, p = 0.047). Amongst all genetic variants investigated, the patients with UGT1A1 rs4124874 AA (n = 11, 1,730.51 ± 1,325.79 h×ng/mL) had a significantly lower AUClast compared with patients with UGT1A1 rs4124874 CC+AC (n = 19 + 28, 4,177.44 ± 3,222.11 h×ng/mL and 3,810.82 ± 2,960.43 h×ng/mL, p = 0.027). None of the SNPs investigated was associated with the PD responses to telmisartan. CONCLUSION Variation of UGT1A1 (rs4124874) affects PK of telmisartan in Chinese patients, highlighting the value of genetic testing in precision medicine as the telmisartan dose could be adjusted based on UGT1A1 genetic variations. .

The efficacy of entecavir and tenofovir in patients with chronic hepatitis B virus (HBV) is inconsistent. To address this issue, we conducted a meta-analysis based on a current review of the literature addressing the efficacy and safety of entecavir and tenofovir. Electronic databases were searched through June 2014 for relevant clinical trials. We included 2 randomized controlled trials, 2 prospective cohort studies, and 7 case-control studies that included 1,656 patients. In the entecavir group, 842 of 992 were nucleos(t)ide-naïve chronic HBV patients, and in the tenofovir group 481 of 664 were nucleos(t)ide-naïve. The virological response to tenofovir was superior to entecavir (RR: 0.82; 95%CI: 0.72-0.93), especially in nucleos(t)ide-naïve chronic HBV patients at 48 weeks (RR: 0.78; 95%CI: 0.65-0.92). Additionally, there was no difference between entecavir and tenofovir for virological response at 24 weeks (RR: 0.87, 95%CI: 0.71-1.05). The alanine aminotransferase normalization rate, serological response, and adverse event rate were also not significantly different between entecavir and tenofovir at 24 or 48 weeks after treatment. These results suggest that tenofovir is a better choice to treat chronic HBV patients than entecavir as it is better able to suppress HBV viral load and has a similar safety profile.

Background and Aim. Aberrant activation of the TGF-β1/Smad pathway contributes to the activation of hepatic stellate cells (HSCs). MicroRNA-195 has been shown to regulate the activation of HSCs. The aim of this study was to investigate the role of miRNA-195 in HSCs activation. Methods. A liver fibrotic rat model induced by diethylnitrosamine was established. Dual luciferase reporter assays were performed to verify that Smad7 was the target of miRNA-195. The expression levels of miR-195, Smad7, and α-SMA in HSC-T6 transfected, respectively, with miR-195 mimic, inhibitor, or control were measured by qRT-PCR. The protein expression of Smad7 was detected by Western blot analysis. Results. Enhanced miR-195 and decreased Smad7 were observed in diethylnitrosamine-induced liver fibrotic rats (P<0.05). Dual luciferase reporter assays showed that the miR-195 mimic significantly suppressed the luciferase activity of a reporter plasmid carrying the binding site of miR-195 on the 3′UTR of Smad7 (P<0.05). The miR-195 mimics activated HSCs, further elevated miR-195 and α-SMA (P<0.01), and reduced the Smad7 level (P<0.05). The miR-195 inhibitors blocked the activation of HSCs, reduced the expression of miR-195 and α-SMA (P<0.01), and upregulated the expression of Smad7 (P<0.05). Conclusion. Collectively, we demonstrated that miRNA-195 activated HSCs by targeting Smad7.

