The purpose of this study is to investigate the effects of multiple-trough sampling design and nonlinear mixed effect modeling (NONMEM) algorithm on the estimation of population and individual pharmacokinetic parameters. Oxcarbazepine and tacrolimus were used as one-compartment and two-compartment model drugs, respectively. Seven sampling designs were investigated using various number of trough concentrations per individual ranging from 1-4. Monte Carlo simulations were performed to produce state-steady trough concentrations. One-compartment model was used to fit simulated data from oxcarbazepine and tacrolimus. The accuracy and precision of the estimated parameters were evaluated using the median prediction error (PE), the median absolute PE and boxplot. The results indicated that trough concentrations could yield reliable estimates of apparent clearance (CL/F). For oxcarbazepine, as the number of trough concentrations per subject increased, the accuracy and precision of CL/F, between-subject variability (BSV) of CL/F and residual variability (RUV) tended to be improved. For tacrolimus, however, although no improvement were observed in the accuracy of CL/F and BSV of CL/F, the PE distribution ranges were significantly narrowed and the RUV estimates were less bias and imprecise. In terms of algorithm, Monte Carlo importance sampling (IMP) and IMP assisted by mode a posteriori estimation (IMPMAP) were consistently better than other methods. Additionally, the sampling design had no significant effects on the individual parameter estimates, which were only depended on the interaction between BSV and RUV in various algorithms. Decreased in BSV and RUV levels can improve the accuracy and precision of the estimation for both population and individual pharmacokinetic parameter estimates.
Algorithms ; Bayes Theorem ; Carbamazepine ; analogs & derivatives ; pharmacokinetics ; Humans ; Immunosuppressive Agents ; pharmacokinetics ; Models, Biological ; Monte Carlo Method ; Nonlinear Dynamics ; Regression Analysis ; Tacrolimus ; pharmacokinetics

Evodiamine is the natural component extracted from Euodiae Fructus. Recently, growing evidence has proved that evodiamine has great effects on suppressing cell viability and proliferation, arresting cell cycle, inducing apoptosis, promoting autophagy, inhibiting the formation of microvascular angiogenesis as well as affecting epigenetic modification in cancer. Recent studies have continuously revealed related signal pathways involved in evodiamine such as PI3K-Akt and JAK-STAT pathways, as well as the impact of evodiamine on survivin, vascular endothelial growth factor and miRNAs. With the development and synthesis of evodiamine derivatives and related herbal formulations, the understanding of antitumor activity of evodiamine is gradually deepening. The important clinical significance and market value of evodiamine can be prospected.

Animals ; Hypothermia ; blood ; Hypoxia ; blood ; Malondialdehyde ; blood ; Myocardial Ischemia ; blood ; Rabbits ; Superoxide Dismutase ; blood

This study was aimed to develop a maximum a posteriori Bayesian (MAPB) estimation method to estimate individual pharmacokinetic parameters based on D-optimal sampling strategy. Meanwhile, the performance of MAPB was compared with the multiple linear regression (MLR) method in terms of accuracy and precision. Pharmacokinetic study of pioglitazone was employed as the example case. The population pharmacokinetics was characterized by nonlinear mixed effects model (NONMEM). The sparse sampling strategy (1-4 points) was identified by D-optimal algorithm using WinPOPT software. The simulated data generated by Monte Carlo method were used to access the performance of MAPB and MLR. As the number of samples per subject decreased, the accuracy and precision of MAPB method tended to get worse. The estimation for CL and Vby MAPB using D-optimal two-point design had less bias with low inter-individual variability, and had more bias and imprecision with high residue variability. The estimation of AUC by MAPB using D-optimal 2 points design had similar accuracy and precision to MLR. However, MAPB estimation was better than MLR while adjusting the sampling time to one hour. Overall, the MAPB method had similar predictive performance as MLR, but MAPB could provide more pharmacokinetic information with higher sampling flexibility.
Area Under Curve ; Bayes Theorem ; Humans ; Hypoglycemic Agents ; pharmacokinetics ; Linear Models ; Monte Carlo Method ; Nonlinear Dynamics ; Thiazolidinediones ; pharmacokinetics

