Physiologically based pharmacokinetic (PBPK) modeling is an important tool to predict pharmacokinetic or pharmacodynamic profiles in special populations, especially in children and infants where designing and conducting clinical studies is difficult. The application of PBPK modeling can effectively promote the development of pediatric drugs and their clinical use. At present, PBPK modeling of pediatric populations is mainly applied in clinical trial design, drug-drug interaction (DDI) risk assessment, and dose selection in children. This review discusses the advantages of PBPK modeling in pediatric drug research and summarizes how to extrapolate a PBPK model from adults to children. The theoretical basis for pediatric PBPK models, the modelling process and important physiological parameters during the modeling process are introduced. Some successful applications of PBPK modeling in pediatric drug research and development are also presented. This review also analyzes the current limitations and future directions of pediatric PBPK modeling.

Objective: To observe the effect of STC-1 gene expression was inhibited on the apoptosis, IL-1β and TNF-α expression and JAK2/STAT3 signal in esophageal cancer cells. Methods: Compared with normal human esophageal squamous epithelial cells Het-1 A, STC-1 expression was detected in human esophageal squamous cell carcinoma KYSE170, Eca109, TE1 and TE10 cells by RTPCR and Western blot; the siRNA sequence that the synthesized STC-1 and the si NRA sequence without interference were transfected into Eca109 cells, which were labeled as STC-1-siRNA group and NC group, and the blank control group was set, cells were transfected for 48 h, the expression of STC-1 were detected by RT-PCR and Western blot. Eca109 cell viability and apoptosis rate were detected by CCK8 and flow cytometry. IL-1β and TNF-α expression were detected by RT-PCR; the expression of Ki67, p53, p-JAK2 and p-STAT3 protein were detected by Western blot. Results: Compared with Het-1 A cells, expression of STC-1 mRNA and protein in KYSE170, Eca109, TE1 and TE10 cells were increased significantly ( P＜0. 05); compared with the control group, STC-1 expression was decreased significantly in STC-1-siRNA group, cell viability was decreased significantly in STC-1-siRNA group, the apoptosis rate was increased significantly in STC-1-siRNA group; IL-1β, TNF-α, Ki67, p-JAK2 and p-STAT3 expression were decreased significantly in STC-1-siRNA group, p53 expression was increased significantly in STC-1-siRNA group ( P＜0. 05). Conclusion: STC-1 was highly expressed in esophageal cancer cells; inhibiting of STC-1 expression could significantly reduce the activity of cancer cells, and increase apoptosis rate, this effect may be related to the inhibition of JAK2/STAT3 signaling pathways and inflammatory factors as IL-1β and TNF-α.

BACKGROUND: Increasing evidence has shown that visit-to-visit variability (VVV) of blood pressure (BP) is associated with an increased risk of cardiovascular disease (CVD). The objective of this study was to evaluate the impact of VVV of systolic blood pressure (SBP) and diastolic blood pressure (DBP) on the risk of CVD among patients with type 2 diabetes mellitus (T2DM) in China. METHODS: We conducted a retrospective cohort study of 10,163 T2DM patients who were not previously diagnosed with CVD from January 2008 to December 2012 in Ningbo, China. The VVV of BP was calculated using five metrics, including standard deviation (SD), coefficient of variation (CV), variation independent of mean, average real variability, and successive variability (SV) of measurements, obtained over a 24-month measurement period. Hazard ratios and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression models for the associations of variability in BP with risk of CVD. RESULTS: A total of 894 CVD events were observed during a median follow-up of 49.5 months. The hazard ratio in the highest quintile of SD of SBP was 1.24 (95% CI, 1.01 to 1.52) compared with patients in the lowest quintile. The association between higher VVV of DBP and risk of CVD was not consistent across different metrics and sensitivity analyses. CONCLUSION: Higher VVV of SBP was associated with an increased risk of CVD, irrespective of the mean SBP level. Future studies are needed to confirm these findings.
Blood Pressure ; Cardiovascular Diseases ; China ; Cohort Studies ; Diabetes Mellitus, Type 2 ; Follow-Up Studies ; Humans ; Retrospective Studies

To establish a quality constant evaluation system of Alismatis Rhizoma decoction pieces,in order to provide reference for regulating the market circulation of this decoction pieces. A total of 18 batches of Alismatis Rhizoma decoction pieces were collected from different pharmaceutical factories,and the morphological parameters of each sample were tested. The content of alisol B 23-acetate in Alismatis Rhizoma decoction pieces was determined by HPLC in the 2015 edition of Chinese Pharmacopoeia,and the parameters such as quality constant and relative quality constant were calculated. The quality constant range of 18 batches of Alismatis Rhizoma decoction pieces was 0. 390-2. 076. If 18 batches of Alismatis Rhizoma decoction pieces were divided into 3 grades,taking 80% of the maximum quality constant as first grade,50% to 80% as second grade,and the rest as third grade,then the quality constant of firstgrade samples was ≥1. 66,the quality constant of second-grade samples was ≥1. 04 and <1. 66,and the quality constant of third-grade samples was <1. 04. The established quality constant evaluation method is objective and feasible,which can be used to classify the grade of Alismatis Rhizoma decoction pieces and provide a reference method to control the quality of this decoction pieces.
Alisma ; chemistry ; Chromatography, High Pressure Liquid ; Drugs, Chinese Herbal ; standards ; Quality Control ; Rhizome ; chemistry

