Permeability is a key factor in the bioavailability of oral drugs. Therefore, in the early stage of drug discovery, accurate and efficient evaluation of drug permeability is essential. The parallel artificial membrane permeability assay (PAMPA) with Caco-2 cells model was used by the industry as early evaluation methods. At present, the Ussing chamber rat model is also widely used. This review summarizes the human data for the in vivo single-pass perfusion technique (Loc-I-Gut) – the gold standard, and then focuses on the basic principles, experimental operation, and efficiency of the three in vitro methods, with correlation to the effective permeability coefficient (P_eff) and fractional absorbed (Fa) in man. We provide recommendations for the use of proper permeability methods at different stages in drug discovery and development.

Objective This study is designed to determine whether an association exists between single nucleotide polymorphism (SNP) variant rs2252673 of insulin receptor(INSR) gene and polycystic ovarian syndrome (PCOS) in Han Chinese in order to identify INSR as a genetic susceptibility factor for PCOS.Methods A total of 224 women with PCOS,192 controls and 672 participants consisting of 224 trios (mother,father and offspring with PCOS) were recruited from the Hospital for Reproductive Medicine Affiliated to Shandong University,from July 2007 to April 2013.Genomic DNA was extracted according to the manufacturer' s protocol.SNP rs2252673 of INSR gene was amplified by PCR and then sequenced on an automated sequencer.Moreover,clinical and metabolic features of the patients with PCOS were compared according to the genotypes.The subjects were divided into twot groups according to body mass index (BMI),and then the results were compared between two groups.And the transmitted disequilibrium test (TDT) was applied for data analysis.Results (1) There were three kinds of genotype of CC,CG and GG.Genotype frequencies of rs2252673 were 8.0％,38.8％,53.1％ and 14.6％,42.2％,43.2％ in the PCOS group and the control group,respectively.The allele frequencies of C and G were 27.5％,72.5％ and 35.7％,64.3％ in the PCOS group and the control group,respectively.There were statistical differences in genotype frequencies and allele frequencies between two groups (all P＜0.05).(2)No significant differences were observed in the different genotype according to clinical and metabolic characteristics of women with PCOS (P＞0.05).But when merging the genotype CG and GG,carriers of the CG and GG genotypes in women with PCOS were slightly associated with total cholesterol (TC) levels (t=2.072,P=0.048) and lower high-density lipoprotein (HDL) levels (t=2.274,P=0.026).Although statistical significance was not achieved,there was an increased tendency in fasting blood glucose (FBG) and fasting insulin (FINS) levels in CG and GG genotypes in PCOS cases.(3)Between the obesity and the non-obesity with PCOS,there was no statistical significance in the genotype and allele frequencies (x2=0.054,P=0.974; x2=0.022,P=0.883).(4)The results of families based analysis shown that genotype distribution of the SNP rs2252673 was in Hardy-Weinberg equilibrium (P＞0.05).After the TDT,the G allele in SNP rs2252673 was over transmitted in families (transmitted∶ non-transmitted=120∶ 88; x2=4.923,P=0.027).There was a transmitted disequilibrium in rs2252673,which implies the association of INSR and PCOS were independent of population stratification.Conclusions There were a association between the SNP variant rs2252673 of INSR gene and the susceptibility to PCOS in Han Chinese women,which was independently of body mass index.The carrier of G allele frequency of rs2252673 may have higher risk of PCOS.

A HPLC-MS/MS multiple-reaction monitoring (MRM) quantitative analysis was made to establish a determination method for drug concentrations of costunolide (Co) and dehydrocostuslactone (De) in blood samples in the positive ion mode, with diazepam as the internal standard substance, in order to study the pharmacokinetic process of sesquiterpene lactones costunolide and dehydrocostuslactone after the oral administration of Weichang'an pills, and provide an theoretical basis for further studies on the substance basis for the anti-diarrhea effect of Weichang'an pills. In the blood samples, Co and De showed a good linearity within concentration ranges 0.700 0-769.7, 2.510-956.0 μg x L(-1), respectively. The results of precision, stability and recovery experiences proved the stability and reliability of the plasma concentration determination method. After the oral administration, the concentrations of Co and De in plasma increased with the increase in dose, with T(max) between 10.65-12.98 h, indicating a long time to reach peak plasma concentrations; C(max) of costunolide and dehydrocostuslactone ranged between 3.750-5.450,15.34-44.52 μg x L(-1), respectively. The in vivo adsorption of Co and De conformed to the one-compartment model, with a longer time to attain the peak plasma concentrations. These results provided an experimental basis for revealing the active substance basis and clinical medication of Weichang'an pills.
Administration, Oral ; Animals ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; pharmacokinetics ; Lactones ; administration & dosage ; blood ; pharmacokinetics ; Male ; Rats ; Rats, Wistar ; Sesquiterpenes ; administration & dosage ; blood ; pharmacokinetics ; Tablets ; administration & dosage ; chemistry ; pharmacokinetics

A series of novel sorafenib analogues were designed and synthesized. The cytotoxic activities of these compounds were tested in four tumor cell lines. Some of the compounds showed potent antiproliferative activity against the tested cell lines with IC50 = 4-20 micromol x L(-1). Some compounds demonstrated competitive antiproliferative activities to sorafenib against tested cancer cell lines. Among them, compound 7c demonstrated significant inhibitory activities on ACHN, HCT116 and MDA-MB-231 cell lines with IC50 values of 9.01, 4.97, 6.61 micromol x L(-1), respectively.
Antineoplastic Agents ; chemical synthesis ; chemistry ; pharmacology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Humans ; Inhibitory Concentration 50 ; Molecular Structure ; Niacinamide ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology ; Phenylurea Compounds ; chemical synthesis ; chemistry ; pharmacology ; Structure-Activity Relationship

