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

Animals ; Antitussive Agents ; pharmacology ; Drug Evaluation, Preclinical ; methods ; Mice

Objective:To investigate frequencies of microsatellite instability(MSI)and loss of heterozygosity(LOH)in renal ceil carcinoma(RCC),and to discuss the relationship of clinicopathological characteristics of RCC with MSI and LOH. Methods:Twelve microsatellite markers located at chromosomes 3p,9p and 14q were selected to investigate microsatellite alterations(MSI and LOH)in 31 RCC specimens and their paired metastasis specimens by polymerase chain reaction- polyacrylamide gel elect rophoresis-ethylene dibromide(PCR-PAGE-EB)staining and sequencing.Results:The frequency of MSI could reached 61.3% and that of LOH could reach 54.8%.The highest frequency of MSI was at locus of D9S168(32.3%);the highest frequency of LOH was at locus of D3S1289(21.4%).No correlation was found between MSI or LOH and the patients' age,sex,pathology type and metastastis,except that MSI was correlated with TNM stage of RCC(P

Objective To observe the protection effects of sodium ?-aescinate(SA) on the nervous function in the rats with early spinal cord injury(SCI). Methods One hundred and twenty SD rats were randomly divided into four groups(n=30).Rats in the blank control group were performed laminectomy only,while those in the other three groups were injured at the level of Tl1 spinal segment by Allen's weight drop method(10 g ?10 cm) and immediately intraperitoneally given normal saline(5.0 mg/kg)(control group), SA(5.0 mg/kg)(SA group) and methylprednisolone(100 mg/kg)(MP group) once daily,respectively.After 8 h,24 h,96 h,7 d and 14 d,spinal cord function change of posterior limb were determined with Rivlin method.The rats were sacrificed and the injured segments were resected for pathological analysis. Results As time prolonged,the rehabilitation of spinal cord function with various degree could be observed in each group.Function rehabilitation was found among the rats in the control group,SA group and MP group 96 h after injury,and more rehabilitation was gained later in the latter two groups,while that was not the case in the control group.Rats in the SA and MP group gained more significant rehabilitation than those in the control group(P0.05).It was revealed by pathological analysis that no necrotic neurons was found in the blank control group,and the necrotic neurons in the SA group and MP group were significantly less than the control group at the same time points(P

Adult ; Aged ; Asteraceae ; Drugs, Chinese Herbal ; adverse effects ; Female ; Hepatic Veno-Occlusive Disease ; chemically induced ; Humans ; Male ; Middle Aged ; Retrospective Studies

Acute Disease ; Adult ; Aged ; Aryldialkylphosphatase ; blood ; Female ; Humans ; Male ; Middle Aged ; Organophosphate Poisoning ; Young Adult