The objective of this study was to evaluate the effect of the CYP3A5*3 allele on the pharmacokinetics of tacrolimus and amlodipine, and drug-drug interactions between them in healthy subjects. Pharmacokinetic drug interactions between tacrolimus and amlodipine were evaluated in a randomized, 3-period, 6-sequence crossover study in healthy Chinese volunteers according to CYP3A5 genotype. A single-dose and multiple-dose study were designed. A 96-h pharmacokinetic study followed either tacrolimus or amlodipine dose, and the washout periods between the study phases were 14 days. In the single-dose study, apparent oral clearance (CL/F) of tacrolimus (5 mg) in CYP3A5 expressers was 3.8-fold (p = 0.008) higher than that in CYP3A5 non-expressers. Amlodipine decreased mean tacrolimus CL/F in CYP3A5 expressers by 2.2-fold (p = 0.005), while it had no effect on that in CYP3A5 non-expressers. The CL/F of amlodipine in CYP3A5 non-expressers was 2.0-fold (p = 0.001) higher than that in CYP3A5 expressers. Tacrolimus increased mean amlodipine CL/F in CYP3A5 expressers by 1.4-fold (p = 0.016) while it had no effect on that in CYP3A5 non-expressers. Tacrolimus slightly reduced the AUC₀-∞ of amlodipine in both CYP3A5 expressers and non-expressers. Dose adjustment of tacrolimus should be considered according to CYP3A5*3 genetic polymorphism when tacrolimus is coadministered with amlodipine.

A sensitive and specific ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) method was developed for analysis of tanshinone ⅡA(TSⅡA), salvianolic acid B(SAB) and ginsenoside Rg₁ (GRg₁) in rat plasma and brain tissues. Male healthy Sprague-Dawley(SD) rats were orally given single dose of Fufang Danshen preparation (TS ⅡA 60 mg•kg⁻¹, SAB 300 mg•kg⁻¹, GRg₁ 150 mg•kg⁻¹, borneol 300 mg•kg⁻¹), and their blood samples and brain tissues were collected at different time points. The drug plasma and brain tissue concentrations of the three analytes were determined by UPLC-MS/MS method. Subsequently, the main pharmacokinetics parameters of plasma and brain tissues were calculated by using Phoenix WinNolin 6.1 software. The methodological test showed that all of analytes in both plasma and brain homogenate exhibited a good linearity within the concentration range(r0.992 2). Their mean recoveries were between 58.86% and 112.1%. Intra-day and inter-day precisions of the investigated components exhibited RSD≤9.7%, and the accuracy(RE) ranged from -9.68% to 8.20% at all quality control levels. The results of accuracy and stability meet the requirements for biopharmaceutical analysis. For TSⅡA, the pharmacokinetics parameters Tmax, Cmax, AUC0-t, MRTlast in the plasma were (1.58±0.081) h, (725.4±88.20) μg•L⁻¹, (2 101.3±124.85) μg•h•L⁻¹ and (3.66±0.05) h, respectively. For SAB, the pharmacokinetics parameters Tmax, Cmax, AUC0-t, MRTlast in the plasma were (1.29±0.21) h, (307.9±46.75) μg•L⁻¹, (537.4±88.24) μg•h•L⁻¹ and (2.08±0.11) h, respectively. For GRg₁, the pharmacokinetics parameters Tmax, Cmax, AUC0-t, MRTlast in the plasma were (1.42±0.20) h, (460.38±154.60) μg•L⁻¹, (383.4±88.16) μg•h•L⁻¹ and (1.87±0.046) h, respectively. For TSⅡA, the pharmacokinetics parameters Tmax, Cmax, AUC0-t, MRTlast in the brain tissue were (0.75±0.22) h, (1.41±0.42) ng•g⁻¹, (4.34±2.48) ng•h•g⁻¹ and (4.00±1.90) h, respectively. For SAB, the pharmacokinetics parameters Tmax, Cmax, AUC0-t, MRTlast in the plasma were (1.08±0.20) h, (21.09±4.850) ng•g⁻¹, (14.83±3.160) ng•h•g⁻¹ and (0.99±0.08) h, respectively. For GRg₁, the pharmacokinetics parameters Tmax, Cmax, AUC0-t, MRTlast in the plasma were (0.50±0.16) h, (130.96±54.220) ng•g⁻¹, (136.24±34.350) ng•h•g⁻¹ and (2.87±0.33) h, respectively. The developed method was successfully applied in pharmacokinetic studies on content of TS ⅡA, SAB and GRg₁ in rat plasma and brain tissues.

