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

Objective To evaluate the practicality of MAGE-1 and MAGE-3 genes encoding proteins used as a target for immunotherapy in renal cell carcinoma and urinary transitional cell carcinoma patients. Methods Reverse transcriptase-polymerase chain reaction (RT-PCR) was used for detection of MAGE-1 and MAGE-3 genes in the specimens from renal cell carcinoma (n=18) and urinary transitional cell carcinoma (n=26),and in 10 specimens taken from the tumor surrounding tissues. Results Positive expression of MAGE-1 and MAGE-3 genes at mRNA was detected in 10(56%) and 11(61%),respectively,of 18 cases of renal cell carcinoma;and expression of both MAGE-1 and MAGE-3 in 8(44%).Out of 26 cases of urinary transitional cell carcinomas,16 (62%) expressed MAGE-1 and 15 (58%) expressed MAGE-3;and 12 (46%) expressed both MAGE-1 and MAGE-3.No expression of MAGE-1 or MAGE-3 was detected in 10 specimens from tumor surrounding tissues. Conclusions The tumor-specific antigens MAGE-1,MAGE-3 genes might be used as molecular markers and specific targets of immunotherapy and gene therapy for renal cell carcinoma and urinary transitional cell carcinoma.

Objective To investigate the radiographic characteristics of degenerative lumbar scoliosis (DLS) and its relationship to osteoporosis. Methods 229 cases (83 males, 146 females) of DLS from January 1998 to June 2005 were reviewed. The mean age was 56.8 years (ranged from 40 to 74 years). The Cobb angle and vertebral stability in coronal plane were measured in anteroposterior radiographs and the changes of lordosis in sagittal plane were observed in lateral radiographs. The bone mineral density(BMD) and T-Score of lumbar spine (L2-L4) were measured using Dual Energy X-ray Absorptiometry. Results The mean Cobb angle is 9.45??4.79?, 151 cases(66%) with the angle less than 10?, 60 cases (26%) with 10?-20?, and 18 cases (8%) with more than 20?. Right side scoliosis were found in 52% (120 cases), left side in 48% (109 cases). 159 cases (69%) companied with gradeⅠ(Nash-Moe) vertebra rotation, 54 cases (24%) with grade Ⅱ. And the vertebra rotation was most evident on scoliosis apex. There were 20 cases (9%) with more than 4 mm lateral translation between the lumbar vertebrae which were usually the apex vertebrae with the most degenerative changes. The physical lordosis decreased in most cases in which 16 cases (7%) developed lumbar or thoracolumbar kyphosis. And the kyphosis degree was not relevant to scoliosis Cobb angle. The mean T-Score of BMD measurement was -1.88?0.17, which was -1.49?0.14, -2.56?0.24, -2.89?0.50 for the groups of with Cobb angle 20? respectively. There were 153 cases (67%) with T10?), and 98 cases (43%) with T

Calcitonin ; blood ; Fluorine ; adverse effects ; Humans ; Occupational Exposure ; adverse effects ; Osteocalcin ; blood

OBJECTIVE:To investigate general regularity and characteristics of adverse drug reactions/events(ADR/ADE)in-duced by Dezocine injection,and to provide reference for safe and rational drug use in clinic. METHODS:Retrieved from Jiangsu Province ADR Database during Jan. 2009-Aug. 2016,ADR/ADE induced by Dezocine injection was analyzed statistically in re-spects of patient's gender and age,usage and dosage,organs/systems involved in ADR,clinical manifestations and outcome. RE-SULTS:Among 1290 ADR/ADE induced by Dezocine injection,there were 40 cases of severe ADR/ADE(3.10％);medical insti-tutions were main reporting units (1276 cases,98.81％). In ADR/ADE cases,female was more male,with ratio of male to fe-male was 1:1.45. ADR/ADE mostly occurred in 45-65 age group(43.49％). Intravenous medication was main route of administra-tion (1137 cases,88.14％). Initial dose of 577 cases was excessive dose (50.75％). ADR/ADE mainly involved gastrointestinal system (54.99％),central and peripheral nervous system (24.72％) and systemic lesions (5.20％). Severe ADR/ADE manifested as anaphylactic shock,palpitation and dyspnea,etc. But anaphylactic shock was not mentioned in drug package inserts. 1283 ADR/ADE(99.46％)were cured or improved . CONCLUSIONS:It is necessary to strengthen drug safety reevaluation of Dezocine injec-tion after being on the market,improve drug package inserts and enhance patients education as so as to reduce and avoid the occur-rence of ADR/ADE.