AIM: To observe of cataract phacoemulsification and intraocular lens implantation in patients with postoperative tear film, and to explore its clinical significance.
METHODS: A total of 106 patients ( 140 eyes ) undergone phacoemulsification were randomly chosen. Subjective dry foreign body sensation were observed at six nodes of period 1d, 1, 2, 3wk, and 1mo. Corneal fluorescein ( FSC ) , basal tear secretion ( SIT ) and tear film break-up time ( BUT) were used to detect functional changes of the tear film. And the correlation between tear film stability and corneal sensitivity was analyzed.
RESULTS: Dry eye cumulative score of postoperative 1d, 1, 2wk was higher than preoperative ( t= 8. 53, P=0.000;t=6. 27, P=0. 000; t=9. 02, P=0. 000). There was no significant difference in dry eye cumulative score at postoperative 3wk, 1mo compared with preoperative ( t=1.91, P= 0. 824; t= 1. 27, P= 0. 069). Corneal epithelial fluorescein staining points of postoperative 1d, 1, 2wk were increased compared with preoperative (t=11. 64, P=0. 000;t=9. 61, P=0. 000; t=8. 87, P=0. 001). There was no significant difference in corneal epithelial fluorescein staining points of postoperative 3wk and 1mo compared with preoperative (t=2. 52, P=0. 746; t=1. 16, P=0. 094). Corneal sensitivity detection values of postoperative 1d, 1, 2wk were significantly higher than that of preoperative (t=9.61, P=0.000;t=9.27, P=0.000;t=11.39, P=0.024), and there was no difference postoperative 3wk and 1mo compared with preoperative (t=1. 19, P=0. 562;t=2. 17, P=0. 501).
CONCLUSION: Phacoemulsification with intraocular lens implantation will reduce the tear film stability in the short term, but after a long rest will be improved to a certain extent.

OBJECTIVETo discuss the novel biomarkers of microRNAs in prostate cancer.

DATA SOURCESThe literatures about microRNAs and prostate cancer cited in this review were obtained mainly from Pubmed published in English from 2004 to 2012.

STUDY SELECTIONOriginal articles regarding the novel role of microRNAs in prostate cancer were selected.

RESULTSMicroRNAs play an important role in prostate cancer such as cell differentiation, proliferation, apoptosis, and invasion. Especially microRNAs correlate with prostate cancer cell epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs), drug sensitivity, cancer microenvironment, energy metabolism, androgen independence transformation, and diagnosis prediction.

CONCLUSIONSMicroRNAs are involved in various aspects of prostate cancer biology. The role of microRNA in the initiation and development of prostate cancer deserves further study.

Biomarkers ; analysis ; Drug Resistance, Neoplasm ; Humans ; Male ; MicroRNAs ; analysis ; physiology ; Prostatic Neoplasms ; diagnosis ; drug therapy ; pathology

To develop a parent-metabolite pharmacokinetic model for risperidone (RIP) and its major active metabolite (9-hydroxyrisperidone) and investigate their pharmacokinetics characteristics in healthy male volunteers, twenty-two healthy volunteers were orally given a single dose of 2 mg RIP. Plasma samples were collected in the period of 96 hours and concentrations of RIP and 9-hydroxyrisperidone were measured by a validated HPLC/MS method. CYP2D6 phenotypes were identified by the T1/2 of RIP and 9-hydroxyrisperidone according to the literature. Model structure identifiability analysis was performed by the similarity transformation approach to investigate whether the unknown parameters of the proposed model could be estimated from the designed experiment. Pharmacokinetics parameters were estimated using weighted least squares method, and the final pharmacokinetics model were tested and evaluated by Monte Carlo simulation. Eighteen volunteers were phenotyped as extensive metabolizers (EM) and four volunteers were identified as intermediate metabolizers (IM). The final model included central and peripheral compartment for both parent (RIP) and metabolite (9-hydroxyrisperidone) respectively. Model structure identifiability analysis indicated that the proposed model was local identifiable. However, if the ratio of RIP converted to 9-hydroxyrisperidone was assumed to be 32% in EM, and 22% in IM, the model could be globally identifiable. The predicted time-concentration curve and AUC(0-t), C(max), T(max) of RIP and 9-hydroxyrisperidone estimated by the established model were in agreement with the observations and noncompartment analysis. Rate constant of RIP conversion to 9-hydroxyrisperidone was (0.12 +/- 0.08) h(-1) and (0.014 +/- 0.007) h(-1) for EM and IM, respectively. Elimination rate constants of RIP were (0.25 +/- 0.18) and (0.05 +/- 0.23) h(-1) for EM and IM, respectively. Model validation result showed that all parameters derived from the concentration data fitted well with the theoretical value, with mean prediction error of most PK parameter within +/- 15%. The established model well defined the disposition of RIP and 9-hydroxyrisperidone simultaneously and showed large inter-individual pharmacokinetics variation in different CYP2D6 phenotype. The model also provide a useful approach to characterize pharmacokinetics of other parent-metabolite drugs.
Adult ; Cytochrome P-450 CYP2D6 ; physiology ; Humans ; Isoxazoles ; pharmacokinetics ; Male ; Models, Biological ; Monte Carlo Method ; Paliperidone Palmitate ; Pyrimidines ; pharmacokinetics ; Risperidone ; pharmacokinetics

OBJECTIVEThe determination of antigenicity and immunogenicity of Leptospira interrogans genus-specific outer envelope proteins (OEPs) will offer evidence for developing universal leptospiral genetic engineering vaccine and detection kit.