Silymarin is used by many patients with chronic hepatitis B, but its efficacy remains unknown. The aim of this investigation was to conduct a meta-analysis to determine the efficacy and safety of silymarin and its combination therapy for the treatment of chronic hepatitis B. We searched Chinese and English reports from January 1966 to December 2011, using 12 databases. Two reviewers independently screened all reports to identify randomized placebo-controlled trials that evaluated silymarin and its combination therapy for the treatment of chronic hepatitis B. Twelve trials satisfied the eligibility criteria for this meta-analysis. Silymarin was equivalent to antiviral drug or protection liver drugs in serum transaminases, viral load and hepatic fibrosis markers. But silymarin combined with antiviral drug or antiviral drug and protection liver drugs significantly reduced the level of serum transaminases, hepatic fibrosis markers and serum TGF-β1, TNF-α, IL-6 versus antiviral drug or protection liver drugs. Silymarin combined with protection liver drugs significantly reduced the level of serum transaminases, TBIL, hepatic fibrosis markers and was equivalent to protection liver drugs in the normalisation rates of serum transaminases, TBIL, but protection liver drugs significantly increased the improvement rates of hepatic fibrosis markers. Silymarin combined with antiviral drug or antiviral drug and protection liver drugs may have potential therapeutic value. Treatment with silymarin appears to be safe and well tolerated. The data are too limited to exclude a substantial benefit or harm of silymarin and its combination therapy on serum transaminases, and also to support recommending this herbal compound for the treatment of chronic hepatitis B.

The aim of the present study was to explore the effect of propofol, a intravenous sedative-hypnotic agent used widely in inducing and maintaining anesthesia, on µ-opioid receptor (MOR) expression in a human neuronal cell line. SH-SY5Y human neuroblastoma cells were treated with various concentrations of propofol (1, 5, 10 or 20 µM) for different lengths of time (6, 12 or 24 h). Real-time quantitative RT-PCR showed that at a concentration range of 1-10 µM, propofol increased MOR mRNA levels in a statistically significant dose- and time-dependent manner within 12 h of treatment. Western blot analyses demonstrated that propofol treatment for 12 h dose-dependently increased the MOR protein levels. In the 12-h SH-SY5Y-treated cells, propofol dose-dependently increased MOR density (Bmax) in the cell membranes. In addition, in the presence of the transcription inhibitor actinomycin D (1 mg/ml), propofol (10 µM) had no significant effect on the MOR mRNA levels over time. The results suggested that propofol dose- and time-dependently enhances MOR expression in SH-SY5Y human neuroblastoma cells at the transcriptional level, leading to an increased density of ligand-binding MORs in the cell membranes. This study demonstrated for the first time a link between propofol and the opioid system, thereby providing new insights into propofol mechanism of action and potential for abuse.

Background There is no single standard chemotherapy regimen for elderly patients with advanced gastric cancer (AGC). A phase III trial has confirmed that both capecitabine monotherapy and capecitabine plus oxaliplatin are well tolerated for elderly patients with AGC, but their economic influence in China is unknown. Objective The purpose of this cost-effectiveness analysis was to estimate the effects of capecitabine monotherapy and capecitabine plus oxaliplatin in elderly patients with AGC on health and economic outcomes in China. Methods We created a Markov model based on data from a Korean clinical phase III trial to analyze the cost-effectiveness of the treatment of elderly patients in the capecitabine monotherapy (X) group and capecitabine plus oxaliplatin (XELOX) group. The costs were obtained from published reports and the local health system. The utilities were assumed on the basis of the published literature. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER) were estimated. One-way and probabilistic sensitivity analyses (Monte Carlo simulations) were performed. Results In the cost-effectiveness analysis, X had a lower total cost ($45,731.68) and cost-effectiveness ratio ($65,918.93/QALY). The one-way sensitivity analysis suggested that the most influential parameter was the risk of requiring second-line chemotherapy in XELOX group. The probabilistic sensitivity analysis predicted that the X regimen was cost-effective 100% of the time, given a willingness-to-pay threshold of $26,598. Conclusions Our findings show that the XELOX regimen is less cost-effective compared to the X regimen for elderly patients with AGC in China from a Chinese healthcare perspective.

