OBJECTIVE To establish a clinical comprehensive evaluation framework for direct oral anticoagulants （DOACs） in the prevention of cancer-associated venous thromboembolism （CAVTE）， providing a methodological reference for the rational prevention and treatment of CAVTE as well as for the formulation and adjustment of macro-management strategies for anticoagulant drugs. METHODS Through literature retrieval， evaluation indicators were collected and organized to establish a preliminary indicator pool. The selection of evaluation indicators was carried out through two rounds of Delphi surveys using average score of indicator importance≥3.5 and a coefficient of variation （CV） ＜0.25 as the screening criteria. Analytic hierarchy process （AHP） was employed to finalize the indicator weights. RESULTS The authority levels （C）r of the two rounds of expert consultations were 0.877 and 0.943， with CV of 0.24 and 0.18， respectively. The Kendall concordance coefficients were 0.331 and 0.535 （P＜0.05）. After expert validation， six primary indicators and forty-six secondary indicators were finalized for inclusion in the evaluation framework. The primary indicators and their weightings， ranked in descending order， were as follows：“ effectiveness” （38.86%）， “safety” （38.86%），“ cost-effectiveness” （10.67%），“ accessibility” （5.51%），“ suitability” （3.48%）， and “innovation” （2.64%）. The secondary indicators exhibited a weight range from 0.02% to 20.25%， with the top five secondary indicators being：“ incidence of intracranial hemorrhage” （20.25%）， “reduction in all-cause mortality” （15.29%）， “decrease in the incidence of pulmonary embolism” （8.82%）， “reduction in the incidence of deep vein thrombosis” （7.25%）， and “drug contraindications” （4.74%）. CONCLUSIONS This study has established an authoritative， scientific， and reliable comprehensive clinical evaluation framework for the use of DOACs in the prevention of CAVTE.

