Inhibitory effect of flufenidone on TGF-β1/Smads pathway in hepatocytes of rats with diethylnitrosamine (DEN)-induced liver injury / 中国临床药理学与治疗学

AIM: To explore the protective effect of fluorofenidone (AKF-PD) on diethylnitrosamine-induced liver injury in rats and its inhibition of the TGF-β1/Smads pathway in hepatocytes. METHODS: Fifty-five male Sprague Dawley (SD) rats were randomly divided into three groups: model group (DEN group, n=20) were gavaged with DEN (10 mg/kg), 5 times for 14 weeks; control group (n=20) were gavaged with saline with the same volume of the model group; treatment group (DEN+AKF-PD Group, n=15), after 4 weeks of modeling, they were gavaged with AKF-PD (500 mg/kg) daily, and stopped at 14 weeks. At the end of experiment, the rats were killed by anesthesia and spinal dislocation. Masson staining was used to observe collagen deposition; primary hepatocytes were extracted and identified, and the levels of α-smooth muscle actin (α-SMA), TGF-β1, Smad3, and Smad7 mRNA, and the expression of Smad3 and Smad7 proteins in hepatocytes were detected. RESULTS: Compared with the control group, Masson staining showed that collagen deposition increased in the DEN group; AKF-PD treatment could significantly improve liver pathological damage and reduce collagen deposition. In addition, compared with the DEN group, the α-SMA, TGF-β1, and Smad3 mRNA levels of the AKF-PD group were significantly reduced, and the Smad7 mRNA level was increased. Moreover, AKF-PD treatment could dependably reduce the expression of Smad3 and increase Smad7. CONCLUSION: AKF-PD can significantly improve liver injury and fibrosis in rats caused by DEN. This effect may be related to the down-regulation of α-SMA, TGF-β1, and Smad3 mRNA levels in hepatocytes and the increase of Smad7 mRNA levels.

Effect of lamivudine and silymarin on liver fibrosis-relevant factors in HBV transgenic mice with alcohol drinking / 中南大学学报(医学版)

Objective:To observe the role of lamividine and silymarin preventing and curing liver fibrosisrelevant factors induced by alcohol drinking in hepatitis B virus (HBV) transgenic mice (Tg mice).Methods:Forty HBV-Tg BALB/C mice with 1.3 copy were randomly divided into 4 groups:a control group,a model group,a lamivudine group and a silymarin group.Tg mice in control group were treated with normal saline via intragastric administration;Tg-mice in the model group were treated with 50％ alcohol (5 mL/kg) once a day via intragastric administration;while Tg-mice in lamivudine group and silymarin group were treated with alcohol (5 mL/kg) plus laminvudine (100 mg/kg) and silymarin (200 mg/kg) once a day via intragastric administration respectively.All groups were raised for 10 weeks.The levels of HBV-DNA copy number,ALT,AST in serum,the degree of inflammation,the degree of fibrosis,the mRNA expression levels of TGF-β 1,Smad3,Smad7 and connective tissue growth factor (CTGF),and the protein expression levels of TGF-β1,CTGF and α-SMA in liver tissue were detected.All the images were scanned with electronic computer and the data were analyzed with SPSS13.0 software.Results:Compared with the control group,liver injury were significantly aggravated,while HBVDNA copies,mRNA levels ofTGF-β1,Smad3,Smad7 and CTGF as well as the protein levels of TGF-β1,CTGF and α-SMA were significantly increased (P＜0.05).Compared with the model group,liver injury were significantly attenuated in silymarine group and lamivudine group,while mRNA levels of TGF-β 1,Smad3 and CTGF as well as the protein levels of TGF-β1,CTGF and α-SMA were significantly decreased;mRNA level of Smad7 was further increased (P＜0.05);the levels of ALT and AST in serum were decreased in the silymarine group (P＜0.05).Conclusion:Lamivudine and silymarin relieve the histological damage in the liver of alcohol-fed Tg mice.The mechanisms for the beneficial effects of lamivudine or silymarin might be related to inhibiting the expression of TGF-β 1,Smad3 and CTGF,modulating the expression of Smads and suppressing the activation of HSC.