Objective To investigate the regulatory effects of endogenous sulfur dioxide (SO2) on collagen accumulation in pulmonary arterial fibroblasts of rats and its mechanisms.Methods Primary rat pulmonary artery fibroblasts were used in the experiment and were divided into 3 groups:the control group,the L-aspartate-beta-hydroxamate(HDX) group and the HDX ± SO2 group.SO2 content of pulmonary artery fibroblasts supernatant was detected by adopting high performance liquid chromatography (HPLC).Collagen type Ⅰ and collagen type Ⅲ in pulmonary artery fibroblasts were determined by using immunofluorescence.Phosphorylation of Smad2/3,protein expression of matrix metalloproteinase (MMP)-13 and tissue inhibitors of MMP (TIMP)-1 were detected by using Western blot.One-way ANOVA was used for multiple group comparisons followed by Bonferroni test for each group.P ＜ 0.05 was considered as significant difference.Results Compared with control group,endogenous SO2 content in HDX group was significantly decreased [(14.30-± 0.48) μmol/L vs.(20.14 ± 0.49) μμmol/L,P ＜ 0.01],the level of Smad2/3 increased (1.03 ±0.31 vs.0.48 ± 0.20,P ＜ 0.01),protein expressions of MMP-13 and TIMP-1 in pulmonary artery fibroblasts were decreased (MMP-13:0.28 ± 0.06 vs.0.75 ± 0.11,P ＜ 0.01;TIMP-1:0.40 ± 0.05 vs.0.66 ± 0.20,P ＜ 0.01),and the ratio of MMP-13/TIMP-1 was decreased (0.71 ± 0.12 vs.1.23 ± 0.45,P ＜0.01).However,contents of collagen Ⅰ and collagen Ⅲ were significantly increased.Compared with HDX group,the level of Smad2/3 phosphorylation in HDX ± SO2 group decreased (0.57 ± 0.16 vs.1.03 ± 0.31,P ＜ 0.01),protein expression of MMP-13 and TIMP-1 upregulated (MMP-13:0.63 ± 0.06 vs.0.28 ± 0.06,P ＜ 0.01;0.59 ± 0.11 vs.0.40 ± 0.05,P =0.015),the ratio of M MP-13/TIMP-1 (1.10 ± 0.22 vs.0.71 ± 0.12,P =0.033) increased,but contents of collagen type Ⅰ and type Ⅲ were reduced obviously.Conclusions SO2 promotes the degradation of collagen and collagen accumulation in pulmonary artery fibroblasts of rats probably by inhibiting Smad2/3 signal pathway,increasing protein expression of MMP-13 and TIMP-1,and upregulating the ratio of MMP-13/TIMP-1.

To observe different expression patterns of β-catenin and its clinical significance in colorectal cancer (CRC).Methods A total of 181 cases of CRC tissues and 30 cases of normal colorectal tissue were investigated by immunohistochemistry for the expression of β-catenin.Results The expression rate of β-catenin was 56.9％ (103/181) in CRC,and higher than that in normal colorectal tissue (P ＜ 0.05).The overexpression of nuclear β-catenin was significantly correlated with histological differentiation,lymph node metastasis and Dukes' stage in CRC (P ＜ 0.05),and no relationship with other pathological parameters,such as age,gender and the depth of infiltration.The incomplete membranous expression of β-catenin was significantly correlated with histological differentiation,the depth of infiltration,lymph node metastasis and Dukes' stage in CRC (P ＜ 0.05).The high expression of nuclear β-catenin related to histological differentiation and Dukes' stage in CRC (P ＜ 0.05).In the follow-up data of 82 cases of CRC,the expression of nuclear β-catenin was associated with poor prognosis,and the 5-year survival rate was significantly lower than that of self-control groups (P ＜ 0.05).Conclusion β-catenin plays important roles in colorectal carcinogenesis.Abnormal expression of β-catenin was related to the aggressive progression of CRC and may be helpful for evaluating the prognosis of patients with CRC.β-catenin is expected to become a new target for diagnosis and treatment of CRC in future.

Human adenovirus (HAdV) is one of the most important pathogens in infants and young children with acute respiratory infections and other diseases. This article reviews the literature on HAdV, including its molecular biological characteristics, detection and typing, and pathogenic mechanism, the clinical features and epidemiological characteristics of HAdV-related diseases, and the prevention and control of HAdV infections. So far, 67 types of HAdV have been identified, including recombinant variants discovered in recent years. The major epidemic strains that cause acute respiratory infections are HAdV-3 and HAdV-7, both of which belong to the subgroup B. HAdV often leads to acute respiratory infections, but it also causes diseases of other systems. HAdV-related diseases have similar clinical manifestations as those caused by other respiratory viruses, but often accompanied by gastrointestinal symptoms. The pathogenic mechanism of HAdV remains unclear, especially for the new recombinant variants, due to few studies on their association with diseases. Because there are no prospective, large randomized controlled trials of HAdV infections, the treatment of HAdV infections is controversial. Vaccine is the most effective measure to reduce respiratory HAdV infections, but it is still not commercially available.
Adenovirus Infections, Human ; virology ; Adenoviruses, Human ; classification ; genetics ; isolation & purification ; physiology ; Animals ; Humans