Objective:To study the role of ethanol extract of Euonymus alatus stems (EAT) and ethanol extract of Euonymus alatus wings (EAW) in anti-hepatic fibrosis induced by carbon tetrachloride in mice, and to explore its preliminary mechanism. Methods:Sixty C57BL/6 mice were selected and randomly divided into healthy control group, carbon tetrachloride model (CTM) group, EAW low dose (EAW-L) group, EAW high dose (EAW-H) group, EAT low dose (EAT-L) group and EAT high dose (EAT-H) group, with 10 mice in each group. Three days before modeling, the mice of EAT-L, EAT-H, EAW-L and EAW-H group were gavaged with EAT or EAW at 2.0 or 8.0 g/kg, respectively, and the mice of healthy control group and CTM group were gavaged with equal volume of pure water, once a day till the 30th day after modeling (total 33 times). Five percent carbon tetrachloride olive oil solution was intraperitoneally injected at 8 mL/kg to establish liver fibrosis model in CTM, EAT-L, EAT-H, EAW-L and EAW-H groups. The mice in the healthy control group were intraperitoneally injected with equal volume of 0.9% sodium chloride solution, twice per week for 30 days, and a total of 9 times of injection. The liver index, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil) and interleukin-6 (IL-6) were detected. Hematoxylin-eosin and Masson staining were used to observe the pathological changes of mouse liver tissue and calculate the collagen volume fraction. The liver inflammatory response and fibrosis degree were evaluated by histological activity index (HAI) and Ishak system score. The level of α-smooth muscle actin(α-SMA)in liver tissue was both detected by immunohistochemistry and Western blotting. The expression of matrix metalloproteinase 2 (MMP2) and extracellular signal-regulated kinase (ERK) 1/2 at protein and mRNA level was detected by Western blotting and fluorescent quantitative polymerase chain reaction. Analysis of variance, Tukey test and Dunn test were used for statistical analysis.Results:The hepatic indexes of EAW-L, EAW-H and EAT-H groups were lower than that of CTM group(0.06±0.01, 0.05±0.01 and 0.05±0.01 vs. 0.07±0.01), and the differences were statistically significant ( q=5.12, 7.70, 7.11; all P<0.01). The serum ALT and AST levels of EAW-L, EAW-H, EAT-L and EAT-H groups were lower than those of CTM group((601.76±141.38), (283.35±42.32), (734.74±116.06) and (391.60±34.33) U/L vs.(982.45±96.04) U/L, (509.49±152.29), (345.41±67.39), (282.30±65.72) and(243.23±45.20) U/L vs.(766.01±114.49) U/L), and the differences were statistically significant ( qALT =9.88, 20.81, 7.65, 17.58, qAST =5.11, 12.52, 14.92, 15.56; all P<0.001). The serum TBil levels of EAW-H and EAT-H groups were lower than that of CTM group((6.81±0.49) and (7.08±1.78) μmol/L vs.(12.68±3.28) μmol/L), and the differences were statistically significant( q=6.31, 6.01; both P<0.01). The serum IL-6 levels of EAW-L, EAW-H, EAT-L and EAT-H groups were lower than that of CTM group((29.26±5.42), (24.28±4.75), (9.05±1.74) and (8.01±1.24) ng/L vs.(53.21±10.05) ng/L); the serum IL-6 level of EAT-L group was lower than that of EAW-L group; the serum IL-6 level of EAT-H group was lower than that of EAW-H group, and the differences were statistically significant( q=12.20, 14.73, 22.48, 22.11, 10.28, 7.96; all P <0.001). The collagen volume fractions of EAW-L, EAW-H, EAT-L and EAT-H groups were lower than that of CTM group (6.15±1.09, 2.91±0.76, 7.07±1.37 and 5.31±0.80 vs. 12.36±1.96); the collagen volume fraction of EAW-H group was lower than that of EAW-L, EAT-L and EAT-H groups, and the differences were statistically significant( q=11.68, 17.78, 9.94, 13.25; 6.10, 7.84, 4.53; all P <0.05). The HAI and Ishak system scores of EAW-H and EAT-H groups were lower than those of CTM group (6.0 (5.5, 7.5) and 7.0 (6.0, 7.5) vs. 13.0 (12.0, 13.0), 1.0 (1.0, 2.0) and 2.0 (1.0, 2.0) vs. 4.0 (3.0, 4.0)), and the differences were statistically significant( ZHAI=3.38, 3.23, Zlshak=3.22, 3.03; all P<0.05). The result of immunohistochemical analysis showed that the expression levels of α-SMA in the mice liver tissues of EAW-L, EAW-H, EAT-L, EAT-H and CTM groups were 4.76±0.36, 2.75±0.29, 3.72±0.34, 5.20±0.79 and 5.98±0.52, respectively. The result of Western blotting showed that the expression levels of α-SMA in the mice liver tissues of CTM, EAW-L, EAW-H, EAT-L and EAT-H groups were 0.96±0.11, 0.67±0.07, 0.22±0.01, 0.78±0.08 and 0.68±0.07, respectively. Two detection methods both showed that the expression levels of α-SMA of EAW-L, EAW-H and EAT-H groups were lower than that of CTM group; the expression level of α-SMA of EAW-H group was lower than that of EAW-L, EAT-L and EAT-H group, and the differences were statistically significant( qimmunohistochemical =6.06, 15.95, 11.18, 9.92, 12.10 and 4.79, qWestern blotting=7.29, 18.34, 6.84, 11.05, 13.97 and 11.49, all P<0.05). The expression levels of MMP2 and ERK1/2 at protein and mRNA levels in the mice liver tissues of EAW-L, EAW-H, EAT-L, EAT-H and CTM groups were 0.18±0.04, 0.16±0.04, 0.28±0.02, 0.21±0.02 and 0.84±0.02, 0.80±0.02, 0.57±0.08, 0.83±0.03, 0.69±0.02 and 0.91±0.04, 18.74±1.90, 10.73±1.24, 24.99±1.84, 7.19±0.48 and 24.68±1.18, 29.44±4.47, 11.96±0.53, 24.75±4.04, 5.30±0.36 and 35.76±0.85, respectively. The expression levels of MMP2 at protein level in EAW-L, EAW-H, EAT-L and EAT-H groups were lower than that in CTM group; the expression levels of ERK1/2 at protein level in EAW-H and EAT-H groups were lower than that in CTM group; the expression level of ERK1/2 at protein level in EAW-H group was lower than that in EAT-H group; the expression levels of MMP2 and ERK1/2 at mRNA level in EAW-H and EAT-H group were lower than those in CTM group; the expression levels of MMP2 and ERK1/2 at mRNA level in EAW-H group were lower than those in EAW-L group; the expression levels of MMP2 and ERK1/2 at mRNA level in EAT-H group were lower than those in EAT-L and EAW-H groups, and the differences were statistically significant( q=22.15, 22.96, 18.87, 21.31; 13.42, 8.53; 4.90; 18.57, 23.29, 16.49, 21.11; 10.66, 12.12; 23.70, 15.38, 13.48, 16.73; all P<0.05). Conclusions:Both EAT and EAW can alleviate carbon tetrachloride-induced liver injury and liver fibrosis in mice, which may be related with inhibiting the expression of ERK1/2 and IL-6 and then affecting the Ras/ERK-MMP2 signaling pathway.

