Aim To establish the pharmacokinetic principles of the zero-order release and the first-order release of mono-compartment drugs administered by non-parenteral route based on the release kinetics of the dosage forms and the intrinsic pharmacokinetic parameters of the active drug, such as the rate constants of the absorption and elimination, and the distribution volume of the drug. Methods By the Laplace transform and the compartmental analysis method, the pharmacokinetic behaviors of the zero-order release and the first-order release of mono-compartment drugs administered by non-parenteral routes were deduced with divisions of the dose being absorbed during the release phase and after the release has terminated. Results The pharmacokinetics of the non-parenteral administration of the zero-order release and the first-order release of mono-compartment drugs were established. Conclusion The pharmacokinetic theories of the zero-order release and the first-order release of mono-compartment drugs administered by non-parenteral route have been established. Since the zero-order release and the first-order release are the primary release patterns, the theory should be a key to explore the pharmacokinetics of the controlled/sustained release dosage forms.

AIM　To assess the pharmacokinetic profile of single doses of meloxicam in healthy Chinese volunteers. METHODS　The plasma concentrations of meloxicam after an oral dose of 15 mg to twenty healthy male volunteers were analized by means of a validated HPLC method. The pharmacokinetic parameters were subjected to Shapiro-Wilk test to determine whether these data were fitted to a normal distribution. RESULTS The twenty volunteers can be classified into extensive metabolizers and poor metabolizers according to pharmacokinetic parameters. The main parameters in the two groups obtained were as follows: T1/2 were 21±4 and 38±9 h, AUC0-∞ were 49±10 and 110±8 μg*h*mL-1, respectively. Even the AUC data in extensive metabolizers were 1.7 times as that reported in White volunteers following the same doses of meloxicam. CONCLUSION　There were significant individual differences in the pharmacokinetics of meloxicam in Chinese volunteers, which may be due to the genetic polymorphism of CYP2C9.

To study the drug-drug interaction of morinidazole and warfarin and its application, a sensitive and rapid liquid chromatography-tandem mass spectrometric (LC-MS/MS) method was developed for the determination of R-warfarin/S-warfarin in human plasma. In a random, two-period crossover study, 12 healthy volunteers received a single oral dose of 5 mg racemic warfarin in the absence and presence of morinidazole. Blood samples were collected according to a pre-designed time schedule. R-warfarin, S-warfarin and methyclothiazide were extracted with ethylether : methylenechloride (3 : 2), then separated on a Astec Chirobiotic V (150 mm x 4.6 mm ID, 5 microm) column using 5 mmol x L(-1) ammonium acetate (pH 4.0) - acetonitrile as mobile phase at a flow-rate of 1.5 mL x min(-1). The mobile phase was splitted and 0.5 mL x min(-1) was introduced into MS. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the negative ion mode. Quantification was performed using multiple reaction monitoring (MRM). The resolution of warfarin enantiomers is 1.56. The linear calibration curves for R-warfarin and S-warfarin both were obtained in the concentration range of 5 - 1 000 ng x mL(-1). Intra- and inter-day relative standard deviation (RSD) for R-warfarin and S-warfarin over the entire concentration range across three validation runs was both less than 10%, and relative error (RE) ranged from -4.9% to 0.7%, separately. The method herein described is effective and convenient, and suitable for the study of metabolic interaction between morinidazole and warfarin. The results showed that coadministration of warfarin with morinidazole did not affect the pharmacokinetics of either R-warfarin or S-warfarin.

A sensitive, rapid and accurate liquid chromatography-tandem mass spectrometric (LC-MS/MS) method with pre-column derivatization was developed for the simultaneous determination of erdosteine and its thiol-containing active metabolite in human plasma. Paracetamol and captopril were chosen as the internal standard of erdosteine and its active metabolite, respectively. Aliquots of 100 microL plasma sample were derivatized by 2-bromine-3'-methoxy acetophenone, then separated on an Agilent XDB-C18 (50 mm x 4.6 mm ID, 1.8 microm) column using 0.1% formic acid methanol--0.1% formic acid 5 mmol x L(-1) ammonium acetate as mobile phase, in a gradient mode. Detection of erdosteine and its active metabolite were achieved by ESI MS/MS in the positive ion mode. The linear calibration curves for erdosteine and its active metabolite were obtained in the concentration ranges of 5-3 000 ng x mL(-1) and 5-10 000 ng x mL(-1), respectively. The lower limit of quantification of erdosteine and its active metabolite were both 5.00 ng x mL(-1). The pharmacokinetic results of erdosteine and its thiol-containing active metabolite showed that the area under curve (AUC) of the thiol-containing active metabolite was 6.2 times of that of erdosteine after a single oral dose of 600 mg erdosteine tables in 32 healthy volunteers, The mean residence time (MRT) of the thiol-containing active metabolite was (7.51 +/- 0.788) h, which provided a pharmacokinetic basis for the rational dosage regimen.

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.

To study the metabolite excretion of theophylline, a rapid and specific method by liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) method for simultaneous determination of theophylline, 1, 3-dimethyluric acid (1,3-DMU), 3-methylxanthine (3-MX) and 1-methyluric acid (1-MU) in human urine was developed using theophylline-d6 and 5-fluorouracil as internal standards. Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the negative mode for mass spectrometric detection. After diluted with methanol and centrifuged, the analytes and ISs were separated on a XDB-Phenyl (150 mm x 4.6 mm, 5 microm) column with a mixture of water-methanol-formic acid (30 : 70 : 0.15) as mobile phase at a flow rate of 0.6 mL x min(-1). The linear calibration curves for theophylline, 1, 3-DMU, 3-MX and 1-MU were obtained in the concentration range of 1.0-250 microg x mL(-1), separately. The method herein described is effective and convenient, and can be used for determination of theophylline and its three metabolites. The results showed that urinary excretion ratio of theophylline, 1,3-DMU, 3-MX and 1-MU is approximately 1 : 3 : 1 : 2 in Chinese subjects, which is similar to the reported excretion pattern in Caucasian.

