Combining the structural features of picotamide and linotroban, a series of N,N'-bis-(halogenophenyl)-4-methoxybenzene-1, 3-disulfonamides were designed and synthesized on the basic principles of drug design. The structures of target compounds were confirmed by IR, 1H NMR and HR-MS, and the in vitro antiplatelet aggregation activity was evaluated by Born turbidimetric method with adenosine diphosphate (ADP) as the platelet aggregation inducers. The assay results showed that twelve compounds (4b, 4f, 4l, 5b, 5d-5g, 5j, 5k, 5m and 5n) were found to have superior anti-platelet aggregation activities than the positive drug picotamide. The preliminary structure-activity relationship (SAR) has been explored.
Adenosine Diphosphate ; Drug Design ; Phthalic Acids ; Platelet Aggregation ; Platelet Aggregation Inhibitors ; chemical synthesis ; chemistry ; Structure-Activity Relationship ; Sulfonamides ; chemical synthesis ; chemistry

Organic anion transporting polypeptide 1B1 (OATP1B1) is an important liver-specific uptake transporter, which mediates transport of numerous endogenous substances and drugs from blood into hepatocytes. To identify and investigate potential modulators of OATP1B1 from natural products, the effect of 21 frequently used natural compounds and extracts on OATP1B1-mediated fluorescein methotrexate transport was studied by using Chinese hamster ovary cells stably expressing OATP1B1 (CHO-OATP1B1) in 96-well plates. This method could be used for the screening of large compound libraries. Our studies showed that some flavonoids (e.g., quercetin, quercitrin, rutin, chrysanthemum flavonoids and mulberrin) and triterpenoids (e.g., glycyrrhetinic acid and glycyrrhizic acid) were inhibitors of OATP1B1 with IC50 values less than 16 µmol · L(-1). The IC50 value of glycyrrhetinic acid on OATP1B1 was comparable to its blood concentration in clinics, indicating an OATPlB1-mediated drug-drug interaction could occur. Structure-activity relationship analysis showed that flavonoids had much higher inhibitory activity than their glycosides. Furthermore, the type and length of saccharides had a significant effect on their activity. In addition, we used OATP1B1 substrates fluvastatin and rosuvastatin as probe drugs to investigate the substrate-dependent effect of several natural compounds on the function of OATP1B1 in vitro. Our results demonstrated that the effect of these natural products on the function of OATPlB1 was substrate-dependent. In summary, this study would be conducive to predicting and avoiding potential OATP1B1-mediated drug-drug and drug-food interactions and thus provide the experimental basis and guidance for rational drug use.
Animals ; Biological Products ; CHO Cells ; Cricetulus ; Drug Interactions ; Fatty Acids, Monounsaturated ; pharmacology ; Flavonoids ; pharmacology ; Indoles ; pharmacology ; Inhibitory Concentration 50 ; Organic Anion Transporters ; genetics ; metabolism ; Rosuvastatin Calcium ; pharmacology ; Structure-Activity Relationship

The paper is to report the pharmacokinetic character of a series of chemical compounds in vitro and in vivo. Metabolism stability of a series of chemical compounds was screened by using rat liver microsomes. The samples of different chemical compounds were combined and then simultaneously detected by LC-MS/MS. Compounds y13, y12 and y11 were screened out by microstability assay in vitro. The pharmacokinetics of compounds y11, y12 and y13 was evaluated by using SD rat. The plasma samples were pooled at the same time. The plasma concentrations were determined by LC-MS/MS. The pharmacokinetic character of two compounds y13, y11 was good by screening in vivo, so they were developed for further research. High-throughput screening of drug candidates in vitro and in vivo was effective, to provide information for the chemical structure information and lower the drug development risk.
Animals ; Chromatography, Liquid ; methods ; Drug Evaluation, Preclinical ; methods ; Female ; High-Throughput Screening Assays ; methods ; Male ; Microsomes, Liver ; metabolism ; Pharmaceutical Preparations ; administration & dosage ; blood ; metabolism ; Pharmacokinetics ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Spectrometry, Mass, Electrospray Ionization ; methods

