�󿼷�������������ֲ�����е�ҩ��ѧ�о�

??OBJECTIVE To investigate the pharmacokinetic characteristics of enteric-coated sodium mycophenolate(EC-MPS) or mycophenolate mofetil (MMF) dispersible tablets after multiple oral doses in early renal transplant patients, providing references for the rational use of the study drugs in clinical practice. METHODS Thirty-eight first-time renal transplant patients were selected and randomly divided into EC-MPS group (n=18) or MMF dispersible tablets group (n=19). The patients received EC-MPS (540 mg, q12h) or MMF dispersible tablets (750 mg, q12h), combined with tacrolimus and methylprednisolone to prevent acute rejection, respectively. Blood samples were collected at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 h after oral administration on the postoperative day 5. Enzyme multiplied immunoassay technique (EMIT) was employed to determine the plasma concentration of MPA. The main pharmacokinetic parameters of the two durgs were assessed. RESULTS Pharmacokinetic parameters on the postoperative day 5 of EC-MPS and MMF dispersible tablet were as follows: AUC_{0-12 h} were(43.62??16.20) and(42.02??14.40)mg??h??L^-1(P>0.05);??_max were (17.85??11.32) and (13.96??5.11) mg??L^-1(P>0.05);t_max were (2.72??1.74) and(1.32??0.42)h(P<0.05); ??₀ were (1.63??1.18) and (1.66??0.93) mg??L^-1(P>0.05); ??₁₂ were(1.84??2.09) and (1.81??1.76) mg??L^-1(P>0.05); CL were (14.12??5.30) and (19.66??5.99) L??h^-1(P<0.05). Most of the patients revealed a second small peak in the 4-12 h after taking MPA in the two study groups. CONCLUSION There are large individual differences of pharmacokinetic between EC-MPS and MMF dispersible tablets in early renal transplant patients. It is necessary to carry out therapeutic drug monitoring of MPA to guide the adjustment of drug dosage.     

替尼类药物关键中间体N-芳基喹唑啉-4-胺化合物的简便合成

目的 研究替尼类药物的关键中间体N-芳基喹唑啉-4-胺化合物的新合成方法,优化反应条件,确定反应底物适用性,推测反应可能机理。方法 以取代邻氨基苯甲腈(1a～1e)和芳胺(2a～2e)为原料,甲酸为反应底物和溶剂,Cu(OTf)₂为催化剂,发生多组分串联反应一锅合成N-芳基喹唑啉-4-胺化合物(3a～3g),考察催化剂及用量、溶剂、反应物用量、反应温度和反应时间对反应的影响。结果 在Cu(OTf)₂的催化下,取代邻氨基苯甲腈、芳胺和甲酸能顺利发生串联的加成/缩合/环化反应,在取代邻氨基苯甲腈5 mmol,芳胺6 mmol,Cu(OTf)₂ 0.5 mmol,甲酸20 mL,110 ℃反应12 h的条件下,以80%～95%的收率得到7个N-芳基喹唑啉-4-胺化合物,目标产物结构经¹H-NMR和¹³C-NMR确证。结论 该方法为合成替尼类药物关键中间体N-芳基喹唑啉-4-胺化合物提供了一种高效简便的绿色工艺,反应条件温和,产物收率高,操作安全简便,对环境友好。     

�����׺�������-��ЧҺ��ɫ���������òⶨ������ҩ�еĻ���ù���ز�����

??OBJECTIVE To develop an immunoaffinity column clean-up and high performance liquid chromatography coupled with triple quadrupole mass spectrometry(HPLC-MS/MS) method to determine aflatoxins in gelatin drugs. METHODS The analysis was performed by an HPLC-MS/MS system with X-Brigde-C₁₈(3.0 mm??50 mm,3.5 ??m)column. Multiple-reaction monitoring (MRM) was performed to identify and quantify aflatoxin B₁,B₂,G₁ and G₂, which were extracted from Asini Coril Colla, Cervil Cornus Colla, and Testudinis Carapacis Colla with 60% methanol solution. RESULTS Linear calibration curves were obtained with r??0.997 9. The precision of the method was showed by RSDs (n=6) ranging from 1.2% to 4.1%. The recoveries were determined at three concentration levels and ranged from 77.3% to 94.6%. The ranges of LOQs were from 0.5 to 0.8 ??g??L^-1 and the RSDs (n=9) of intra-day precision and inter-day precision were from 1.1% to 2.9% and from 1.5% to 2.8%, respectively. CONCLUSION The method is specific, simple and rapid to detect aflatoxins in gelatin drugs.     