OBJECTIVE: To evaluate the necessity and suitability of the anti-HCV ELISA teot gray zone setted up by 7 blood station laboratories. METHODS: 7 blood station laboratories were coded as 1, 2, 3, 4, 5, 6 and 7 respectively; 8 kinds of ELISA reagents were coded as A, B, C, D, E, F, G and H respectively. 1 or 2 of 8 ELISA reagents produced by different manufactories were used to detect the anti-HCV in specimens of same group by 7 blood station laboratories; the Westen blot was used to detect the specimens with difference of detected results so as to difine the serological status of specimens. The true positive rate of specimens detected by laboratories and gray zone-comfirined positive rate of specimens were accounted so as to analyze the necessity of setting up the gray zone for anti-HCV ELISA test of 7 blood station laboratories; the optimal cut-off value for anti-HCV ELISA test was determined in 7 blood station laborafories by ROC curve and the changes of sensitivity and specificity of 3 different cut-off value(laboratory work cut-off value, manifactory-recommended cun-off value and optimal cut-off value) were compared so as to analyze the suitability of gray zone for anti-HCV ELISA test in 7 blood station laboratories. RESULTS: The true positive rate detected by 7 blood station laboratories, out of which coded 1 laboratory used 2 kinds of coded A, B reagents was 95.40%(1A), 99.23% (1B), 94.25% (2C), 96.17% (3D), 98.08% (4E), 96.93% (5F), 97.32%(6G) and 93.10%(7H). Except for 2C(94.25%) and 7H(93.10%), the true positive rate detected by laboratoies which not sutted up gray zone, the gray zone-con-firmed positive rate in 6 blood station laboratories setted up gray zone: was 0.00%, 0.00%, 21.43%, 0.00%, 0.00%, 0.00% and 38.89%. The comparison of 3 different cut-off valuces by ROC curve showed that the anti-HCV cut-off values in 5 laboratories(1B, 2C, 4E, 5F and 6G) were as follows: optimal cut-off value＞manufactory recommeded cut-off value＞laboratory work cut-off value, thus use of manufactory-recommeded cut-off value abreadly has reached the high sensitivity requinements for laboratory screening; however, the optimal cut-off value in laboratories 1A, 3B and 7H, thas the appropriate gray zone should be used. In 6 laboratories setting up gray zone, the gensitivity in 3D, 7H laboratories only a little improved (1.60% and 2.70% raspectively) in Eamparison between laboratory work cut-off value and manufactorg-recommeded cut-off value; moreover, the sensitivity in other laboratories not is changed, but the specificity decreased (0.20%-0.50%). CONCLUSION In addition to setting up the appropriate gray zone in laboratories 1A, 3D and 5H, the gray zone in other laboratories may be cancelled. Even in the same laboratory, the setting up the gray zone also should be scientifically assessed, the same scale cannot be blindly used, thus appropniate strategies should be established.
Enzyme-Linked Immunosorbent Assay ; Hepatitis C ; Hepatitis C Antibodies ; Humans ; ROC Curve ; Sensitivity and Specificity

OBJECTIVE: To explore the effect of electroacupuncture on the improvement of insulin resistance after knee joint replacement based on the combined spinal and epidural anesthesia and postoperative epidural analgesia. METHODS: Eighty patients with insulin resistance but normal blood glucose were randomly divided into a control group and an observation group, 40 cases in each group.Both groups of patients underwent combined spinal and epidural anesthesia and postoperative epidural analgesia for knee arthroplasty. On the basis of the treatment,electroacupuncture (EA) was applied during the operation and within 1 month after the operation in the observation group, and EA was used at Hegu (LI 4), Qihai (CV 6), Zhongwan (CV 12), Pishu (BL 20), Shenshu (BL 23), etc. once every other day. The control group was not treated with electroacupuncture. Fasting blood glucose and fasting insulin were recorded 30 min before surgery (T), immediately (T), 1 d (T), 3 d (T), 7 d (T) and 1 month (T) after surgery, and the insulin resistance (IR) index was calculated. RESULTS: Compared with those at T time point, the IR index of the control group at T, T, T and T time points and the observation group at T, T, T time points were lower (all <0.05). Compared with the control group at the same time point, the IR index of the T and T time points in the observation group was significantly lower (both <0.05), and it was lower than the insulin resistance standard. CONCLUSION Combined spinal and epidural anesthesia and postoperative epidural analgesia can improve short-term insulin resistance. Combined with EA, the improvement of insulin resistance is more obviously and longer.
Acupuncture Points ; Anesthesia, Epidural ; Arthroplasty, Replacement, Knee ; Electroacupuncture ; Humans ; Insulin ; Insulin Resistance