HPLC-ELSD was applied to explore the absorption mechanism of pulchinenosides (B3, BD, B7, B10, B11) in rats. The experimental results showed that the absorption rate constant, Ka value (B3, BD) and Permeability coefficient, Peff value (B3, B7) displayed significant difference (P <0.05) in various intestinal segments, The Ka value and Peff value of PRS was different from each other with the highest absorption in duodenum (duodenum > jejunum > colon > ileum); The PRS displayed excessive satuation as the concentration increased over 0.05-2.5 g · L(-1). There were no obvious linear correlations between Peff values and concentrations in duodenum (0.6007 ≤ R2 ≤ 0.7727); Ka and Peff value declined when the PRS was perfused with P-glycoprotein promoter digoxin, on the other hand, inclined when perfused with P-glycoprotein inhibitor verapamil with significant difference among PRS B3, BD, B7, B11 (P <0.05). All the above results demonstrated that B3, BD, B7 were greatly influenced by absorption sites, duodenum was the main absorption site; PRS didn't entirely transported in a concentration dependent manner, and the transporter-protein involved the transportation, so the intestinal absorption of the five pulchinenosides was not entirely passive diffusion; and PRS might be the substrates of P-glycoprotein.
ATP-Binding Cassette, Sub-Family B, Member 1 ; physiology ; Animals ; Intestinal Absorption ; Male ; Oleanolic Acid ; pharmacokinetics ; Pulsatilla ; chemistry ; Rats ; Rats, Wistar ; Saponins ; pharmacokinetics

Objective To determine the risk factors related to tuberculosis infection among people living with HIV/AIDS and to develop strategies for preventing the co-infection.Methods A 1:2matched nested case-control study was carried out to analyze the influencing factors of tuberculosis among people living with HIV/AIDS.Results 1018 people living with HIV/AIDS were followed up for one year with a total number of 736.75 person-years,among them 62 tuberculosis cases were diagnosed.The incidence density of tuberculosis among people living with HIV/AIDS was 8.42 persons per 100 person-years.Factors as education level(OR=0.483),vaccination history of Bacille Calmette Guerin(OR=0.561),CD_4~+ count T-lymphocyte(OR=0.356),unemployment(OR=1.976),living alone(OR=2.646),and smoking(OR=2.215)were significantly related to the prevalence of tuberculosis among people living with HIV/AIDS.Conclusion High education level,with vaccination history of Bacille Calmette Guerin and high level of CD_4~+ T-lymphocyte count were protective factors while being unemployed,living alone,and smoking habit were risk factors related to the prevalence of tuberculosis among people living with HIV/AIDS.

The breeding of domestic rabbits (Oryctolagus cuniculus) for human consumption has a long tradition in China. Infections that can affect the production of meat or even be transmitted from animals to humans are important to monitor, especially for public health reasons as well as for their impact on animal health. Thus, a total of 1,132 domestic rabbit sera from 4 regions in China were collected for serological screening for Encephalitozoon cuniculi and for Toxoplasma gondii by ELISA and modified agglutination test (MAT), respectively. Antibodies to E. cuniculi were detected in 248/1,132 (21.9%) sera tested while antibodies against T. gondii revealed a seroprevalence of 51/1,132 (4.5%). We believe that the present results are of epidemiological implications and public health importance due to the acknowledged susceptibility of humans to E. cuniculi and T. gondii infections. Therefore, routine screening tests of domestic rabbits are proposed considering the zoonotic potential of these parasites.
Animals ; Animals, Domestic/blood/microbiology/parasitology ; Antibodies, Fungal/*blood ; Antibodies, Protozoan/*blood ; China/epidemiology ; Encephalitozoon cuniculi/*immunology/isolation & purification ; Encephalitozoonosis/blood/microbiology/*veterinary ; Female ; Male ; Rabbits/blood/microbiology/parasitology ; Seroepidemiologic Studies ; Toxoplasma/*immunology/isolation & purification ; Toxoplasmosis, Animal/*blood/parasitology

OBJECTIVETo investigate the specific antitumor immune response induced by idiotype protein (Id)-pulsed dendritic cells (DC) in vitro.