Clinical pharmacy is an important part of hospital pharmacy. Education of clinical pharmacy is one of the most important tasks in clinical pharmacy personnel training. At present, there is a considerable progress in the development of clinical pharmacy education in China, however, the professional quality of clinical pharmacists is still insufficient and there is a gap between the disciplinary education and clinical practice. In this article, we discuss the origin, development, academic degree, curriculum, teaching methods and practice certification of clinical pharmacy education in China and in United States, in order to explore the applicable methods of clinical pharmacy education in China. It will provide ideas and references for the optimization of the training of clinical pharmacy professionals, accelerating the development of clinical pharmacy in China.

Memantine is a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist clinically approved for moderate-to-severe Alzheimer's disease (AD) to improve cognitive functions. There is no report about the proteomic alterations induced by memantine in AD mouse model yet. In this study, we investigated the protein profiles in the hippocampus and the cerebral cortex of AD-related transgenic mouse model (3×Tg-AD) treated with memantine. Mice (8-month) were treated with memantine (5 mg/kg/bid) for 4 months followed by behavioral and molecular evaluation. Using step-down passive avoidance (SDA) test, novel object recognition (NOR) test and Morris water maze (MWM) test, it was observed that memantine significantly improved learning and memory retention in 3xTg-AD mice. By using quantitative proteomic analysis, 3301 and 3140 proteins in the hippocampus and the cerebral cortex respectively were identified to be associated with AD abnormalities. In the hippocampus, memantine significantly altered the expression levels of 233 proteins, among which PCNT, ATAXIN2, TNIK, and NOL3 were up-regulated, and FLNA, MARK 2 and BRAF were down-regulated. In the cerebral cortex, memantine significantly altered the expression levels of 342 proteins, among which PCNT, PMPCB, CRK, and MBP were up-regulated, and DNM2, BRAF, TAGLN 2 and FRY1 were down-regulated. Further analysis with bioinformatics showed that memantine modulated biological pathways associated with cytoskeleton and ErbB signaling in the hippocampus, and modulated biological pathways associated with axon guidance, ribosome, cytoskeleton, calcium and MAPK signaling in the cerebral cortex. Our data indicate that memantine induces higher levels of proteomic alterations in the cerebral cortex than in the hippocampus, suggesting memantine affects various brain regions in different manners. Our study provides a novel view on the complexity of protein responses induced by memantine in the brain of AD.
Alzheimer Disease ; Animals ; Axons ; Brain ; Calcium ; Cerebral Cortex ; Cognition ; Computational Biology ; Cytoskeleton ; Hippocampus ; Learning ; Memantine ; Memory ; Mice ; Mice, Transgenic ; N-Methylaspartate ; Proteome ; Ribosomes ; Water

OBJECTIVE:To provide reference for formulating drug price regulation policy and promoting reasonable drug price. METHODS:According to WHO and HAI drug price standard investigation,questionnaire survey(supplemented by field investigation)about sale price of 63 commonly used drugs with large consumption sum was conducted among 3 districts of different economic development levels in Hubei province. Median price ratio(MPR)was calculated statistically. Primary interview survey(supplemented by literature investigation)about drug distribution cost was conducted among managerial staff of pharmaceutical wholesale and retail enterprises,hospital pharmacy administrators. Suggestions were put forward to control distribution cost and standardizing drug price based on analysis and discussion. RESULTS:Totally 120 questionnaires were sent out,and 118 were effectively received,with effective recovery of 98.33%. Thirty managerial staff from drug wholesale and retail enterprises,hospital pharmacy department were interviewed for investigation of drug distribution cost. MPR of 63 drugs ranged 0.05-44.55 in different types of sample institutions. Among 67 specifications of 53 kinds of drugs,median retail price of 38 specifications(56.72%)was higher than international reference price in first-level sample medical institutions. Among 79 specifications of 63 kinds of drugs,median retail price of 57 specifications(72.15%)was higher than international reference price in second-level sample medical institutions. Among 80 specifications of 63 kinds of drugs,median retail price of 63 specifications(78.75%)was higher than international reference price in third-level sample medical institutions. Among 50 specifications of 37 kinds of drugs,median retail price of 42 specifications(84.00%)was higher than international reference price in sample pharmaceutical retail enterprises. In all sample institutions,maximum MPR of 13 specification were lower than 1;those of 12 specification ranged from 1 to <2;those of 23 specifications ranged from 2 to <5;15 specification ranged from 5 to <10;those of 17 specification were higher than 10. MPR of third-level medical institution samples were higher than those of second-level and first-level ones,and pharmaceutical retail enterprises(P<0.01). MPR of second-level medical institution samples and pharmaceutical retail enterprises were higher than those of first-level medical institutions(P<0.01). There was no statistical significance in the levels of MPR between second-level medical institutions and pharmaceutical retail enterprises(P>0.05). MPR of sample institutions in well-developed regions were higher than in medium-developed or less-developed regions(P<0.01). MPR of sample institutions in medium-developed regions were higher than in less-developed regions(P<0.01). MPR of original drugs were all higher than those of generic drugs in different types of sample institutions(P<0.01). There was no statistical significance in MPR of original drugs among different types of sample institutions(P>0.05). At the same time,MPR of generic drugs in third-level medical institution samples were higher than in second-level and first-level ones and pharmaceutical retail enterprises (P<0.05 or P<0.01). MPR of second-level medical institution samples and pharmaceutical retail enterprises were higher than in first-level ones(P<0.05). There was no statistical significance between second-level medical institution samples and pharmaceutical retail enterprises(P>0.05). Drug production and circulation cost,centralized bidding and purchasing price in Hubei province were higher than the national level. CONCLUSIONS:The drug price of Hubei province is in high level,especially that of three-level medical institutions is higher than other institutions;drug price of well-developed region is higher than those of medium-level and less-developed region;the price of original drugs are higher than those of generic drugs. The cost of pharmaceutical industry,drug circulation cost and the addition of drug price during application link eventually lead to the higher retailing price of drugs. Comprehensive policy measures need to be taken to control the cost of the whole process of drug distribution and to regulate the price of drugs.

