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.

Background: The objective of this study was to assess the variation in academic citation and social media mentions across orthopedic subspecialties in general orthopedic surgery journals. Methods: An internet-based study was performed of 666 articles from four orthopedic journals published from January 2018 to February 2019. Each publication was categorized by its subspecialty within orthopedics: arthroplasty, hand and upper extremity, foot and ankle, orthopedic oncology, pediatric orthopedics, shoulder, spine, sports medicine, orthopedic trauma, basic science, and miscellaneous. For each publication, academic citations were quantified using Google Scholar and Web of Science, and social media mentions were quantified using Twitter. Comparisons of continuous data among various subspecialties were performed using analysis of variance. Results: The average number of citations per publication was 7.4 ± 9.0 on Google Scholar, 4.5 ± 5.3 on Web of Science, and 2.8 ± 8.7 on Twitter. The number of academic citations differed significantly by subspecialty on Google Scholar (p < 0.001) and Web of Science (p < 0.001). There was no difference in social media mentions on Twitter by subspecialty (p = 0.8). The most highly cited subspecialties, adjusted for number of publications, were arthroplasty, orthopedic oncology, and sports medicine, while the least highly cited subspecialties were hand and upper extremity, pediatric orthopedics, and orthopedic basic science. Conclusions There is significant baseline variation in the citation of orthopedic publications among various subspecialties. Our findings argue against the use of a uniform threshold to gauge scholarly success in orthopedic surgery. The variation in citation of orthopedic publications across subspecialties support the use of subspecialty-specific benchmarks to gauge academic productivity.

ObjectiveTo explore the association between angiotensin converting enzyme (ACE) gene insertion/deletion(I/D) polymorphism and cerebral infarction among Chinese people. MethodsThe ACE gene polymorphism was determined by PCR-RFLP in 242 patients with cerebral infarction and 283 controls. Multiple logistic regression was performed to explore the risk factors for cerebral infarction. ResultsAfter adjusting age, gender, alcohol drinking, smoking, education,history of diabetes mellitus and the primary hypertension, there was no significant association between ACE I/D polymorphism and cerebral infarction, either was hypertension and diabetes mellitus. The primary hypertension significanlly increased risk of cerebral infarction (OR=7.28,P =0.000). Both ACE ID/DD genotype and the primary hypertension showed a significant gene-environment interaction(r=1.62,OR=7.29), something as super multiplicative type 2 interaction. ConclusionAlthough ACE gene polymorphism is not risk factors of cerebral infarction, but ID/DD genotype had shown significant gene-environment interaction with primary hypertension in occurrence of cerebral infarcion.

Objective To analyze the risk factors for delayed gastric emptying (DGE) after pancreaticoduodenectomy.Methods Clinical data of 213 patients who underwent pancreaticoduodenectomy at our hospital from January 1996 to December 2011 was retrospectively analyzed.Results The overall incidence of DGE was 40.8％ (87/213).The incidence of grade A,grade B and grade C DGE was 14.1％ (30/213),14.5 ％ (31/213) and 12.2％ (31/213) respectively.Median postoperative hospital stay was significantly prolonged in patients with DGE:30.5,32 and 61 days for grade A,B and C respectively versus 21 days in patients without DGE (x2 =66.171,P =0.000).Univariate analysis showed that operation time (≥420 min),intraoperative blood loss (≥ 1000 ml),Child alimentary reconstruction and pancreatic fistula were risk factors for postoperative DGE.Multivariate analysis using Logistic regression identified three variables as independent risk factors associated with postoperative DGE,namely,Child alimentary reconstruction (OR =2.098),intraoperative blood loss (≥ 1000 ml) (OR =2.525) and pancreatic fistula (OR =4.821).Grade C DGE was more frequently seen in patients suffering from postoperative pancreatic fistula.Conclusions The incidence of DGE after pancreaticoduodenectomy is still high.DGE prolongs the postoperative hospital stay significantly.The incidence of DGE could be reduced by Roux-en-Y reconstruction and reducing intraoperative blood loss.Postoperative pancreatic fistula is significantly associated with DGE,especially grade C DGE.