METHODSDC was generated from peripheral blood monocytes of the multiple myeloma (MM) patients using GM-CSF, IL-4, and TNF-alpha. The DCs were pulsed with idiotypic fragment, the F(ab')2 fragment of M protein from MM patient at the immature stage. The morphologic characteristics of the cells were observed with light and electron microscopes. The phenotypic features were analyzed with FACS, MTT assay was employed to evaluate the proliferation of autologous T cells and the inhibition rate of MM cells.

RESULTSDC precursors in peripheral blood could be induced to typical mature DC in medium containing GM-CSF, IL-4 and TNF-alpha. Mature DC with Id could increase the proliferation of the autologous T cells and activate naive T cells to become tumor specialized cytotoxic T lymphocytes (CTL). The CTL at different doses showed significant inhibition on or killing ability to autologous MM cells in vitro.

CONCLUSIONSIn a suitable cytokine environment, the DC precursors from peripheral blood of MM patients could be induced to functional DC, and vaccination of Id-pulsed DC could induce active antitumor immune response.

Adult ; Aged ; Antibodies, Anti-Idiotypic ; immunology ; Cancer Vaccines ; immunology ; Cells, Cultured ; Dendritic Cells ; immunology ; Female ; Humans ; Immunotherapy, Active ; Male ; Middle Aged ; Multiple Myeloma ; immunology ; therapy ; T-Lymphocytes, Cytotoxic ; immunology

OBJECTIVETo investigate the association of the exon 8 and intron 8 polymorphisms of the human urate transporter 1 gene SLC22A12 with primary hyperuricemia (HUA) in Chinese Han population.

METHODSGenomic DNA from 215 individuals with HUA and 323 controls was extracted. The exon 8 and intron 8 of the SLC22A12 gene was amplified by polymerase chain reaction (PCR). PCR product was sequenced directly. Single nucleotide polymorphisms (SNPs) were detected and the association of the SNPs with primary HUA was assessed.

RESULTS(1) Two SNPs were identified, they were T1309C located in exon 8 (rs7932775) and -103A to G located in intron 8. Pairwise linkage disequilibrium analysis displayed an absolute linkage disequilibrium between the two SNPs (D'= 1). (2) The minor allele frequencies for both SNPs were 51.9% in HUA patients, which were significantly different from that of controls (42.4%)(P< 0.01). (3) The genotype frequencies of GG+ GA and CC+ CT in HUA patients were significantly higher than that in controls (80.0% vs. 69.0%, P< 0.01). (4) Individuals of both GG+ GA and CC+ CT genotypes had 1.79 fold increase of HUA risk (OR= 1.794, 95%CI: 1.19-2.70).

CONCLUSIONThese findings indicated that T1309C and -103A to G polymorphisms of the SLC22A12 gene were associated with primary HUA in Chinese Han population.

Adult ; Aged ; Aged, 80 and over ; Asian Continental Ancestry Group ; genetics ; Base Sequence ; Case-Control Studies ; China ; ethnology ; Ethnic Groups ; genetics ; Exons ; genetics ; Female ; Gene Frequency ; Genotype ; Humans ; Hyperuricemia ; genetics ; Introns ; genetics ; Linkage Disequilibrium ; Male ; Middle Aged ; Molecular Sequence Data ; Organic Anion Transporters ; genetics ; Organic Cation Transport Proteins ; genetics ; Polymorphism, Single Nucleotide ; genetics

OBJECTIVETo explore the methods of the treatment and the principles of the prevention of bronchus-pleural fistula (BPF) after pneumonectomy.

METHODSThe clinical data of 15 cases of BPF after pneumonectomy in 815 lung cancer cases treated from July 1999 to June 2006 were analyzed retrospectively.