It has been reported that Ginkgo biloba extract (GBE) is an inducer or inhibitor of microsomal cytochrome P450 (CYP) 2C19, and diazepam is a substrate of CYP2C19. Thus, it could be expected that GBE may alter the metabolism of diazepam.The pharmacokinetic parameters of diazepam and one of its metabolites, N-demethyldiazepam, were compared after oral administration of diazepam (10 mg) in the absence or presence of oral GBE (120 mg bid, for 28 days) in 12 healthy volunteers. The pharmacokinetic analysis was performed using a noncompartmental method.The 90% confidence intervals (CIs) of the ratios of mean pharmacokinetic parameters of diazepam presence and absence of GBE were well within the 80-125% bioequivalence range, indicating no pharmacokinetic interaction. The ratio of AUC(0-408) with GBE to AUC(0-408) without GBE was 95.2 (90%CI: 91.6-98.8) and 101.8 (90%CI: 99.4-104.1) for diazepam and N-desmethyldiazepam, respectively. The two drugs were well tolerated, and no drug-related serious adverse events were reported.The above data suggest that GBE, when taken in normally recommended doses over a 4-week time period, may not affect the pharmacokinetics of diazepam via CYP2C19 and the excretion of N-desmethyldiazepam in healthy volunteers. No drug-drug interaction was observed between GBE and diazepam.

Flupentixol and an internal standard, loperamide were extracted from human plasma by liquid–liquid extraction and analyzed on a Thermo Hypersil HyPURITY C18 column, with 10 mM ammonium acetate–acetonitrile–methanol (26:62:12, v/v/v) as mobile phase, coupled with electrospray ionization mass spectrometry (ESI–MS). The protonated analyte was quantified by selected-ion monitoring (SIM) with a quadrupole mass spectrometer in a positive-ion mode. The calibration curve was linear (r = 0.9990) over the concentration range: 0.039–2.5 ng mL−1. Intra-day and inter-day precision (RSD%) were less than 13.05%. The established method was successfully applied for the determination of pharmacokinetics of flupentixol in human plasma.

This study aimed to investigate the effects of cytochrome P450 2D6*10 (100C > T, rs1065852) genotype on the pharmacokinetics of dimemorfan in healthy Chinese subjects. Data were evaluated from 24 subjects in two pharmacokinetic studies who received an oral dose of 40 mg of dimemorfan syrup (n = 12) or dimemorfan tablet (n = 12) after providing written informed consent and being divided into three groups: subjects with CYP2D6*10 CC (n = 5), CYP2D6*10 CT (n = 11) and CYP2D6*10 TT (n = 8). CC homozygotes and CT heterozygotes were defined to be C allele carriers. The CYP2D6*10 was genotyped by polymerase chain reaction–restriction fragment length polymorphism. Dimemorfan was measured by LC–MS/MS. There was significant difference in C max, AUC0–t , AUC0–inf, V z , and CL values of dimemorfan observed among the three CYP2D6*10 genotype groups (GLM, a P T, rs1065852) polymorphism can affect the pharmacokinetics of dimemorfan in humans, not dosage forms.

To evaluate the effect of Notoginseng Radix on hepatic expression of transforming growth factor beta1 (TGF-beta1) and connective tissue growth factor (CTGF) in rats with alcoholic liver disease (ALD), in order to discuss its protective effect on alcoholic cirrhosis.Fifty SD male rats were divided into the normal control group, the model group, the high-dose and low-dose Notoginseng Radix groups (3.0, 12.0 g x kg(-1)) and the magnesium isoglycyrrhizinate group (24 mg x kg(-1)), with 10 rats in each group. Apart from the control group, other groups were administered with ethanol-cornoil-pyrazole for 14 weeks to establish the alcoholic liver disease model. During the establishment of the model, the high-dose and low-dose Notoginseng Radix groups were administered with 12 g x kg(-1) x d(-1) Notoginseng Radix for 14 weeks, once everyday. Efforts were made to detect liver function, pathology with Masson staining, and the expressions of TGF-beta1, Smad3, Smad7 and CTGF mRNA.Compared with the rats in model group, rats in Notoginseng Radix groups showed significant reduction in liver ALT, AST, collagen fiber deposition, and TGF-beta1, Smad3 and CTGF mRNA expressions in liver tissues, with the increase in the expression quantity of Smad7 mRNA. There were differences between the Notoginseng Radix groups. No significant difference was observed between the high-dose Notoginseng Radix group and the magnesium isoglycyrrhizinate group.Notoginseng Radix can affect TGF-beta1/Smads signaling pathway and reduce the expression of CTGF.