Molecular mechanisms of FK506-induced hypertension in solid organ transplantation patients / 中华医学杂志(英文版)

<p><b>OBJECTIVE</b>Tacrolimus (FK506) is an immunosuppressive drug, which is widely used to prevent rejection of transplanted organs. However, chronic administration of FK506 leads to hypertension in solid organ transplantation patients, and its molecular mechanisms are much more complicated. In this review, we will discuss the above-mentioned molecular mechanisms of FK506-induced hypertension in solid organ transplantation subjects.</p><p><b>DATA SOURCES</b>The data analyzed in this review were mainly from relevant articles without restriction on the publication date reported in PubMed. The terms "FK506" or "tacrolimus" and "hypertension" were used for the literature search.</p><p><b>STUDY SELECTION</b>Original articles with no limitation of research design and critical reviews containing data relevant to FK506-induced hypertension and its molecular mechanisms were retrieved, reviewed and analyzed.</p><p><b>RESULTS</b>There are several molecular mechanisms attributed to FK506-induced hypertension in solid organ transplantation subjects. First, FK506 binds FK506 binding protein 12 and its related isoform 12.6 (FKBP12/12.6) and removes them from intracellular ryanodine receptors that induce a calcium ion leakage from the endoplasmic/sarcoplasmic reticulum. The conventional protein kinase C beta II (cPKCβII)-mediated phosphorylation of endothelial nitric oxide (NO) synthase at Thr495, which reduces the production of NO, was activated by calcium ion leakage. Second, transforming growth factor receptor/SMAD2/3 signaling activation plays an important role in Treg/Th17 cell imbalance in T cells which toget converge to cause inflammation, endothelial dysfunction, and hypertension following tacrolimus treatment. Third, the activation of with-no-K(Lys) kinases/STE20/SPS1-related proline/alanine-rich kinase/thiazide-sensitive sodium chloride co-transporter (WNKs/SPAK/NCC) pathway has a central role in tacrolimus-induced hypertension. Finally, the enhanced activity of renal renin-angiotensin-aldosterone system seems to play a crucial role in the pathophysiology of FK506-induced hypertension.</p><p><b>CONCLUSION</b>FK506 plays a predominant role in the pathophysiology of hypertension in solid organ transplantation subjects.</p>

Transforming growth factor-β1 regulates the telomerase reverse transcriptase in rat hepatic stellate cells / 中南大学学报(医学版)

OBJECTIVE@#To determine the effect of transforming growth factor-β1 (TGF-β1) on the expression of telomerase in hepatic stellate cells (HSCs) in rats and the role of TGF-β1 in the development of liver fibrosis.@*METHODS@#Primary HSCs were isolated from normal rats by density gradient separation and divided into 2 groups for culturing. The morphology of HSCs was identified by the inverted fluorescence microscope. The purity of HSCs was identified by immunohistological expression and fluorescence analysis. One group of HSCs was treated with different concentrations (0, 0.1, 1, and 10 ng/mL) of TGF-β1 for 24 h, while the other group was treated with 1 ng/mL TGF-β1 and cultured for 3, 6, and 9 days. The mRNA expression of telomerase reverse transcriptase (TERT) was assessed and compared by polymerase chain reaction.@*RESULTS@#Cell morphology showed that TGF-β1 triggered the differentiation of HSCs from a quiescent phenotype into highly activated myofibroblasts. TERT mRNA expression in the primary HSCs showed slight increase with the culture time, though with no statistical difference between the results at various time points (P>0.05). TGF-β1 at 0.1 ng/mL did not significantly affect the TERT mRNA level compared with the 0 ng/mL group, while 1 ng/mL and 10 ng/mL TGF-β1 significantly decreased the level of TERT mRNA (P0.05). TGF-β1 at 1 ng/mL significantly inhibited TERT mRNA expression 6 days after the treatment (P<0.05). TGF-β1 inhibited the expression of TERT mRNA level in the HSCs in both dose- and time-dependent manner.@*CONCLUSION@#TGF-β1 may contribute to the transdifferentiation of HSCs by reducing TERT levels to develop hepatic fibrosis.

