Aim To show the performance of the weighted modification method in the clinicaldesign of combination drug therapy. Methods A scheme combined by Drug1, Drug2and Drug3 was used to treat infants with iron deficiency anemia for 2 wk in a hypo-thetical clinical trial. Thirty-six infants were randomly into 6 compound groups. Threedrugs in the scheme were divided into 6 dose levels, which were evenly distributed to the6 groups according to the weighted modification method. The increased Hb (?Hb) wasrecorded at 2, 3, 4 wk after the treatment (po ). The dose-effect data at 4 wk wereanalyzed by the method, and then the doses in scheme were modified by the analyticresult. The modified doses in the scheme would be further demonstrated. ResultsDrug1 and Drug2 were principal drugs, but Drug1 had larger contribution to the com-bined effect (△Hb) than Drug2. Drug3 had little effect. There was a strong synergismbetween Drug1 and Drug2 with the weighted coefficient (b1) = 2. 636 (P

The principle of the relative operating characteristic (ROC) curve, along with constructing curve, a cutoff value between therapeutic and non-therapeutic concentration, formula for calculation, and statistic analysis, was introduced. Illustrated by an example, ROC was an important tool in analysis of the fixed effect model. It can beapplied to determine the relationship between a blood concentration and its action, probability of certain concentration producing therapeutic action, and high or low limit of therapeutic window, etc.

In clinical and experimental therapeutics, the quantitative analysis of drug interaction will supply a tool for optimizing and evaluating a combination in the study of compound drug, the design of combination drug therapy, and the evaluation of traditional medicine formulae. This paper listed the systematic methods of the quantitative analysis, including the weighted modification method for optimizing constituents, doses and ratio in combination, the parameter method and the reflection method for dynamic analysis of drug interaction, and a comprehensive method for multiple response indexes. The software CoDrug about these methods also was introduced.

Qualitative data are often converted to quantitative data by ranking in pharmacodynamical statistics. Some common questions were listed and discussed with examples in this paper, including ranking method and the selection of statistical method.

On the basis of analyzing the transition and development trend of current medical and pharmaceutical mode,this article proposed that in the process of pharmacy talents training,not only biological,but also the construction of natural drugs knowledge should be stressed.In addition,the necessity of natural drugs knowledge construction as well as its practice and future blueprint in our university were illuminated intensively,in order to provide reference for the training of pharmacy talents in local colleges.

Objective To investigate the effect of multidrug resistance protein 4 (MRP4) overexpression on lipopolysaccharide (LPS)-induced vascular endothelial hyperpermeability of rat pulmonary micro-vascular endothelial cells (PMVECs) and its molecule mechanism. Methods Three to six passages of PMVECs were cultured in vitro, and they were divided into three groups: the cells in LPS group were only challenged by LPS 10 μg/mL after being cultured in serum-free medium for 24 hours; the cells in Ad-shRNA and Ad-MRP4 groups were infected with the empty virus control or recombinant adenovirus expressing MRP4 for 2 hours, and then were cultured in serum-free medium for 24 hours followed by stimulation of LPS 10 μg/mL. Endothelial permeability was assayed by the Transwell chamber models at 2, 6, 12, and 24 hours after LPS stimulation. Intracellular cyclic adenosine monophosphate (cAMP) levels were detected by enzyme-linked immunosorbent assay (ELISA). The morphological characteristics and distribution of F-actin was determined by laser confocal fluorescence microscope. The protein expressions of MRP4,β-catenin, vascular endothelium-cadherin (VE-cad) and ZO-1 were measured by Western Blot. Results ① After LPS stimulation, endothelium permeability and intracellular cAMP levels in PMVECs were significantly increased, peaked at 12 hours, and then decreased after 24 hours. Compared with LPS group and Ad-shRNA group, PMVECs of Ad-MRP4 group were exhibited a significant increase in endothelial permeability [12-hour permeability (A value):1.88±0.06 vs. 1.12±0.17, 1.10±0.18] and a significant decrease in intracellular cAMP level [12-hour cAMP (μg/L):2.39±0.02 vs. 2.97±0.01, 3.00±0.02, all P < 0.05]. There was no significant difference in endothelium permeability and intracellular cAMP levels at all time points between the LPS group and the Ad-shRNA group (all P > 0.05).② Under laser confocal fluorescence microscope, after LPS stimulation, the stress fiber formation was induced in three groups. But there were pronounced irregular aggregation of fiber in PMVECs of Ad-MRP4 group. ③ Furthermore, compared with LPS group and Ad-shRNA group, protein expression of MRP4 in Ad-MRP4 group was dramatically increased (gray value: 0.76±0.03 vs. 0.44±0.02, 0.43±0.02, both P < 0.05), and the protein expressions of β-catenin, VE-cad, and ZO-1 were significantly decreased [β-catenin (gray value): 0.14±0.03 vs. 0.23±0.04, 0.23±0.03);VE-cad (gray value): 0.21±0.01 vs. 0.34±0.02, 0.35±0.04; ZO-1 (gray value): 0.14±0.02 vs. 0.37±0.06, 0.33±0.07, all P < 0.05]. There was no significant difference in all protein expressions between the LPS group and Ad-shRNA group (all P > 0.05). Conclusion MRP4 overexpression can decrease intracellular cAMP levels, reduce intercellular junction protein expression, and then exaggerate LPS-induced vascular endothelial hyperpermeability.