Objective:To investigate the transport mechanism of punicalagin in MDCK monolayer model .Methods:The safe con-centration of punicalagin in MDCK cells was determined by CCK8 assay.Millicell -ERS was used to measure cell monolayer TEER value to determine the integrity of the cell monolayer .The effects of direction , drug concentration , time, P-gp inhibitor and EDTA-Na2 on the absorption and transport of punicalagin were studied systematically .And then the drug concentration was analyzed by HPLC to calculate the apparent permeability coefficient (Papp) and efflux ratio(ER).Results: Punicalagin transport in MDCK cells was time and concentration dependent .Punicalagin showed poor absorption in MDCK cells .Papp from apical to basolateral side ( AP-BL) within the concentration range of 100-300μg· ml-1 was (6.13 ±0.12) ×10 -7 cm· s-1 , (6.96 ±0.26) ×10 -7 cm· s-1 and (5.94 ±0.10) ×10 -7 cm· s-1 , respectively .P-gp inhibitor and EDTA-Na2 could significantly increase the transport of punicalagin in AP-BL direc-tion, while the transport decreased at 4℃.Conclusion:The transport mechanism of punicalagin might be passive diffusion as the dom-inating process involving active transportation .Punicalagin is one of P-gp substrates with exocytosis and absorbed via the paracellular route.

Sulfated polysaccharides are with hydroxyl group containing sulfate radicals, which can be obtained by natural extraction or chemical modification of sulfation. Recent studies have shown that sulfated polysaccharides exhibit different levels of antitumor activ-ity, especially in comparison with those before chemical modification; therefore, they have attracted wide attention. This article briefly reviewed the domestic and foreign researches on the antitumor effects of natural sulfated polysaccharides and chemical synthesized sul-fated polysaccharides in recent years.

Diabetic nephropathy ( DN) is one of the complications of diabetes, which is closely related to the pathogenesis of in-flammation. This article summarized the relevant literatures on the correlation between MCP-1 , TNF-α and DN, and the intervention of traditional Chinese medicine with DN. In kidney tissues, oxidative stress and NF-κB-dependent signal pathways induced the increase of monocyte chemoattractant protein-1 (MCP-1) expression, which could induce macrophage accumulation, proteinuria increase, renal fibrosis and renal clearance capacity decrease, and further leading to kidney damage. The clinical and experimental trails showed tumor necrosis factorαmRNA and protein levels in serum, urine and renal tissues were closely related with DN, which could be used as a bio marker to provide clinical guidance. As the therapeutic targets,MCP-1 and TNF-αcould give a novel insight into the clinical treatment of DN. Some traditional Chinese medicines or monomer could ameliorate DN by inhibiting MCP-1 and/or TNF-α. Thus, further verifi-cation or clinical application of those traditional Chinese medicines is worth trying.

Punicalin is an important ellagic tannin in Pericarpium Granati with the pharmacological effects such as antioxidation,anti-bacteria,antivirus and anti-inflammation.The studies on Pericarpium Granati at home and abroad were reviewed in the paper,and the extraction,separation,content determination,pharmacological activities and metabolism of punicalin were also summarized to provide theoretical basis for the development and application of punicalin.

ABSTRACT Ellagitannin is a complex compound of plant polyphenols, and it is an effective substance in many commonly used natu-ral drugs. Ellagitannin has been widely used in medicine, cosmetics, food, health care products and the other fields. The article re-viewed the structure source, biological activity and metabolic outcomes of ellagitannin in order to provide basis for the in-depth resear-ches and the resource development of natural medicines rich in tannins.