OBJECTIVE: To evaluate the efficacy and safety of salvianolate in elderly patients with unstable angina pectoris (UAP). METHODS: A prospective double-blind randomized placebo-controlled multicenter trial in elderly patients with UAP from 13 third-grade class-A hospitals in China was performed. A total of 318 patients were randomly allocated in a 1:1 ratio to an experimental group (160 patients) and a control group (158 patients). The experimental group was treated with salvianolate for 14 days on the basis of conventional medicine, and the control group was given a placebo for 14 days with the same criteria. Follow-up was lasted 28 days in both groups. The primary endpoint was biweekly frequency of angina pectoris attacks. The secondary endpoints included biweekly dosage of nitroglycerin, the Seattle Angina Questionnaire, angina pectoris severity and duration, myocardial injury markers, high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP), as well as major adverse cardiovascular events (MACEs). Safety was assessed according to adverse events and serious adverse events. RESULTS: Baseline characteristics were similar between treatment groups. Compared with those in the control group, the frequency of biweekly angina attacks (2.92 vs . 4.08, P=0.025), the biweekly dosage of nitroglycerin, as well as the severity and duration of angina attacks (P<0.01) were reduced by salvianolate. The Seattle Angina Questionnaire score was also significantly improved in the experimental group than in the control group (P<0.05). No significant differences were observed between the two groups with respect to the incidence of MACEs. Salvianolate was well tolerated. CONCLUSIONS Salvianolate appear to have efficacy and well tolerated for elderly patients with UAP. [ClinicalTrials.gov identifier: NCT03037047].

As a rare endangered medical plant that newly cultivated,little experimental information is available for growth and metabolites of Tetrastigma hemsleyanum in response to nitrogen( N). The effects of different levels of N on growth of T. hemsleyanum and the content of phytochemicals( polysaccharide,total flavonoids and phenolics) and antioxidant activity( ABTS and FRAP) in stems and leaves were investigated in this study. A certain amount of N had positive effects on most of biological traits,and excessive dose of N went against growth of T. hemsleyanum. With N levels decreased,the polysaccharide content in stems and leaves had no significant change,while the total flavonoid and phenolic content,and antioxidant activities increased steadily. Antioxidant activities and total flavonoid and phenolic content had significant positive correlation. Excessive N fertilizer should be avoided by cultivation.
Antioxidants ; Flavonoids ; Nitrogen ; Phenols ; Phytochemicals ; Plant Extracts ; Plant Leaves ; Vitaceae

Danhong injection (DHI) and ceftriaxone sodium were used in combination based on their experimental uses in clinic. This study was designed to investigate the impact of ceftriaxone on pharmacokinetics and pharmacodynamics of the phenolic acids from DHI. After administration of DHI for 7 d, ceftriaxone (CFTX) was combined with DHI for the next 7 d in adult male Sprague-Dawley (SD) rats. All the drugs were administered through caudal vein. UHPLC-TQ-MS was applied in determining the plasma concentration of p-coumaric acid (p-CA), salvianolic acid D (SaD), rosmarinic acid (RA) and salvianolic acid B (SaB). The pharmacokinetic parameters of the combination group or the Danhong injection alone group were calculated by statistical moment method, C_max and the average of the area under the curve AUC_0-t using 90% confidence interval of the bioequivalence and bioavailability degree module in DAS 3.2.8 statistic software. The results showed that C_max of p-CA, SaD, RA and SaB were unqualified within 90% confidence intervals for bioequivalence statistics. And the results showed that AUC_0-t of SaD, RA and SaB within 90% confidence intervals for bioequivalence statistics were unqualified. There were no significant difference in the t_max (P>0.05). The results of anticoagulation in vivo showed that the international normalized ratio (INR), prothrombin time (PT), thrombin time (TT) and activated partial thromboplastin time (APTT) were significantly increased when combined with CFTX (P<0.05 or P<0.01). The results in antithrombotic effects revealed that the thromboxane B₂ (TXB₂) level in serum was significantly decreased (P<0.01) in the combination group compared with Danhong injection alone. However, there was no significant difference in antiplatelet effects. These results suggest that CFTX may enhance the anticoagulation and antithrombotic effects of DHI through altering pharmacokinetics and pharmacodynamics in SD rats.

The occurrence and development of tumors are closely related to the tumor microenvironment. Among them, tumor immune microenvironment and tumor metabolic microenvironment play important roles in tumor. Tumor immunotherapy is a way to kill tumor cells by activating the body's immune system. Tumor immunotherapy has shown good therapeutic effects in a variety of solid tumors. In recent years, significant progress has been made in tumor immunotherapy. The Warburg effect indicates that tumor cells use aerobic glycolysis to acquire energy. In the tumor, the energy metabolism pathway is abnormal, and the tumor microenvironment can induce the reprogramming of tumor cell metabolism. Therefore, targeting tumor metabolism is also of great significance for tumor treatment. In this paper, we reviewed the research progress of drug targets related to tumor immunology and tumor metabolism in recent years, as well as the progress of drug development.