RESULTSThe occurrence rate of BPF after right pneumonectomy was 3.9% (12/310), higher than 0.6% (3/505) of left pneumonectomy (P < 0.01). The occurrence rate of BPF in cases with positive cancer residues in stump of bronchus was 22.7% (5/22), higher than 1.3% (10/793) of the cases with negative stump of bronchus (P < 0.01). The occurrence rate of BPF in the cases received preoperative radio- or chemotherapy was 5.0% (6/119), higher than 1.3% (9/696) of the cases received operation only (P < 0.05). There were no BPF occurred in the 76 cases whose bronchial stump were covered with autogenous tissues. All of the cases diagnosed as BPF were undertaken either closed or open chest drainage. Two cases were cured by thoracentesis aspiration and infusion antibiotics repeatedly. Two cases were cured by blocking the fistula with fibrin glue after sufficient anti-inflammatory treatment and hypertonic saline flushing. Six cases were discharged with a stable condition after closed drainage only. One case was discharged with open drainage for long time and 1 case was cured by hypertonic saline flushing after failure to cover the BPF using muscle flaps. Three cases died of multi-organs functional failure.

CONCLUSIONSBPF are related to the bronchial stump management and positive or negative residue of tumor at the bronchial stump. Autogenous tissues covering of the bronchial stump is a effective method for decrease the rate of BPF and especially for those patients received preoperative radio- or chemotherapy and right pneumonectomy. It should be performed for early mild cases with repeated thoracentesis aspirations or blocking the fistula with fibrin glue together with antibiotics. Chest closed drainage immediately and flushing with hypertonic saline repeatedly are effective methods for BPF.

Adult ; Aged ; Aged, 80 and over ; Bronchial Fistula ; epidemiology ; prevention & control ; therapy ; Female ; Humans ; Lung Neoplasms ; surgery ; Male ; Middle Aged ; Pleural Diseases ; epidemiology ; prevention & control ; therapy ; Pneumonectomy ; adverse effects ; methods ; Postoperative Complications ; etiology ; prevention & control ; therapy ; Retrospective Studies ; Treatment Outcome

OBJECTIVETo investigate the influence of HCV genotype on the IFN treatment of patients with chronic hepatitis C.

METHODSThe genotypes of HCV virus were determined in the patients enrolled into the Randomized, opened and controlled trial of Peg-IFN alpha-2a (Pegasys) treatment, controlled with IFN-alpha-2a (Roferon-A), on chronic hepatitis C patients in China. The serum ALT levels and HCV RNA concentration of the patients were detected in the time of before treatment, the end of therapy and follow-up. The influence of HCV genotype on the IFN treatment of patients with chronic hepatitis C was analyzed in intention to treat (ITT) population.

RESULTSThe HCV genotypes of 202 cases were determined. 158 (78.2%) cases infected with genotype 1 HCV and 44 (21.8%) cases with genotype non-1. For overall patients, the viral response at the end of treatment (ETVR) and sustained viral response (SVR) rates were 53.8% and 25.3% respectively in patients with genotype 1 HCV, but in genotype non-1 patients those was 61.4% and 43.2%, and the difference of SVR between genotype 1 and non-1 was significant (P=0.021). After grouped by the used drugs, in the patients given Pegasys treatment, the ETVR rates of patients with genotype 1 and non-1 HCV infection were 76.8% and 81.0%, the difference was not significant (P=0.686), but the difference of SVR rates, which were 35.4% and 66.7%, of the patients was significant (P=0.01). The viral relapse rate of genotype 1 was 55.6%; it was significant higher than that of genotype non-1 (23.5%) (P=0.02). In Roferon-A group, the ETVR and SVR rates of patients with genotype 1 HCV were 29.0% and 14.5%, which were lower, but not significant, than those of patients with genotype non-1 (43.5% and 21.7%). The viral relapse rate of genotype 1 was 72.7% and higher, but not significant, than that of genotype non-1 also (50.0%) (P=0.21).

CONCLUSIONHCV genotype could affects the efficacies, mainly the sustained responses, of IFN treatment of patients with chronic hepatitis C, and the effects of IFN were related to the kinds of drugs and therapeutic course.

Antiviral Agents ; therapeutic use ; Genotype ; Hepacivirus ; classification ; genetics ; Hepatitis C, Chronic ; drug therapy ; virology ; Humans ; Interferon-alpha ; therapeutic use ; Polyethylene Glycols ; therapeutic use ; Recombinant Proteins ; Recurrence