Physiologically based pharmacokinetic model (PBPK), a mechanistic mathematic model, which can simulate the absorption, distribution, metabolism and excretion of drugs, is being more widely used in pharmaceutical research and development areas. This article reviews primarily the recent advances in the procedure of establishing a PBPK model, including specifying of the PBPK model structure, specification of the tissue model, writing of equations, set of model parameters, simulation and evaluation. Application significance, major challenges and future developments of PBPK model in pharmaceutical areas are also discussed.
Animals ; Biological Transport ; Computer Simulation ; Humans ; Models, Biological ; Pharmaceutical Preparations ; chemistry ; metabolism ; Pharmacokinetics ; Software ; Tissue Distribution

According to the existing Provisions for Drug Registration (SFDA Order No. 28), applications for new drugs of traditional Chinese medicine are divided into two parts: the applications for drug clinical trial and for drug production (including new drug certificate). It will last for about 10 years from the application for drug clinical trial to get approving, and it also remains many problems and the low probability to succeed. From the sight of pharmaceutical review, there are mainly two aspects of regulatory compliance and technical issues, mainly for changes without approval of the competent authorities of the country. For example, sample preparation and approval of clinical trial process are significant changes. Technical problems are reporting incomplete data or information submitted does not comply with the technical requirements for review, such as: production process validation does not provide information, the preparation of samples for clinical trials and field inspection, production information, or the information provided does not meet the technical requirements. This paper summarizes the frequently asked questions and to make recommendations to advise applicants concerned, timely detection of problems, avoid risk, improving the quality and efficiency of the application for registration.
China ; Drug Approval ; legislation & jurisprudence ; Drug Evaluation ; legislation & jurisprudence ; Humans ; Legislation, Drug ; Medicine, Chinese Traditional

BACKGROUND:Metabolic syndrome greatly harms the human body, and is affected by many factors. Through constructing diet-induced animal models, we can better analyze the relationship between nutritional factor and metabolic syndrome, and provide reliable references for the clinical treatment of this disorder. OBJECTIVE:To construct obese mouse models with high-fat diet feeding and discuss the relationship between nutritional factor and metabolic syndrome. METHODS:Thirty mice were selected and randomly divided into model group (n=20) and control group (n=10), and were fed with high-fat and normal animal feeds for 10 consecutive weeks. RESULTS AND CONCLUSION:Compared with the control group, after 1 week of feeding with high-fat animal feeds, body weight of mice in the model group raised, and differences gradualy increased with the feeding time increased. After 8 weeks of feeding, body mass index of mice in the model group significantly raised (P < 0.05). After 4 weeks of feeding, fasting venous blood glucose level of mice in the model group significantly raised, and showed a gradual rise trend with feeding time. After 5 weeks of feeding, fasting insulin level of mice in the model group also began to rise. The oral glucose tolerance test showed that mice in the model group showed a gradual downward trend of glucose tolerance with feeding time. After 8 weeks of feeding, serum levels of total cholesterol and high density lipoprotein cholesterol in the model group significantly raised (P < 0.05). After 10 weeks of feeding, serum levels of triacylglycerol, total cholesterol, low density lipoprotein cholesterol and high density lipoprotein cholesterol in the model group raised (P< 0.05). The results demonstrate that obese mouse models were successfuly constructed with high-fat diet feeding, which can simulate the natural progression of metabolic syndrome in human, moreover, the nutritional factor is closely related to metabolic syndrome.

The publication of the scientific theses and their management are significant for the development of technology and science in the hospital.Therefore.they play an important role iU the hospital management.The retrospective analysis on the theses that published in the last 5 years and embodied by SCI was conducted using the statistics method and analyzed the first 10 departments in the published theses in this paper.The specialty of our hospital and the shortcoming in the scientific research was concluded from the analysis result.The amount of the theses increased steadily,and the research capability of the key subjects and key departments were promoted.The amount and the quality of the theses reflected an important indicator of the development strategy that means to develop the hospital through science.technology and education.Therefore,these conclusions could offer some valuable information to the manage department of t}le hospital.