��ҩ��Ҷ����ζ�Ӵ�������������Ը���ά����ʵ���о�

??OBJECTIVE To study the effects of Kadsura coccinea alcohol extract(KCAE) on rats with immunologic hepatic fibrosis and research the possible mechanisms in it. METHODS Totally 60 SD male rats were randomly divided into 6 groups: a normal control group,a model group, a compound Biejia-ruangan tablets group(0.7 g??kg^-1), KCAE high, middle and low dose groups(1.68, 0.84, 0.42 g??kg^-1) at ten in each groups. Except for the normal control group,other groups were duplicated intraperitoneal injection of porcine serum twice a week at dose of 0.5 mL??time^-1. The rats in treatment groups were intragastric administration respectively, meanwhile, the rats in normal control and model groups were treated with the same volume of distilled water, once a day for 15 weeks. The liver was weighed to calculate the liver index. Alanine aminotransferase(ALT), aspartate aminotransferase(AST), total protein(TP), albumin(ALB) and total bilirubin(TB) were evaluated by the Mind-Ray automatic biochaemical analyzer. The expression level of procollagen ??(PC??), collagen type ??(??-C), laminin(LN), hyaluronic acid(HA), transforming growth factor-??1(TGF-??1), interkeukin-10(IL-10), interferon-??(IFN-??) and tumor necrosis factor-??(TNF-??) in serum were detected by ELISA. The degrees of fibrosis were evaluated by HE and Masson straining, and the expression levels of TGF-??₁ in liver tissue were assessed by Western blot. RESULTS Compared with model group, the liver index of KCAE high-dose group was decreased significantly(P??0.01). The expression levels of ALT, AST, TP, ALB, TB were within normal range, the differences were not statistically significant(P>0.05). KCAE could decrease the level of PC??, IV-C, LN, HA, TGF-??₁, TNF-?? and increase the level of IFN-?? in serum. KCAE could alleviate the hepatic fibrosis in rats(P??0.01) and inhibit the expression of TGF-??₁ in the liver tissues significantly(P??0.01). CONCLUSION KCAE has an anti-immunologic hepatic fibrosis effect in rats and the mechanisms possibly involve effectively regulating inflammatory cytokines, reducing extracellular matrix expression and inhibiting the expression of TGF-??₁.     

7�ֲ�ͬ����ʯ����������ֶ��ǿ������Ϳ��������о�

??OBJECTIVE To identify seven species from Umbilicariales and study the chemical constituents, antioxidant and anti-inflammatory activities of crude products from the hot-water extraction. METHODS The seven species from Umbilicariales were identified using ITS sequence analysis, and the seven crude polysaccharides were extracted from the species by water extraction method. RESULTS Umbilicaria esculenta, Umbilicaria yunnana, Dermatocarpon miniatum and Lasallia papulosa were identified, and the main components of crude polysaccharides from the species were carbohydrates. The crude polysaccharides (JUY) from Umbilicaria yunnana of Jiangxi had the best antioxidant ability, it exhibited a higher scavenging activity of superoxide radicals (EC₅₀=0.56 mg??mL^-1) than Vc (EC₅₀=1.67 mg??mL^-1), and the scavenging activity for hydroxyl radicals (EC₅₀=0.53 mg??mL^-1) was comparable to Vc (EC₅₀=0.51 mg??mL^-1). Anti-inflammatory experimental results show that JUY has the best anti-inflammatory effects, and the better inhibitory effect of IL-1?? than dexamethasone (P<0.01). CONCLUSION The species from Umbilicariales of seven different areas were identified as four genera. The crude polysaccharides (JUY) from Umbilicaria yunnana of Jiangxi had the best antioxidant and anti-inflammatory activities.     