Objective Curcumin and MS-275,an inhibitor of histone deacetylase (HDAC),are promising anti-tumor agents. The aim of present study was to investigate the mechanisms of apoptosis induced by combined use of MS-275 in low dosage and curcumin in prostate cancer cell line DU145. Methods MTT assay was used to evaluate the lethal effect on DU145 cells by solitary use of MS-275 and or combined with curcumin. The changes in cell life cycle was detected by flow cytometry. The expressions of the survival signaling pathways were determined by Western blotting. Results Solitary application of MS-275 or curcumin may inhibit the growth of DU145 cells in a time and dose-dependent manner. The combination of MS-275 (1?mol/L) and curcumin (20?mol/L) exhibited obvious cytotoxic effect on cell viability,which was only 45.9% 48h after the combined treatment. Cell cycle assay showed that the combination of MS-275 and curcumin resulted in obvious appearance of sub-G1 phase in DU145 cells,implying that the cell apoptosis had been induced. The results of Western blotting showed that after treatment of MS-275 or curcumin singly,the phosphorylation level of Akt and ERK kinase declined slightly,however,when MS-275 and curcumin were used together,there appeared a prominent inhibitory effect on Akt and ERK kinase,indicated by a sharp decline of their phosphorylation level,and at the same time,the level of cleaved PARP,a hallmark of apoptosis,was increased in DU145 cells. Conclusion Combined use of MS-275 and curcumin may exert a synergistic cytotoxic effect on the viability of DU145 cells,and exhibit an inhibitory activity on Akt and ERK kinases to induce apoptosis.

In this paper,adverse drug reaction(ADRs)of two groups using ionic contrast media(ICM)and nonionic contrast media(NICM)respectively for conventional an- giography(CA),DSA and contrast enhanced CT(CTE)were analysed and compared with the recent literature. The results of this study indicated that(1)using ICM for CA,DSA and CTE,the in- cidence of ADRs is higher than that of NICM because of its high osmolarity,the effect of electric charge and chemotoxicity;however,even in the at-risk patients the incidence of ADRs; can be significantly decreased by using NICM.(2)the incidence of ADRs in patients with rapidly intraarterial injection is higher than that of intravenous injection;(3)the patients with ADRs to ICM previously could be reexamined by using NICM without inducing the ADRs (4)using lower concentration or/and volume of NICM than that of ICM may obtain superior images than the equivalent ICM because of the little influence of NICM on the plasma volume and the concentration of intravascular contrast midia;and(5)though NICM is surely a safe and ideal contrast midia,it still must be careful to use in at-risk patients. Because of its high cost limiting its universal use,a selective use in at-risk patients for the intavenous examinations is proposed by us.Excluding the usual high risk factors describ- ed in literature,we suggested that if the patients with the following factors,NICM should be the preferred choice for the angiography and CTE:(1)the post-operative patients of biain disease;(2)the patients with coma or shock;(3)the patients with peripheral aterial of ve- nous thrombosis and(4)the patients for interventional procedures of cardioascutlar system (CVIR). In addition to,the authors pointed out that some new problems concerning with the con- trast media(CM)must be noticed in the procedures of CVIR:the overdose of CM,he ad- verse effects resulted from the mixing of CM with other pharmaceutical products injected and the evaporated hyperc oncentatian decomposition,or carbonization of the CM resulted from the interaction within high energy equipment or under high temperature.

Objective:To investigate the effects of Porhyromonas endodontalis(P.e)liopolysaccharide(LPS)on the expression of IL-23mRNA and protein in mouse osteoblasts MC3T3-E1 and the role of phosphatidylinositol 3-Kinases (PI3K)signaling pathway in this process.Methods:MC3T3-E1 cells were treated with different concentrations of P.e LPS for different hours,or pretreated with LY294002,a special PI3K inhibitor.The IL-23 mRNA and protein expression levels were detected by real-time PCR and Western blot respectively.Results:The level of IL-23 mRNA increased in MC3T3-E1 cells with the increase of concentration and the treatment time of P.e LPS(P <0.05).The IL-23 protein expression was increased by P.e LPS in a time dependent manner(P <0.05).The mRNA and protein of IL-23 decreased(P <0.05)after pretreatment with LY294002.Conclusion:P.e LPS can induce the expression of IL-23 mRNA and protein in MC3T3-E1 cells,and the PI3K signaling pathway may play a part in this process.

Objective To clarify the role of B7-H1 in the immune privilege after corneal transplantation in homogeneity variant mice.Methods We established the experimental animal model of allograft mice by using C57BL/6 mouse as donor and Balb/c mouse as recipient.We allocaated the mice with long time survival (＞50 days) corneal graft into survival group,mice with rejection occurring in 50 days into rejection group,and normal C57BL/6 mice into control group.The transplanted corneal grafts were obtained for future reference at the 8th week after transplantation in survival group,and the time of rejection in rejection group.The expression of B7-H1 mRNA was detected by using immunohistochemistry and real time quantitative PCR (RT-PCR),and the relationship between B7-H1 and the immune privilege after corneal transplantation was analyzed. Results The B7 H1 mRNA was highly expressed in epithelium and endothelium of corneal grafts both in survival and control group,in comparison to an obviously lower expression in rejection group.The relative expression level of B7-H1 mRNA was 200.0 ± 11.5 in survival group,44.7 ± 10.8 in control group,and 6.9 ± 12.0 in rejection group,respectively. There were statistically significant differences among the three groups (F=241.164,P＜0.01 ).The was a significant correlation between the level of B7-H1 mRNA and occurrence rate of rejection in corneal graft (P＜0.01 ).Conclusion The results suggest that the immune privilege after corneal transplantation might be mediated by B7-H1,which plays an important role in maintaining the state of corneal immune privilege.

Bilirubin ; Child ; Duodenogastric Reflux ; diagnosis ; Esophageal Diseases ; diagnosis ; Esophagus ; metabolism ; Gastroesophageal Reflux ; diagnosis ; Humans