ObjectiveTo investigate the effect of β-adrenergic receptor(β2AR) stimulation on vascular smooth muscle cell apoptosis in physiological state and receptor overexpression model.Methodsβ2AR overexpression model was established by transgenic techniques. Hoechst 33342 staining as well as flow cytometer(FCM) detected were chosen to measure the incidence of vascular smooth muscle cell apoptosis.ResultsVascular smooth muscle cell exhibited significantly fewer viable cell rate when stimulated with β2AR agonist isoproteronol for 48 hours compared with control (P<0.01),while no difference at the time point of 24 hours. Much fewer viable rate detected by FCM and high apoptotic rate by Hoechst staining were observed when VSMCs overexpressing β2AR were stimulated with isoproteronol for 24 hours (P<0.01).ConclusionStimulation of physiological and overexpressing β2AR could induce apoptosis of vascular smooth muscle cell.

The aim of this study was to investigate the effect of Bu-Shen-An-Tai recipe (BSATR) and its two components (Bushen recipe, and Huoxue recipe) on endometrial morphology during peri-implantation in superovulated mice. Mice were randomly divided into five groups, including the normal (N), model (M), Bushen (BS), Huoxue (HX) and Bu-Shen-An-Tai (BH) groups. The uteri were collected on day 4 of pregnancy, and the endometrium thickness, microvessel density (MVD) and number of pinopodes observed. Compared with the M group, the endometrial thickness in the BS, HX and BH groups was significantly increased and there was a significant difference in endometrial thickness between the BS and the BH groups. The mean MVD was significantly lower in the M group than in the N group, and there was a significant increase in MVD in the BS, HX and BH groups as compared with the M group. Compared with the M group, the pinopode scores in the endometrium were significantly increased in the HX and BH groups; and the BS group had significantly higher pinipode scores than the HX and BH groups. In conclusion, the results of the present study demonstrated that the recipes (Bushen, Huoxue and BSATR) could improve the endometrial environment by regulating the endometrial thickness, MVD and the number of pinopodes at the window of implantation. Moreover, the Huoxue recipe and the BSATR were more efficient than the Bushen recipe, with the BSATR tending to have the most beneficial effects.

OBJECTIVETo study the effect of Guishen Pill (GSP) on expression levels of Oct-4, MVH, and Egr-1 in mice with diminished ovarian reserve (DOR).

METHODSTotally 40 female C57BL/6J mice were randomly divided into 4 groups, the normal control group, the model group, the GSP group, and the dehydroepiandrosterone (DHEA) group, 10 in each group. Pregnant mare serum gonadotropin (PMSG), human chorionic gonadotropin (HCG), and prostaglandin F2α (PGF2α) were sequentially administrated to produce superovulation. The DOR model was established by exposing to ozone inhalation. Mice in the GSP group were intragastrically administered with GSP at 0.3 mL. Those in the DHEA group were intragastrically administered with DHEA at 0.3 mL. Equal volume of normal saline was intragastrically administered to mice in the normal control group and the model group. All mice wer treated for 21 days. Serum levels of estrogen (E2), progestogen (P), and anti-Müllerian hormone (AMH) were measured by ELISA. Changes of Oct-4, anti-AMH, and early growth response gene-1 (Egr-1) mRNA in ovaries were dtected by Real-time PCR.

RESULTSCompared with the model group, serum levels of E2, P, and AMH, as well as contents of estrogen receptor (ER), progestogen receptor (PR), MVH, and Oct-4 mRNA significantly increased in the GSP group and the DHEA group (P < 0.05).

CONCLUSIONGSP could improve expression levels of Oct-4, MVH, and Egr-1 mRNA in DOR mice and their ovarian function.