OBJECTIVES: We aim to obtain the intra-subject coefficient of variability of a highly variable antidepressant agomelatine in humans, and propose an adjusted bioequivalence assessment strategy. METHODS: A single-dose, randomized crossover design was conducted in four periods (reference administered thrice, placebo administered once) separated by seven days. A validated LC-MS/MS assay was used to measure drug concentrations in serial blood samples. RESULTS: The intra-subject coefficient of variability was calculated using the residual variance of ANOVA analysis, and the results for Cmax and AUC0-t was 78.34% and 43.52%, respectively, in Chinese healthy subjects. The sample size required for standard BE study were 124(192, 340) if the expected deviation between the reference and generic products was set to 0 (5%, 10%). CONCLUSIONS: Agomelatine meets the criteria for highly variable drug in Chinese healthy male subjects, and the traditional BE criteria for agomelatine needs to be adjusted to alleviate the resource and ethical burden of using a large numbers of subjects in clinical trials. Our clinical data on the intra-subject variability of agomelatine PK in Chinese healthy population enables to adjust bioequivalence (BE) assessment approach for agomelatine based on the RSABE approaches recommended by regulatory agencies. TRIAL REGISTRATION: ChiCTR.org ChiCTR-TTRCC-13003835.

Chlorogenic acid (ChA) is proposed as the major bioactive compounds of Lonicerae Japonicae Flos (LJF). Forty-two Wistar rats were randomly divided into seven groups to investigate the pharmacokinetics and tissue distribution of ChA, via oral administration of LJF extract, using ibuprofen as internal standard, employing a high performance liquid chromatography in conjunction with tandem mass spectrometry. Analytes were extracted from plasma samples and tissue homogenate by liquid–liquid extraction with acetonitrile, separated on a C18 column by linear gradient elution, and detected by electrospray ionization mass spectrometry in negative selected multiple reaction monitoring mode. Our results successfully demonstrate that the method has satisfactory selectivity, linearity, extraction recovery, matrix effect, precision, accuracy, and stability. Using noncompartment model to study pharmacokinetics, profile revealed that ChA was rapidly absorbed and eliminated. Tissue study indicated that the highest level was observed in liver, followed by kidney, lung, heart, and spleen. In conclusion, this method was suitable for the study on pharmacokinetics and tissue distribution of ChA after oral administration.

A new rhodamine-based probe 1 was designed and synthesized as a new fluorescent molecular probe for HClO in PBS buffer at physiological condition. The free probe 1 almost nonfluorescence, however, a drastic enhancement of fluorescence intensity was observed in the presence of HClO. The new probe 1 exhibits good sensitivity and selectivity for HClO over other reactive oxygen and/or nitrogen species in PBS buffer, and the probe was successfully applied to image endogeneous HClO in the living cells.