�Ǽ׻�����Ҷ�ỹԭø�����̬����󳦰����߸���������Ч��������о�

??OBJECTIVE To investigate the association between methylene tetrahydrofolate reductase (MTHFR)C677T polymorphism and the efficacy of the adjuvant chemotherapy with XELOX regimen for patients who had underwent radical resection of colorectal cancer. METHODS Sixty-two patients who had received chemotherapy with XELOX regimen following radical resection of colorectal cancer were tested for MTHFR C677T polymorphism using Kompetitive Allele-Specific PCR to analyze the association of MTHFR C677T polymorphism with the prognosis and adverse reactions to chemotherapy. RESULTS Among the 62 patients with colorectal cancer, there were 3 allelotypes (C/C, C/T and T/T)at the MTHFR C677T locus, and their frequencies were 46.8%,40.3%,and 12.9%, respectively. The recurrence free survival time was prolonged in C/T and T/T group than C/C group(Log-rank=4.778, P<0.05). Specifically, the relapse rate was 58.6% in patients with C/C allelotype, which was significantly higher than 33.3% in patients with T/T and C/T allelotype(Log-rank=3.985,P??0.05). TNM stage(HR=5.326, P<0.05) and MTHFR C677T polymorphism(HR=0.284,P<0.05) were shown to be the prognostic factors for postoperative adjuvant chemotherapy. The toxicities of chemotherapy were primarily gastrointestinal reactions and bone marrow suppression, without statistically significant differences across different allelotypes (P>0.05). CONCLUSION MTHFR C677T polymorphism is associated with the prognosis with adjuvant chemotherapy with XELOX regimen, and is not associated with the toxicities of chemotherapy. TNM stage IV is predicative of worse prognosis with postoperative adjuvant chemotherapy.     

���㶹�������԰�Ѫ��ϸ������ֳ�������ü�����

??OBJECTIVE To explore the effect of total coumarins isolated from Hedyotis diffusa (total coumarins from Hedyotis diffusa, TCHD) on proliferation inhibition of leukemia cells, and to explore its related mechanism. METHODS The purity of TCHD prepared by ethanol reflux extraction was tested by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) system. The cells (KG-1 Kasumi-1, THP 1 cells, U937 cells and K562 cells) were treated with TCHD(0.02, 0.04, 0.06, 0.08, 0.10 mg??mL^-1) for 24 or 48 h, the inhibitive effect of TCHD on cells growth were determined by MTT method. After Kasumi-1 cells were incubated with TCHD for 24 h,the apoptosis of cells were analyzed by flow cytometry stained with Annexin V/PI. The expression levels of caspase-3, caspase-8, caspase-9,PARP and Bcl-2 family protein were assayed by Western blot. RESULTS TCHD in certain concentration range could markedly inhibit the proliferation of AML cells, their IC₅₀ on Kasumi-1, THP-1 KG-1, U937 and K562 cells were 0.077, 0.083, 0.096, 0.087, 0.096 mg??mL^-1 for 24 h, and 0.059, 0.067, 0.072, 0.064, 0.068 mg??mL^-1 for 48 h. TCHD has significant inhibitory effect on Kasumi-1, which was stronger than those on other cell lines, and showed a dose- and time-dependent manner(r=0.357,P<0.05). The apoptotic proportion of Kasumi-1cells in 0, 0.02, 0.04, 0.06, 0.08, 0.10 mg??mL^-1 TCHD treatment groups for 24 h were (5.33??0.41)%, (7.99??0.45)%, (10.22??0.32)%, (20.10??1.99)%, (28.66??0.67)% and (33.24??2.12)%, respectively. After treated with TCHD(0.02-0.06 mg??mL^-1) for 24 h, G₀/G₁ phase ratio of Kasumi-1 detected by flow cytometry were (51.43??3.21)%, (62.91??2.35)% and (76.42??4.14)%, respectively, which were significantly higher than that of the control group (35.8??5.25)% (P<0.05).Western blot results showed that different concentrations of TCHD could activate caspase-8, caspase-9, caspase-3 and PARP, promote the expression of cyto-C, down-regulate the cyclin E and CDK6, CDK2, p-CDK2 and cyclin D₁ protein, and up-regulate the expression of p21 proteinin concentration- dependent manner(P<0.01). CONCLUSION TCHD can obviously inhibit the proliferation of Kasumi-1 in a dose- and time-dependent manner, which may relate to the apoptosis of Kasumi 1 induced by activating caspase-3, 9, PARP protein through the mitochondrial pathways and Kasumi-1 cell block in G₀/G₁ phase through the influence of CDK2, p-CDK2, CDK4/6, cyclin E, cyclin D₁ and p21.     