The aim of this study is to evaluate anti-tumor activities and mechanism of a novel kinase inhibitor ZLJ213 which targeted Aurora A and vascular endothelial growth factor receptor (VEGFR) in vitro and in vivo against human colon cancer. Results showed that ZLJ213 inhibited cell proliferation and induced cell cycle arrest and apoptosis of HCT1 16 and SW48 cell lines. In HCT116-derived xenograft, ZLJ213 dosed at 100 mg · kg(-1) inhibited tumor growth by 73.24%. The IC50 of ZLJ213 on the expression of p-Aurora A was 0.258 µmol · L(-1) analyzed by ELISA. Under the concentration of 0.08 µmol · L(-1), ZLJ213 could inhibit the activities of Aurora A, Histone H3 and VEGFR of HCT116 and SW48 cell lines. Simultaneously, ZLJ213 induced activation of Caspase 3 and PARP cleavage. Above data suggested that ZLJ213 had the ability to inhibit cell proliferation and induce cell apoptosis both in vitro and in vivo in colon cancer, and down-regulate the expression of p-Aurora A and p-VEGFR. ZLJ213 might be a potential therapeutic agent against colon cancer.
Animals ; Apoptosis ; Aurora Kinase A ; antagonists & inhibitors ; Cell Cycle Checkpoints ; Cell Line, Tumor ; drug effects ; Cell Proliferation ; Colonic Neoplasms ; pathology ; Humans ; Protein Kinase Inhibitors ; pharmacology ; Receptors, Vascular Endothelial Growth Factor ; metabolism ; Xenograft Model Antitumor Assays

OBJECTIVETo compare the effect of citric acid stimulation on salivary alpha-amylase (sAA), total protein (TP), salivary flow rate, and pH value between Pi deficiency (PD) children and healthy children, thereby providing evidence for Pi controlling saliva theory.

METHODSTwenty PD children were recruited, and 29 healthy children were also recruited at the same time. Saliva samples from all subjects were collected before and after citric acid stimulation. The sAA activity and amount, TP contents, salivary flow rate, and pH value were determined and compared.

RESULTS(1) Citric acid stimulation was able to significantly increase salivary flow rate, pH value, sAA activities, sAA specific activity and sAA amount (including glycosylated and non-glycosylated sAA amount) in healthy children (P<0.05), while it could markedly increase salivary flow rate, pH value, and glycosylated sAA levels in PD children (P<0.05); (2) Although there was no statistical difference in determined salivary indices between the two groups (P>0.05), salivary indices except salivary flow rate and glycosylated sAA levels decreased more in PD children. There was statistical difference in sAA activity ratio, sAA specific activity ratio, and the ratio of glycosylated sAA levels between PD children and healthy children (P<0.05).

CONCLUSIONPD children had decreased response to citric acid stimulation.

ObjectiveTo investigate the effects of fluid percussion injury(FPI) on survival and differentiation of transplanted human embryonic neural stem cells (HNSCs) in rats. MethodsThe HNSCs were separated from the cerebral cortex of the 8-week-old fetal and were cultured in DMEM/F12 combinated with EGF, bFGF and LIF. The rat models of FPI were made with fluid percussion system. The HNSCs labeled with BrdU were transplanted into the injured zone 24 hours after brain injury, then the rats were killed at the 1st and 4th week post-transplanted stages, and the brain slices were stained with immunocytochemistry. The GFAP, MAP-2, and BrdU positive cells were investigated.ResultsThe transplanted HNSCs migrated to the whole brain, and differentiated into GFAP and MAP-2 positive cells. MAP-2 positive cells were observed at 1 week post-transplanted stage, on the contrary, more GFAP positive cells were discovered 4 weeks after transplantation. Part of the HNSCs migrated to the choroids plexus of the lateral ventricle and microvessels. ConclusionThe transplanted HNSCs survive in the injured zone, and differentiate into astrocytes gradually during the recovery. The host devours part of the HNSCs.

Objective To explore the clinical,radiological findings and pathogenic factor of spondylometaphyseal dysplasia.Methods Five cases were reported and the relevant documents were studied retrospectively.Plain X-ray film was performed in all patients.Results There were 4 male and 1 female,age ranged from 4 to 15 years with average of 9 years.The main features of 5 cases included delayed bone age,stature short,short trunk,waddling gait noted,scoliosis in 2 cases,kyphoscoliosis in 1 case,severe genu valgum in 2 cases.The main X-ray appearance of 5 cases is multiple irregularities of long bones metaphyses associated with platyspondylia,epiphysis is normal.Type Ⅰ SMD in 2 cases,Type Ⅱ SMD in 1 case,Type Ⅲ SMD in 2 cases.Conclusion When we meet children with delayed bone age and stature short,and muhiple irregularities of long bones metaphyses associated with platyspondylia were seen in X-ray plain film.we should think about spondylometaphyseal dysplasia.

Adsorption resin separation is one of the new technologies developed after ion exchange resin in the 60's of the 20th century. It was early used in the fields of the wastewater treatment, pharmaceutical industry, chemical engineering, analytical chemistry, clinical detection and treatment. In recent years, the technique of adsorption resin separation has been widely used in research on active constituent of traditional China medicine. The recent application was reviewed in this paper.
Adsorption ; Drugs, Chinese Herbal ; isolation & purification ; Plants, Medicinal ; chemistry ; Resins, Synthetic ; Saponins ; isolation & purification ; Technology, Pharmaceutical ; methods

Blood Chemical Analysis ; methods ; Humans ; Metronidazole ; blood ; Spectrophotometry, Ultraviolet