Peginterferon alpha versus other antiviral regimes for Chinese HBeAg-positive chronic hepatitis B patients / 中南大学学报(医学版)

OBJECTIVE@#To conduct a meta-analysis to determine the efficacy of peginterferon alpha (PEG-IFN α) therapy versus IFN α, adefovir dipivoxil (ADV) and entecavir (ETV) for HBeAg-positive chronic hepatitis B patients in China.@*METHODS@#MEDLINE database and 3 main Chinese biomedical databases between 1966 and 2012 was retrieved. Two reviewers independently screened all reports to identify randomized controlled trials that evaluated PEG-IFN α therapy for the treatment of chronic hepatitis B in China.@*RESULTS@#Fourteen trials met the eligibility criteria for this Meta analysis. PEG-IFN α therapy was more effective than IFN α therapy in achieving ALT normalization, serum HBV DNA clearance, HBeAg seroconversion, serum HBeAg clearance and fibrosis improvement in Chinese hepatitis B patients (P<0.05). PEG-IFN α was obviously superior to ETV in HBeAg seroconversion and serum HBeAg clearance (P<0.05), but the seroconversion rate was low. The combination therapy of PEG-IFN α and ADV was more effective than ADV monotherapy in ALT normalization, serum HBV DNA clearance and HBeAg seroconversion (P<0.05). PEG-IFN α showed no priority to other treatment regimes in HBsAg clearance.@*CONCLUSION@#Treatment with PEG-IFN α is safe and effective, and can be prescribed as firstline treatment options for chronic hepatitis B patients in China. Data are too limited to exclude a substantial benefit or harm of PEG-IFN α combination therapy for CHB patients in China.

The effect and mechanism of alcohol on liver injury in hepatitis B virus transgenic mice / 中国药理学通报

Aim To investigate the synergistic effects and possible molecular mechanism of hepatitis B virus (HBV) and alcohol on liver injury in HBV transgenic mice(HBV-Tg mice).Methods 20 HBV-Tg mice and 20 wild-type mice were randomly divided into 4 groups:alcohol-fed Tg mice and alcohol-fed Wt mice, and they were given intragastric administration with alcohol. Control Tg mice and control Wt mice received intragastric administration with saline.All groups were rasied for 10 weeks.The levels of ALT and AST in serum, the degree of inflammation, the degree of fibrosis, the mRNA expression of TGF-β_1, Smad3, Smad7, CTGF and the protein expression of TGF-β_1, CTGF, α-SMA in liver tissue were detected.Results The serumlevel of ALT and AST, the mRNA expression of TGF-β_1, Smad3, Smad7, CTGF and the protein expression of TGF-β_1, CTGF, α-SMA in liver all increased markedly in alcohol-fed Tg mice. Alcohol consumption induced hepatocyte steatosis and hepatic inflammation in alcohol-fed Tg mice, but the change of liver fibrosis was not remarkable.Conclusion HBV and alcohol have synergistic effects on early liver injury, possibly by enhancing the expression of TGF-β_1, Smad3, CTGF, α-SMA and inducing unbalanced expression of Smads.