��Ѫ�����ศ��ҩ��Լ��Թ����ۺ�����������������Ѫ��Ӱ��Ļع��Է���

??OBJECTIVE To analyze the usage of the adjuvant huoxuehuayu drugs in patients with acute coronary syndrome(ACS), observe the impact of the drugs on upper gastrointestinal haemorrhage(UGH),and provide a reference for the clinical rational use of the adjuvant huoxuehuayu drugs. METHODS The ACS patients were enrolled in our hospital during May to July 2016. And the patients were divided into four groups according to whether using the adjuvant huoxuehuayu drugs: not use, used one kind, used two kinds, used ??three kinds of huoxuehuayu drugs. Then we collected medical history, therapeutic measures and other baseline data, gathered the data of the usage of the adjuvant huoxuehuayu drugs, evaluated CRUSADE bleeding risk and analyzed frequency of occurrence of UGH. RESULTS Overall 503 ACS patients were enrolled, there was no significant differences among the four groups when the medical history, essential medicines and intervene frequency were compared respectively. On the other hand, the incidence rate of UGH increased significantly with CRUSADE bleeding risk rank increasing incrementally.For very low and low bleeding risk ACS patients, there were no significant differences in UGH incidence rate among the four groups; For moderate and high bleeding risk ACS patients, UGH incidence rate increased significantly in ACS patients using more than one kind of huoxuehuayu drugs compared with other two groups(P??0.05). For very high bleeding risk ACS patients, UGH incidence rate increased significantly in ACS patients using 2 and ??3 kinds of huoxuehuayu drugs compared with patients using one kind drug, P=0.009,0.025 respectively. CONCLUSION For moderate and high bleeding risk ACS patients, UGH incidence rate increase significantly in ACS patients using ??2 kinds of huoxuehuayu drugs. A significant increase in the incidence rate of UGH with CRUSADE bleeding risk rank increasing, the use of huoxuehuayu drugs shoud be controled strictly, especially for very high bleeding risk ACS patients.     

������ȡ���֬�����յ�BV2ϸ����֢��Ӧ���ü�����̽��

??OBJECTIVE To investigate the anti-inflammatory effects of extract of Scutellaria baicalensis Georgi (SGE) and underlying mechanism by using LPS-induced microglial BV2 cells. METHODS MTT assay was used to observe the cell viability. The content of NO in cell supernatant was measured by Griess reagent. The levels of IL-1??, IL-6 and TNF-?? were detected by ELISA kits. The intracellular TLR4 expression was assayed by Western blotting. RESULTS The levels of NO, IL-1??, IL-6 and TNF-?? were significantly increased induced by LPS in the supernatant of BV2 cells (all P<0.01). However, co-treatment with SGE 100 ??g??mL^-1 significantly decreased the production of related inflammatory factors including NO (P<0.01), IL-1??(P<0.01), IL-6 (P<0.01) and TNF-?? (P<0.05). Furthermore, SGE significantly inhibited the TLR4 expression induced by LPS in BV2 cells. CONCLUSION SGE is able to alleviate LPS-induced inflammatory responses in BV2 cells through down-regulation of TLR4 protein expression suggesting that SGE has therapeutic potential for the treatment of neuroinflammatory diseases.