The study aims to evaluate the bioequivalence of valsartan hydrochlorothiazide tablets, and to investigate the potential cause of bioinequivalence. This was a single-center study with an open, randomized double-way crossover design. Test and reference preparations containing 160 mg of valsartan and 25 mg of hydrochlorothiazide were given to 36 healthy male volunteers. Plasma concentrations of valsartan and hydrochlorothiazide were determined simultaneously by LC-MS/MS. The pharmacokinetic parameters and relative bioavailability were calculated, while the bioequivalence between test and reference preparations were evaluated. The dissolution profiles of test and reference preparations in four different mediums were determined via dissolution test and HPLC. The similarity was investigated according to the similarity factors (f2). The F(o-t) and F(0-infinity) were (139.4 +/- 65.2)% and (137.5 +/- 61.2)% for valsartan of test preparations. It led to get the conclusion that test and reference preparations were not bioequivalent for valsartan. A significant difference was observed between test and reference tablets in the valsartan dissolution test of pH 1.2 hydrochloric acid solution. The key factor of the bioinequivalence might be that dissolution of valsartan in acid medium has marked difference between two preparations.
Administration, Oral ; Adolescent ; Adult ; Angiotensin II Type 1 Receptor Blockers ; administration & dosage ; adverse effects ; blood ; pharmacokinetics ; Antihypertensive Agents ; administration & dosage ; adverse effects ; blood ; pharmacokinetics ; Area Under Curve ; Chromatography, Liquid ; Cross-Over Studies ; Drug Liberation ; Humans ; Hydrochlorothiazide ; administration & dosage ; adverse effects ; blood ; pharmacokinetics ; Male ; Tablets ; Tandem Mass Spectrometry ; Therapeutic Equivalency ; Valsartan ; administration & dosage ; adverse effects ; blood ; pharmacokinetics ; Young Adult

Objective To prepare controlled release microspheres of vascular endothelial growth factor(VEGF)& calcium alginate and observe their effect on proliferation of human umbilical vein endo- thelial cells(HUVEC)in order to provide theoretical basis for controlled release of VEGF facilitating an- giogenesis of tissue engineering bone.Methods VEGF-calcium alginate microspheres were prepared by using the needle extrusion/external gelation method to investigate physicochemical character and in vitro release of VEGF.According to the different ingredients added into the culture medium,the seconda- ry cultured HUVEC were divided into four groups,ie,control group,microsphere group,VEGF group and VEGF-calcium alginate microsphere group,in which the proliferation of the cultured HUVEC was ob- served with cell counting method,MTT method and flow cytometry.Results The calcium alginate mi- crospheres were revealed as spherical shape and evenly distributed,with mean grain diameter of(560?50)?m,carrying capacity of 0.72 ng/mg and the encapsulation efficiency of 54%.Smooth controlled re- lease in VEGF-alginate microspheres lasted for more than 10 days.Proliferation of the cultured HUVEC was accelerated the most in VEGF group at the beginning but in EGF-calcium alginate microsphere group at midanaphase compared with other groups,with statistical difference(P＜0.05).There was no statis- tical difference upon cell counting,cell activity and time point of cell cycle between control group and mi- crosphere group.Conclusion VEGF-sodium alginate microapheres can continue activity of VEGF,re- lease VEGF for over 10 days and promote proliferation cultured HUVEC for a long time.

Objective To evaluate therapeutic effects and toxicity of advanced non-small cell lung cancer (NSCLC)treated by combining chemotherapy on ifosfamide(IFO)and vinorelbine(NVB).Methods 107 cases pa- tients with advanced NSCLC were enrolled.IFO was given in a dosage of 1.5g/m~2 on day 1 to 4.and NVB in a dosage of 25mg/m~2 on day 1 and 8.It was repeated every three or four weeks,up to two to four cycles.Results Two patients had complete response and 40 patients had partial response.The overall response rate was 47.7% ,the median survival time 10.3 months,1-year and 2-year survival rate was 42% and 12.3%,respectively.The main toxicity was bone marrow suppression.Conclusion The regimen is effective,sale and tolerable in advanced non- small cell lung cancer therapy.