Objective To investigate the protective effect of multidrug resistant associated protein 4 (MRP4) inhibitor on rats with sepsis-induced acute lung injury (ALI). Methods Sixty Sprague-Dawley (SD) rats were randomly divided into sham group, sepsis group and MRP4 inhibitor MK571 treatment group, with 20 rats in each group. Sepsis model was reproduced by cecal ligation and puncture operation (CLP), and the rats in sham group were only received celiotomy without ligation and puncture. Rats in MK571 treatment group were intraperitoneally injected with MRP4 inhibitor MK571 (20 mg/kg) 30 minutes before model reproduction, while rates in sham group and sepsis group were given the same amount of normal saline. Twenty-four hours later, the femoral artery blood of mice was collected, and arterial blood gas analysis was measured. Serum tumor necrosis-α (TNF-α) was determined by enzyme-linked immunosorbent assay (ELISA). The lung tissues were collected, and the wet/dry weight ratio (W/D) was calculated. The expression of MRP4 protein in lung tissue was determined by Western Blot. Results Compared with sham group, arterial blood pH value and arterial partial pressure of oxygen (PaO2) were significantly lowered [pH value: 7.18±0.03 vs. 7.40±0.03; PaO2 (mmHg, 1 mmHg = 0.133 kPa): 63.15±6.24 vs. 98.05±2.58], while arterial partial pressure of carbon dioxide (PaCO2) was dramatically higher in the sepsis group (mmHg: 56.60±8.30 vs. 37.85±3.18), serum TNF-α level in the sepsis group was significantly increased (ng/L: 146.24±19.99 vs. 25.77±9.83), the W/D ratio of lung tissue was significantly increased (7.75±0.47 vs. 4.09±0.58), and the expression of MRP4 protein was up-regulated in the sepsis group (gray value: 0.153±0.006 vs. 0.087±0.005, all P < 0.05). Compared with the sepsis group, arterial blood pH value (7.30±0.02 vs. 7.18±0.03) and PaO2 (mmHg: 80.30±5.34 vs. 63.15±6.24) were significantly elevated in the MK571 treatment group, while PaCO2 was dramatically decreased (mmHg: 29.25±3.24 vs. 56.60±8.30), the serum level of TNF-α was significantly decreased (ng/L: 97.96±16.72 vs. 146.24±19.99), the W/D ratio of lung tissue was significantly reduced (5.89±0.51 vs. 7.75±0.47), and MRP4 protein expression was significantly down-regulated (gray value: 0.124±0.006 vs. 0.153±0.006, all P < 0.05). Conclusion MRP4 inhibitor may improve lung function in rats with sepsis-induced ALI by down-regulating MRP4 protein expression and reducing levels of inflammatory cytokines, which exerts protective effect on ALI.

Validation is a documented process that provides a high degree of assurance. The computer system does exactly and consistently what it is designed to do in a controlled manner throughout the life. The validation process begins with the system proposal/requirements definition, and continues application and maintenance until system retirement and retention of the e-records based on regulatory rules. The objective to do so is to clearly specify that each application of information technology fulfills its purpose. The computer system validation (CSV) is essential in clinical studies according to the GCP standard, meeting product's pre-determined attributes of the specifications, quality, safety and traceability. This paper describes how to perform the validation process and determine relevant stakeholders within an organization in the light of validation SOPs. Although a specific accountability in the implementation of the validation process might be outsourced, the ultimate responsibility of the CSV remains on the shoulder of the business process owner-sponsor. In order to show that the compliance of the system validation has been properly attained, it is essential to set up comprehensive validation procedures and maintain adequate documentations as well as training records. Quality of the system validation should be controlled using both QC and QA means.

Due to a great amount of data in clinical trials, the data cleansing needs to adopt a variety of measures, including the latest developed visual check approach. According to the different types of clinical data and the different stages in the course of clinical data management, this study reviews 8 types of visual graphics that show the relevance and trend among the data. The series of graphics can rapidly detect abnormal data, monitor clinical research in real-time, make the data management process much easier and improve the clinical trial efficiency and data quality.

Electronic case report forms (eCRFs) instead of the traditional paper case report forms (pCRFs) are increasingly used by investigators and sponsors of clinical research. We include a total of 14 phase III studies (8 pCRF, 6 eCRF) to compare paper and electronic data documentation both quantitatively and qualitatively in clinical studies. The result suggests that adaptions of electronic data capture (EDC) in clinical trials have the advantages in optimization of data capture process, improvement of data quality and earlier clinical decision compared to paper-based methods. Furthermore, the successful implementation of EDC requires accouplements with corresponding data management processes and reallocation of resources.