Determination of amodiaquine in human plasma by high performance liquid chromatography / 中国新药与临床杂志

AIM:To establish HPLC method for the determination of amodiaquine in human plasma.METHODS: Amodiaquine and internal standard(hydroxychloroquine) were analyzed on C18 column(150 mm ×4.6 mm, 5 μm) with methanol: water:triethylamine: orthophosphoric acid (21:77.5:1:0.5 )as mobile phase at the flow rate of 1.0 mL · min-1The UV detector was set at 294 nm. RESULTS: The retention times of amodiaquine and internal standard were 5.82, 8.56 min, respectively. The calibration curve was linear in the range from 10 to 1 000 μg ·L- 1 ( r = 0.999 8, n = 9 ). The limit of quantitation was5 μg· L-1. The extraction recovery was between 75.5 % and 82.7 %, and the methodological recovery was between 97.0 % and 104.8 %. The intra-day and inter-day RSD were less than 6.0 % and 7.5 %, respectively. CONCLUSION: This HPLC method is simple, sensitive and suitable for pharmacokinetic study of amodiaquine.

Study on the relative bioavailability of diclofenac sodium extended action tablet in human body / 中国医师杂志

0.05)in healthy volunteers.

REPORT OF PAINLESS GASTROSCOPY IN 1100 PATIENT / 中国内镜杂志

Objective:The study was attempted to improve the manipulation and eliminate patient's fear for gastroscopy combined with intravenous injection.Methods:A total of 1350 patients wasrandomized into test group (n=1100 given intraveous protofol and midazolam)and the control (n=250,without anesthetics).Patient's feeling,heart rate,blood oxygen saturation,blood pressure,operative duration and operator' satisfaction were recored and analysed.Results:Data in test group showed less complaints,easier manipulation,high satisfaction and no difference in operative duration and blood oxygen saturation as compared with the control.After intravenous administration of protofol and midazolam,patient's heart rate and blood pressure (systolic and diastolic pressure) significantly decreased.Conclusions:With intravenous use of protofol and midazolam,gastroscopy can be achieved effectively,painlessly and safely.

Cost-effectiveness Analysis of the Antibiotic Application in 230 Patients Undergoing Laparoscopic Cholecystectomy / 中国药房

To explore the rational use of antibiotics in patients undergoing laparoscopic cholecystectomy(LC).METHODS： The antibiotic use in the selected operation patients was retrospectively studied.230 patients were divided into four groups.A group： Perioperative administration of drug； B group： Preoperative administration for 3 to 7 days and perioperative administration； C group： Perioperative administration and postoperative administration for 2 to 7 days； D group： Preoperative administration for 2 to 7 days， perioperative administration and postoperative administration for 2 to 7 days.Four groups were compared about the efficacy， length of hospital stay and hospitalization expenses.RESULTS： There were no significant differences in efficacy among A， B， C， D and in average length of hospital stay and hospitalization expenses between A and D groups.A group was the lowest in two indices and had the best cost-effectiveness ratio.CONCLUSION： There is clinical significance of preventive antibiotic application in LC patients； perioperative use is the best choice； Cefazolin is the first choice.

Literature Analysis of 646 Cases of Drug-induced Cardiovascular Diseases / 中国药房

OBJECTIVE:To find out the incidence and general patterns of drug-induced cardiovascular diseases and to guide rational use of drugs METHODS:By using literature metrological method 646 cases of drug-induced cardiovascular diseases which were reported in Chinese literatures in 1995～2000 were analysed RESULTS:Among those 646 cases,the incidence of arrhythmia was 59 8% The kinds of induced drugs were up to 155 and the most easily inducing one was cardiovascular system drug,which amounted to 37 2%(240/646) Propafenone had the highest incidence of all in inducing cardiovascular diseases(75 cases) There were 35(5 4%) fatal cases mainly caused by cardiovascular system drugs Most of the patients with drug-induced cardiovascular diseases were in middle-age and old age CONCLUSION:To reduce the rate of drug-induced diseases,cardiovascular system drugs should be rationally administrated and stictly supervised

Cost-minimization Analysis on 2 Therapeutic Schemes for Community Acquired Respiratory Tract Infection / 中国药房

0.05);the total costs of L 1 group and L 2 group were424.76yuan and270.90yuan respectively,the cost of L 1 group was58%,higher than that of L 2 group.CONCLUSION:Considering from the perspective of pharmacoeconomics,L 2 group was a better one.