Animals ; Anti-Mullerian Hormone ; metabolism ; Dehydroepiandrosterone ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Early Growth Response Protein 1 ; metabolism ; Estrogens ; Female ; Mice ; Mice, Inbred C57BL ; Octamer Transcription Factor-3 ; metabolism ; Ovarian Reserve ; Ovary ; Pregnancy ; Receptors, Estrogen ; metabolism ; Superovulation

12E7 Antigen ; Adnexa Uteri ; surgery ; Adult ; Aged ; Aged, 80 and over ; Antigens, CD ; metabolism ; Cell Adhesion Molecules ; metabolism ; Diagnosis, Differential ; Female ; Follow-Up Studies ; Granulosa Cell Tumor ; drug therapy ; metabolism ; pathology ; surgery ; Humans ; Hysterectomy ; methods ; Inhibins ; metabolism ; Middle Aged ; Neoplasm Recurrence, Local ; Neoplasm Staging ; Ovarian Neoplasms ; drug therapy ; metabolism ; pathology ; surgery ; Survival Rate ; Vimentin ; metabolism

Objective To investigate the short?term functional connectivity (FC) changes of default mode network (DMN) after liver transplantation (LT) by using seed?based functional connectivity analysis of resting?state functional MRI (rs?fMRI). Methods Eighteen cirrhotic patients as transplant candidates and 20 healthy controls were included in this study. All the patients underwent rs?fMRI examination before and one month after LT. The data were analyzed using DPARSF and REST software. Seed?based functional connectivity analysis was used to isolate the DMN. The posterior cingulate cortex (PCC) was chosen as seed region for the DMN map. Maps of the DMN were compared among the groups. Values of Z reflecting the functional connectivity of 3 groups were obtained. Two?sample t?test was performed to explore the DMN difference between cirrhotic patients and controls, and we used paired t tests to examine for any differences in functional connectivity before and after LT. Pearson correlation analysis was performed to explore the relationship between the changes of functional connectivity with that of clinical indexes and neuropsychological test scores pre?and post?LT. Results Typically spatial distributions of the DMN were found in all the groups. According to paired t test, post?LT patients showed increased FC in left medial prefrontal cortex (t=3.31, P<0.05), while decreased FC in left precuneus and left lateral temporal cortex (t=-3.37,-4.53,respectively, both P<0.05). Compared to healthy controls, pre?LT patients showed decreased FC in the right precuneus, bilateral medial prefrontal cortex, bilateral inferior parietal cortex, and bilateral lateral temporal cortex(t=-4.32—3.00, all P<0.05), and post?LT patients showed decreased FC in right precuneus, left posterior cingulate cortex, bilateral inferior parietal cortex, and bilateral lateral temporal cortex(t=-4.33—2.99,all P<0.05). Pearson correlation analysis revealed positively correlation between the changes of functional connectivity in left medial prefrontal cortex with that of DST (r=0.543, P=0.02). Conclusions This study found that the DMN FC of post?LT patients still lower than that of healthy controls one month after LT. The left medial prefrontal cortex was the first brain region that showed increased FC, while the FC of some regions continued to decrease, suggesting that brain function reorganization can continue after LT. Rs?fMRI can be used to observe the DMN changes in post?LT patients.

Objective:Osteoprotegerin (OPG) is a key molecule negatively regulating osteoclast differentiation and activation; and the conserved mycobacterial heat shock 70 (HSP70) peptide p111-125 has also been found to inhibit inflammation reactions in chronic arthritis. BaculoDirectTM baculovirus expression system was selected to express recombinant OPG-HSP70 in insect cells.Methods:The human functional fragment (p22-194) of OPG and functional fragment (p111-125) of mycobacterial HSP70 gene were cloned into the transfer vector pENTRTM/SD/D-TOPO. The recombinant plasmid was performed an LR reaction with the BaculoDirectTM Linear DNA to generate recombinant baculovirus DNA. The cultured Sf9 insect cells were directly transferred with the recombinant baculovirus DNA,and the pure recombinant baculovirus was obtained. Then recombinant baculovirus was infected Sf9 insect cells again to express the OPG-HSP70 gene.Results:The target protein was detected at the time of 48h post infection,reached at highest yield at the time of 72h post-infection. A 28kDa protein immunostaining band was detected by Western blotting from lysate of those cells.And the purified protein was obtained by using Ni-NTA system. Functional stuies on the fusion protein showed it significantly reduce osteoclast cell number[(3.10?0.640) cells under each microscope field in treatment group by comparing to (10.70?0.817)cells in the control group] in the osteoclast inhibition test,and reduce the inflammation reaction in a delayed type hypersensitivity (DTH) mice model (P