METHODSIn this study, Ni-NTA affinity chromatography is used to purify the recombinant products rLipL21, rOmpL1/1, rOmpL1/2, rLipL32/1, rLipL32/2, rLipL41/1 and rLipL41/2 expressed by the major genotypes of four leptospiral OEPs of 15 serogroups. SDS-PAGE is applied to examine the expression and purity of the recombinant proteins. Rabbits are intracutaneously immunized with the recombinant proteins to obtain antisera. Microscope agglutination test (MAT) is used to measure the cross inmmunoagglutination titers of antisera. The OMPs of the reference standard strains belonging to 15 serogroups of L. interrogans in China and L. biflexa strain Patoc I are prepared using salt-denature method. By each of the antisera as the first antibody, Western blot assay is established to detect the natural expressions and immunoreactivity of the four OEPs.

RESULTSThe outputs of rLipL21, rLipL32/1, rLipL32/2, rLipL41/1l, rLipL41/2, rOmpL1/1 and rOmpL1/2 are 10%, 40%, 35%, 15%, 10%, 30% and 15%, respectively. Each the purified recombinant proteins shows a single fragment after SDS-PAGE. Each the rabbit antisera displays extensive cross immunoreactivity between the products expressed by different genotypes of the same gene and the MAT titers ranging from 1:2-1:128. All the four OEPs can be detectable in the OEPs preparations. However, LipL21 is found to exist only in L. interrrogans.

CONCLUSIONThe results of this study indicate that all the four OEPs are superficial genus-specific antigens of Leptospira which can be used as the candidate antigens of leptospiral universal vaccine and detection kit.

Animals ; Antibody Formation ; Antigens, Bacterial ; immunology ; Electrophoresis, Polyacrylamide Gel ; Genetic Engineering ; Immunization ; Leptospira interrogans ; classification ; immunology ; Membrane Proteins ; Rabbits ; Recombinant Proteins ; immunology ; Serotyping

AIMTo develop limited sampling strategy (LSS) for estimation of C(max) and AUC(0-t) and assessing the bioequivalence of two pioglitazone hydrochloride (PGT) preparations.

METHODSHealthy subjects (n = 20), enrolled in a bioequivalence study, were received 30 mg PGT po of reference or test formulation. The plasma concentration of PGT was determined by the validated HPLC method. A multiple linear regression analysis of the Cmax and AUC(0-t) against the PGT concentration for the reference formulation was carried out to develop LSS models to estimate these parameters. The models were internally validated by the Jackknife method and externally validated using simulated sets generated by Monte Carlo method. The best model was employed to assess bioequivalence of the two PGT formulations.

RESULTSThe linear relationship between pharmacokinetics parameters and single concentration point was poor. Several models for these parameters estimation met the predefined criteria (r2 > 0.9). The Jackknife validation procedure revealed that LSS models based on two sampling times (C1, C2.5 and C1.5, C2.5 for C(max); C1.5, C9 and C2.5, C9 for AUC(0-t) predict accurately. Mean prediction errors (MPE) were less than 3%, and mean absolute prediction error (MAE) were less than 9%. The prediction error (PE) beyond 20% was less than 5% of total samples. Model external validation by Monte Carlo simulated data indicated that the most informative sampling combinations were C1.5, C2.5 for C(max), and C1.5, C9 for AUC(0-t), respectively. MPE and MAE of the proposed models were less than 5% , and 9% respectively. The PE beyond 20% was less than 5% of the total. Bioequivalence assessment of the two PGT formulations, based on the best LSS models, provided results similar to those obtained using all the observed concentration-time data points, and indicated that the two PGT formulations were bioequivalent.

CONCLUSIONThe LSS method for bioequivalence assessment of PGT formulations was established and proved to be applicable and accurate. Thus, it could be considered appropriate for PGT bioequivalence study with inexpensive cost of sampling acquisition and analysis. Key words: pioglitazone hydrochloride; limited sampling strategy; Monte Carlo simulation; bioequivalence

Administration, Oral ; Adult ; Area Under Curve ; Chromatography, High Pressure Liquid ; Humans ; Hypoglycemic Agents ; administration & dosage ; blood ; pharmacokinetics ; Male ; Models, Biological ; Monte Carlo Method ; Sample Size ; Therapeutic Equivalency ; Thiazolidinediones ; administration & dosage ; blood ; pharmacokinetics

Fracture Fixation ; methods ; Hip Fractures ; surgery ; Humans ; Venous Thrombosis ; prevention & control