The Use of Tacrolimus in 932 Renal Transplant Recipients / 中国药房

OBJECTIVE:To objectively evaluate the immunosuppressive effect and safety of tacrolimus(FK 506) in renal transplant recipients METHODS:932 recipients receiving FK 506,reported in literature,were retrospectively analyzed RESU_LTS:The incidence of acute rejection was low in 547 recipients who received FK 506 immediately after transplantation Most of the recipients who received CsA and FK 506 successively showed alleviation of rejection and improvement of liver function The ARDs of FK 506 were rise of blood sugar(18 10%) and toxicity to nervous system(12 25%) CONCLUSION:FK 506 is a po_wer immunosuppressant and can be used to treat CsA-resistant rejection

Cost-effectiveness Analysis of the Antibiotic Application in 230 Patients Undergoing Laparoscopic Chole-cystectomy / 中国药房

OBJECTIVE:To explore the rational use of antibiotics in patients undergoing laparoscopic cholecystectomy(LC) METHODS:The antibiotic use in the selected operation patients was retrospectively studied 230 patients were divided into four groups A group:Perioperative administration of drug;B group:Preoperative administration for 3 to 7 days and perioperative administration;C group:Perioperative administration and postoperative administration for 2 to 7 days;D group:Preoperative administration for 2 to 7 days,perioperative administration and postoperative administration for 2 to 7 days Four groups were compared about the efficacy,length of hospital stay and hospitalization expenses RESULTS:There were no significant differences in efficacy among A,B,C,D and in average length of hospital stay and hospitalization expenses between A and D groups A group was the lowest in two indices and had the best cost-effectiveness ratio CONCLUSION:There is clinical significance of preventive antibiotic application in LC patients;perioperative use is the best choice;Cefazolin is the first choice

Content Determination of Gatifloxacin in Human Plasma by HPLC / 中国药房

OBJECTIVE: To establish a HPLC method for content determination of gatifloxacin in human plasma.METHODS: The Analytical column was C18,the mobile phase consisted of acetonitrile-30mmol/L ammonium acetate-triethylamine-orthophosphoric acid (20∶80∶1.0∶0.7) with a flow rate of 1.0ml/min,the detection was performed at UV 294nm.RESULTS: The calibration curve was linear in the concentrations ranging from 0.1 to10.0?g /ml (r=0.9 992).The detection limit was 0.05?g/ml.The intraday RSD was less than 8% and interday RSD was less than 10%.The average recovery was (101.67?3.06)%.CONCLUSION: The method is simple, sensitive, accurate and suitable for determination of gatifloxacin in human plasma and pharmacokinetic study.

Reversal effect of cinobufacine on adriamycin resistancehuman breast cancer cells / 中国药理学通报

Aim To investigate the reversal effect of cinobufacine(Cino)on adrimycin(ADM)resistant human breast cancer cell line MCF-7/ADM.Methods The cytotoxic effect of Cino or ADM and the sensitivity of ADM to cells was determined by MTT assay.The intracellular concentration of ADM was detected by HPLC. The expression of P-glycoprotein(P-gp)was examined by flow cytometric(FCM) .Results The maximum non-toxic dose Cino(15 mg?L-1) increased the sensitivity of ADM in MCF-7/ADM,decreased the IC50 of ADM in MCF-7/ADM from 38.14 mg?L-1 to 12.93 mg?L-1, and significantly increased the intracellular concentration of ADM in MCF-7/ADM and reduced the expression of P-glycoprotein.Conclution The results showed that Cino can partially reverse multidrug resistance(MDR)of MCF-7/ADM cells and the mechanism might be associated with the increase of intracellular accumulation of ADM and the reduced expression of P-glycoprotein(P-gp)in MCF-7/ADM cells.