Nuclear factor-kappa B (NF-kappaB) regulates the expression of various genes, several genes involved in inflammation and tumorigenesis, including those of the liver. A role for NF-kappaB has been implicated in the pathogenesis of hepatocellular carcinoma. This transcription factor can regulate hTERT gene transcription. Expression of hTERT was found to be at high levels in hepatocellular carcinoma. However, positive effects of NF-kappaB on hTERT protein synthesis in HepG(2) cells are unknown. In this study, we show that LPS (specific binding to TLR4 to activate NF-kappaB) was positive for NF-kappaB p65 mRNA expression and activation, and also up-regulated hTERT mRNA and protein expressions at 36h in a dose-dependent manner. In contrast, MG-132 (blocking the activity of 26S proteasome and thereby preventing nuclear translocation of NF-kappaB) significantly inhibited activation of NF-kappaB and mRNA expression. And also reduced the expression of hTERT at both mRNA and protein levels at 36h in a dose-dependent manner. Furthermore, dexamethasone inhibited LPS-induced activation of NF-kappaB and expression of the hTERT in HepG(2) cells. These findings suggest that NF-kappaB may modulate hTERT mRNA level, importantly, in protein level in HepG(2) cells and dexamethasone inhibits LPS-induced hTERT via blocking NF-kappaB.

Objectives:The aims of this study were to investigate the pharmacokinetic (PK) properties of aripiprazole in the steady state in Han Chinese adults with schizophrenia and to compare them between Han Chinese and white populations described in the literature.Methods:This prospective, open4abel, pilot study was conducted at the Mental Health Institute, Xiang-ya Second Hospital, Central South University, Changsha, China. Male and female hospitalized patients aged 18 to 45 years diagnosed with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)-defined schizophrenia, with a Positive and Negative Syndrome Scale (PANSS) total score ⩾60 (indicating schizophrenia of at least mild severity) were eligible. On study days 1 and 2, patients were pretreated with aripiprazole 10 mg PO QD, followed by 10 mg g12h on days 3 to 21. Blood samples were drawn for analysis on day 21 before dosing and 1, 3, 4, 5, 12, 24, 48, 72, 96, 144, and 192 hours after the morning dosing of aripiprazole on day 21. Patients received low-dose (25–100 mg/d) clozapine on day 25 until day 28. The samples were assessed using high-performance liquid chromatography-mass spectrometry and compartment model analysis for aripiprazole. PK properties included mean residence time (MRT) steady-state Cmax (Css max), time to Css max (Tmax), elimination t/12, apparent oral clearance (CL/F), and apparent volume of distribution (V/F). Adverse effects were monitored using physical examination (including vital sign measurements), electrocardiography, electroencephalography, and clinical laboratory testing (including biochemistry, hematology, and urinalysis) at baseline and at the end of the study. Patients were asked about adverse events on days 1 to 7 and at random intervals thereafter. Patients were also instructed to report any spontaneous symptoms they experienced.Results:Twelve patients were enrolled (6 men, 6 women; mean [SD] age, 26.1 [7.0] years; mean [SD] weight, 56.6 [9.0] kg; mean [SD] PANSS score, 116.8 [12.2]). Aripiprazole exhibited linear kinetic characteristics on a 2-compartment model. After multiple oral doses (10 mg g12h), the mean (SD) t1/2, Css max, Tmax, MRT, V/F, and CL/F were 62.2 (9.0) hours, 557.3 (135.5) ng/mL, 2.6 (1.1) hours, 84.5 (11.2) hours, 173 (48) L, and 1.9 (0.5) L/h, respectively. In Chinese patients, the t/12 values were numerically similar (62.2 [9.0] vs 68.1 [22.9] hours); Css max values were numerically higher (557.3 [135.5] vs 393 [181 ] ng/mL); and V/F and CL/F values were numerically lower (V/F: 173 [48] vs 196 [66] L; CL/F: 1.9 [0.5] vs 3.4 [1.6] L/h) compared with healthy white male volunteers. Adverse effects were mild to moderate: lightheadedness (5 of 12 patients), somnolence (3), tachycardia (3), hypodynamia (2), and extrapyramidal symptoms (EPS) (1). The EPS (convulsive movement of the muscles related to the larynx) led to one patient's discontinuation of the study.Conclusions:In this small pilot study of the PK properties of aripiprazole 10 mg PO g12h in Han Chinese patients with schizophrenia, the mean t1/2 value was numerically similar to that previously reported in a population of healthy white male volunteers. However, the mean Css max value was numerically higher, and V/F and CL/F values were numerically lower, compared with those in healthy white male volunteers.