A chiral LC-MS/MS method for the simultaneous analysis of desvenlafaxine (DVS) enantiomers in human plasma was developed and applied to a pharmacokinetic study on 12 Chinese healthy volunteers. d6-Desvenlafaxine was used as internal standard (IS). Chromatographic separation was performed on the Astec Chirobiotic V chiral column (150 mm x 4.6 mm, 5 μm). The assay was linear over the concentration range of 0.500-150 ng x mL(-1) for both enantiomers (r2 > 0.99). The method was successfully applied to a stereoselective pharmacokinetic study of 100 mg desvenlafaxine sustained release tablets on 12 Chinese healthy volunteers under fasting conditions. The results showed that the pharmacokinetic parameters were similar to both enantiomers in Chinese healthy volunteers. The AUC(0-t), and C(max) of the two enantiomers were about 1.5 times higher than those of blacks and whites reported in the literature.

Objective To analyze the prevention and treatment of postoperative hemorrhage after pancreaticoduodenectomy. Methods The clinical data of 142 patients undergoing pancreaticoduedenectomy from Jan 1995 to Dec 2008 were retrospectively analyzed. Results The incidence of postoperative hemorrhage was 14.1% (20/142), the mortality caused by this complication was 35% (7/20). Among these patients, intra-abdominal hemorrhage occurred in seven cases, and gastrointestinal hemorrhage occurred in 14 cases, with one case suffering both. There were three and four cases of early and delayed intra-abdominal hemorrhage respectively. Early and delayed gastrointestinal hemorrhage occurred in three and eleven cases respectively. Univariate analysis showed that operative blood loss, blood transfusion, infection and pancreatic fistula were significantly associated with postoperative hemorrhage. Multivariate analysis using Logistic regression identified two variables as independent factors associated with postoperative hemorrhage, namely, infection(OR=6.918) and pancreatic fistula(OR=3.948). Conclusions The incidence and mortality of hemorrhage after pancreaticoduodenectomy is still high. Skillful operation and prevention of pancreatic fistula, infection and stress ulcer are the key paints for reducing postoperative hemorrhage. Proper treatments should be used according to the site, onset and severity of hemorrhage.

Objective To investigate the expression of Toll-like receptors(TLRs) in condyloma acuminatum(CA) lesions and their possible roles in the pathogenesis of CA. Methods The expressions of TLR1-10 mRNA level in the lesions of CA and in the cervix scrape cells from the patients with human papillomavirus(HPV) negative chronic cervicitis were detected by real-time quantitative fluorescent PCR. HPV typing was detected by HPV GenoArray test kit. Results Low-risk HPV type 6 and type 11 were the most prevalent types in the forty CA cases with positive rate of 77.5% and 55% respectively. 55% CA patients were found infected with more than two types of HPV. 35% CA patients were concurrently infected with high-risk HPV. The expressions of TLR3, 7, 8 mRNA were higher than other TLRs and the expression of TLR9 mRNA was lower than others in the lesions of CA. No significant differences of the TLR1-10 mRNA levels were found between HPV6 and HPV11 positive CA lesions, so did it between low-risk and high-risk HPV concurrent infected CA lesions. The expressions of TLR1-3, TLR5-8, TLR10 mRNA, especially TLR2, TLR7 and TLR8 in the lesions of CA were significantly higher than that in cervix scrape cells of HPV negative chronic cervicitis. There were no significant differences of TLR4 and TLR9 mRNA levels between the two groups. Conclusion There were higher expressions of some TLRs (3, 7, 8) and lower expression of TLR9 in the lesions of CA. Compared with HPV negative chronic cervicitis, the expressions of TLR1-3, TLR5-8, TLR10 mRNA in the lesions of CA were up-regulated. The expression profile of TLRs in different type of HPV infected CA lesions had no significant differences. Our results suggested that the expression profile of TLRs in CA may be associated with the HPV infection. Whether it was associated with the immune escape mechanism and persistent infection of HPV need further demonstration.

Purpose　To introduce a method to isolate cDNA clones using bacteriophage P1-derived artificial chromosome (PAC) or bacterial artificial chromosome (BAC) as probe for hybridization and try to find some novel genes related to hepatocellular carcinoma.　Methods　PAC 579 (D17S926 locus) and BAC 1529 (D17S1529 locus) in the deletion region of chromosome 17p13.3 in human hepatocellular carcinoma were chosen to screening the human liver cDNA library as probe for hybridization. The isolated positive cDNA clones were partially sequenced, then analyzed by computer comparison and Southern blot.　Results　After three cycles of screening, 78 and 8 candidate positive cDNA clones were isolated using PAC 579 and BAC 1529 probes respectively. Further analysis indicated 18 cDNA clones isolated by PAC 579 probe and 5 cDNA isolated by BAC 1529 probe were potential novel genes related to hepatocellular carcinoma.　Conclusions　The isolation of cDNA clones using PAC and BAC probes is effective and practical.