Adult ; Bile Duct Neoplasms ; diagnosis ; metabolism ; pathology ; surgery ; Bile Ducts, Intrahepatic ; Carcinoma, Hepatocellular ; metabolism ; pathology ; Carcinoma, Squamous Cell ; diagnosis ; metabolism ; pathology ; surgery ; Cholangiocarcinoma ; diagnosis ; metabolism ; pathology ; surgery ; Cholecystectomy ; methods ; Diagnosis, Differential ; Hepatectomy ; methods ; Humans ; In Situ Hybridization ; Keratin-19 ; metabolism ; Keratin-7 ; metabolism ; Keratin-8 ; metabolism ; Magnetic Resonance Imaging ; Male ; RNA, Viral ; metabolism ; Tomography, X-Ray Computed

Non-small cell lung cancer (NSCLC) patients, with sensitive epidermal growth factor receptor (EGFR) mutations react well to tyrosine kinase inhibitors (TKIs). However, the efficacy of TKIs on patients with the same mutant types differs dramatically. It is implied that the different quantities of mutant alleles could be one of the reasons underlying. Patients with high abundance of EGFR mutation might benefit more from TKIs. There are no universal standards for the definition of EGFR mutant abundance. Abundance could be semi-quantified according to the different sensitivities of detection methods, quantified with quantifying detection techniques such as digital PCR or next generation sequencing, or quantified based on the expression of mutant proteins. hTe different abundances of primary and metastatic diseases could reflect the heterogeneity of the tumors. The pre-treatment level or the dynamic change of EGFR mutant abundance could help observe the course of the diseases and predict the efficacy of TKIs. TKIs resistance could be detected by change of abundance prior to image manifesta-tions. Besides, the abundance of T790M could also predict drug efficacy and resistance of the first and third generation TKIs. Thus the detection of EGFR mutant abundance has important clinical significance. The standardization and correction of abun-dance needs more exploration.

OBJECTIVETo evaluate the clinical efficacy and efficacy sustainable time of acupuncture in knee osteoarthritis (KOA).

METHODSThe non-randomized concurrent control trial was adopted. One hundred and ninety-three cases of KOA were divided into an immediate acupuncture group (group A, 97 cases) and a delayed acupunc-weeks at the end of treatment. In group B, the same acupuncture therapy was applied after waiting 4 weeks. The acupoints in the two groups were Liangqiu (ST 34), Dubi (ST 35), Zusanli (ST 36), Yanglingquan (GB 34), Yinlingquan (SP 9), Xuehai (SP 10), Xiyan (EX-LE 4), Xiyangguan (GB 33). WOMAC (Western Ontario and McMasters Universities Osteoarthritis) was used for the assessment of the primary index and VAS (visual analogue scale) was for the secondary index. The evaluation was accomplished by the patients at the beginning of trial, on the 4th and 8th weeks. In each group, 72 patients finished the trial and the data of the lost cases were included in the final data analysis.

RESULTSIn the 4th week of trial, WOMAC score was (25. 8+/-22.0) in group A difference (P<0. 001). VAS scorewas (31. 8+/-24. and was (43.8+/-22.2) in group B, indicating the significant 6) in group A and was (56. 6 +/-25. 8) in group B, indicating very significant difference (P<0. 001). In the 8th week, the efficacy was reduced slightly in the follow-up of group A, but it was improved apparently as compared Acupuncture relieves joint pain and improves joint function obviously.by th patiĩeffr,a Mtaetfti-?an tf ri-with that before treatment.

CONCLUSIONAcupuncture relieves joint pain and improves joint function obviously.The effect of acupuncture is still sustainable in 4 weeks after terminating the treatment.

Acupuncture Points ; Acupuncture Therapy ; Adult ; Aged ; Arthralgia ; therapy ; Female ; Humans ; Male ; Middle Aged ; Osteoarthritis, Knee ; therapy ; Treatment Outcome

OBJECTIVETo observe the clinical effects of combined type external fixator in treating complex tibial metaphyseal fractures.

METHODSFrom January 2007 to July 2012, 34 patients with complex tibial metaphyseal fractures were treated with combined type external fixator in different stagings. There were 23 males and 11 females, with a mean age of 41.3 years (ranged, 16 to 63), and the course of disease were from 1 h to 8 d. In the patients, 31 cases were open fractures, 11 cases with type II, 13 cases with type III A, 7 cases with type III B according with Gustilo classification; 19 cases were tibia plateau fractures, 6 cases with type II, 1 case with type IV, 5 cases with type V, 7 cases with type VI according to Schatzker classification; 15 cases were distal tibial fractures (one were bilateral fractures), 2 fractures with type A2, 1 fracture with type A3, 1 fracture with type C1, 5 fractures with type C2, 7 fractures with type C3 according to AO classification. Rasmussensn scoring system and AOFAS Ankle Hind-foot Scale were respectively used to assess the joint function of knee and hip.

RESULTSWound surface of 19 patients obtained at phase I healing and 15 patients obtained at phase III healing. Superficial wound infections occurred in 2 cases and bone non-union necessitated reoperation occurred in 2 cases (final fractures obtained bone healing after the second operation). All patients were followed up from 6 to 38 months with a mean of 14.3 months. At the final follow-up,according to Rasmussensn scoring system, 5 fractures got excellent results, 11 good, 3 fair, the mean Rasmussen score was 23.58 +/- 3.98; according to AOFAS Ankle Hind-foot Scale, 5 fractures got excellent results, 8 good, 3 fair, the mean AOFAS Ankle Hind -foot Scale was 80.75 +/- 14.21.

CONCLUSIONCombined type external fixator can well maintain the stability of the fractures, had advantages of low incidences of soft tissue complications and less influence to joint motion in treatment of complicated tibial metaphyseal fractures. However there were some limitations in long-term use.

Adolescent ; Adult ; Female ; Follow-Up Studies ; Fracture Fixation ; instrumentation ; methods ; Humans ; Male ; Middle Aged ; Radiography ; Recovery of Function ; Tibial Fractures ; diagnostic imaging ; physiopathology ; surgery ; Treatment Outcome ; Young Adult

This paper is aimed to develop rapid, sensitive and convenient HPLC-MS/MS methods for the quantification of levosimendan and its metabolites OR-1855 and OR-1896 in human plasma. According to the different natures of the compounds, two sets of liquid chromatography and ionization modes were used for determination the concentration of levosimendan and its metabolites OR-1855 and OR-1896 in human plasma, separately. Following protein precipitation with methanol, the levosimendan and internal standard (rosuvastatin) were separated on a Capcell MG III C18 column (35 mm x 2.0 mm ID, 3 microm) with the mobile phase consisted of methanol-15 mmol x L(-1) ammonium acetate-formic acid (55: 45: 0.02, v/v/v). A tandem mass spectrometer equipped with electrospray ionization source was used as the detector and operated in the negative ion mode. Its metabolites OR-1855, OR-1896 and internal standard doxofylline were extracted from plasma by liquid-liquid extraction with ethyl acetate. Chromatographic separation was performed on a Zorbax Extend C18 column (150 mm x 4.6 mm ID, 5 microm) with the mobile phase consisted of methanol-15 mmol x L(-1) ammonium acetate-formic acid (65 :35 :0.1, v/v/v). A tandem mass spectrometer equipped with electrospray ionization source was used as the detector and operated at the positive ion mode. The linear concentration ranges of the calibration curves for levosimendan and OR-1855 and OR-1896 were 0.10-50.0 ng x mL(-1), 0.20-100 ng x mL(-1), 0.20-100 ng x mL(-1), respectively. The lower limits of quantification of levosimendan and OR-1855 and OR-1896 were 0.10 ng x mL(-1), 0.20 ng x mL(-1), 0.20 ng x mL(-1), respectively. The methods proved to be sensitive, simple and rapid, and suitable for the pharmacokinetic study of levosimendan injection.
Acetamides ; blood ; Cardiotonic Agents ; blood ; metabolism ; Chromatography, High Pressure Liquid ; methods ; Humans ; Hydrazones ; blood ; metabolism ; Male ; Pyridazines ; blood ; metabolism ; Spectrometry, Mass, Electrospray Ionization ; methods ; Tandem Mass Spectrometry ; methods

The in situ gel systems can form gel in situ after administration to achieve sustained release, thus provides a promising strategy for drug delivery systems. The aim of this study was to design and prepare in situ gel systems for the oral delivery of ibuprofen (IBU-ISG) and study its pharmacokinetics in Beagle dogs. The characteristics of the basic material of gellan gum (Kelcogel, Kel) and sodium alginate (Manugel, M) were studied through investigating the complex viscosity of the Kel or M solution with or without different concentrations of calcium ion or sodium citrate to ascertain the amount range of the excipients. The measurement of complex viscosity of the solution (0. 5% Kel and 1% M) with different concentrations of sodium citrate and calcium ion was carried out to select the suitable proportion of calcium ion and sodium citrate. The formulation of binary IBU-ISG was optimized by monitoring the complex viscosity before gelling in vitro release property. The optimized formulation contains 1.0% sodium alginate, 0.5% gellan gum, 0. 21% sodium citrate and 0.056% calcium chloride. A single oral dose of IBU-ISG and reference formulation (IBU suspension) were given to each of the 6 healthy Beagle dogs, ibuprofen in plasma at different sampling times was determined by RP-HPLC. The pharmacokinetics parameters in 6 Beagle dogs were calculated. The Tmax of IBU-ISG and reference formulation were (1.8 +/- 0.6) and (0.4 +/- 0. 1) h. The Cmax values were (29.2 +/- 7.6) and (37.8 +/- 2.2) microg x mL(-1). The T(1/2) were (2.3 +/- 0.5) and (2.0 +/- 0.9) h, and the AUC(0-t) were (131.0 +/- 38.6) and (117.3 +/- 23.1) microg x mL(-1) x h, respectively. The binary IBU-ISG was successfully prepared.
Administration, Oral ; Alginates ; chemistry ; Analgesics, Non-Narcotic ; administration & dosage ; blood ; pharmacokinetics ; Animals ; Area Under Curve ; Calcium Chloride ; chemistry ; Citrates ; chemistry ; Delayed-Action Preparations ; Dogs ; Drug Compounding ; methods ; Drug Delivery Systems ; Excipients ; Female ; Glucuronic Acid ; chemistry ; Hexuronic Acids ; chemistry ; Ibuprofen ; administration & dosage ; blood ; pharmacokinetics ; Male ; Polysaccharides, Bacterial ; chemistry ; Viscosity

AIM:To investigate the role of autophagy in inhibition of human lung cancer PC 9 cell proliferation by ursolic acid(UA)as well as the underlying mechanism.METHODS:MTT assay and Trypan blue exclusion test were performed to analyze the effect of UA on the proliferation of PC 9 cells.The PC9 cells were treated with UA,and autophagy was observed under fluorescence microscope through acridine orange staining.The expression of autophagy-associated pro-teins LC3 and ATG5 in the PC9 cells were detected by Western blot.The effect of UA,3-methyladenine(3-MA)3-MA or their combination on the cell viability was measured by MTT assay.RESULTS:The viability of PC9 cells was significantly inhibited by UA(P<0.05 or P<0.01).The number of bright red fluorescence positive cells was significantly increased after treatment with UA.The protein expression of LC3-II and ATG5 was significantly up-regulated compared with control group(P<0.01).Furthermore,combination of UA and 3-MA resulted in a substantial decrease in cell viability compared with using UA alone(P<0.01).CONCLUSION: UA inhibits the proliferation and induces the autophagy of the PC 9 cells,in which autophagy plays a protective role.The inhibition of autophagy significantly promotes the death of the PC 9 cells induced by UA.