A pathway profile-based method for drug repositioning

Finding new applications for existing pharmaceuticals,known as drug repositioning,is a validated strategy for resolving the problem of high expenditure but low productivity in drug discovery.Currently,the prevalent computational methods for drug repositioning are focused mainly on the similarity or relevance between known drugs based on their "features",including chemical structure,side effects,gene expression profile,and/or chemical-protein interactome.However,such drug-oriented methods may constrain the newly predicted functions to the pharmacological functional space of the existing drugs.Clinically,many drugs have been found to bind "off-target"(i.e.to receptors other than their primary targets),which can lead to undesirable effects.In this study,which integrates known drug target information,we propose a disease-oriented strategy for evaluating the relationship between drugs and disease based on their pathway profile.The basic hypothesis of this method is that drugs exerting a therapeutic effect may not only directly target the disease-related proteins but also modulate the pathways involved in the pathological process.Upon testing eight of the global best-selling drugs in 2010(each with more than three targets),the FDA(Food and Drug Administration,USA)-approved therapeutic function of each was included in the top 10 predicted indications.On average,60% of predicted results made using our method are proved by literature.This approach could be used to complement existing methods and may provide a new perspective in drug repositioning and side effect evaluation.     

Preparation and cellular uptake of PLGA particles loaded with lamivudine

Poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles loaded with lamivudine and coated with bovine serum albumin (BSA) were prepared via a double emulsion method. The influences of experiments parameters such as volume of inner aqueous phase, concentration of organic phase and ultrasonication time on the particle size and drug entrapment efficiency were investigated, obtaining PLGA particles with a diameter of ~260 nm and drug entrapment efficiency of ~35%. The particles were observed by scanning electron microscopy and transmittance electron microscopy, showing a core-shell structure. BCA assay found that 58 mg BSA was present on/in 1 g LPB particles. The loaded lamivudine showed a burst release at beginning and sustained release until 24 h in physiological conditions. Low pH could accelerate the release of lamivudine from PLGA particles, making the PLGA particles potential intelligent intracellular drug carriers. The PLGA particles were readily internalized into the human liver cells within a short time and increased gradually with the prolongation of incubation time regardless of the loading of lamivudine. The particles either resided within lysosomes or transferred to cytoplasm, but could not enter into the cell nucleus. The cell viability was not significantly influenced in the presence of the particles regardless of lamivudine encapsulation, suggesting that this kind of particles may be a good candidate for the intracellular anti-hepatitis B drug delivery.     

固载蛋白类药物的壳聚糖基管式膜的制备及体外缓释性能研究

以壳聚糖为载体,牛血清白蛋白(BSA)为模型药物,配制一定浓度的壳聚糖/药物溶液,将该溶液涂渍在硅胶导尿管表面,成功制备了壳聚糖基管式膜材料.考察了不同pH条件下该材料对蛋白类药物的缓释性能,并初步探讨了缓释机理.结果表明,固载蛋白类药物的壳聚糖膜材料在三种不同pH介质中对BSA均有明显的缓释作用,且在中性介质中效果最好,缓释时间超过36h,BSA缓释总量达6.0mg.该载体生物相容性好,对缓解病人术后因导尿管留置引发的尿路感染及其它副作用具有潜在的应用前景.     

壳聚糖基水凝胶药物控制释放体系

水凝胶具有良好的亲水性,充分膨胀后具有与机体组织相似的物理性质,如柔软、有弹性、与生物液之间的界面张力低等。另外,水凝胶还具有孔径、机械强度和尺寸可调性等优点,适于作为药物控制释放的载体形式。壳聚糖是一种天然高分子材料,具有生物活性、良好的生物相容性、完全可降解性及无毒性等优点,是良好的药物控制释放载体材料。以壳聚糖为基材,通过物理方法或化学方法,可制备出pH敏感型、温敏型、光敏型等多种形式、不同性能的水凝胶。就壳聚糖基水凝胶的制备方法进行了详细地论述,包括通过物理作用形成水凝胶的方法及通过化学交联作用制备水凝胶的方法,探讨了壳聚糖基水凝胶对药物的担载和释放,并对其未来的发展前景进行了展望。     

Silk Fibroin Microspheres： Preparation and Application for Controlled Drug Delivery

Silk fibroin （SF）, a natural protein polymer, has several unique properties such as aqueous processability, biocompatibility, and biodegradability. Due to these advantageous properties, it is promising for applications in various fields, especially drug delivery. In this paper, the simple preparation of SF microspheres was discussed via self-assembly. Some of SF＇s physicochemical properties and morphology were also investigated. The results show that the morphology, size and size distribution of silk microspheres depend upon various processing parameters, especially including volume ratios among SF, ethanol and polyvinyl alcohol （PVA）. Regular silk microspheres were obtained in PVA solution when adjusting the volume ratios of silk to ethanol from 20：1 to 20： 9. We also found that SF microspheres with various appearances were formed by addition of different PVA solution concentrations under a constant silk solution to ethanol volume ratio. From the Fourier transform infrared spectroscopy（FTIR） of silk microspheres, it was found that introducing ethanol into the SF solution induced conformational change from random coil to β-sheet. Additionally, under the observation of scanning electron microscopy （ SEM）, the shape of self-assembled silk microspheres was determined to be spherical. Finally, SF＇s potential as drug delivery carriers was discussed in the experimental results.     

342株肠球菌的临床分类及耐药性分析

目的:了解肠球菌的临床分离率及其对常用抗生素的耐药性,指导临床合理使用抗生素。方法:用Vitek 2 Compact法进行细菌鉴定及常规药敏试验。结果:临床分离到的342株肠球菌中,粪肠球菌有140例,阳性率40.9%,屎肠球菌有186例,阳性率54.4%,其它肠球菌有16例,阳性率4.7%。342株肠球菌主要分离自尿液254例,阳性率74.3%;血液28例,阳性率8.2%;脑脊液21例,阳性率6.1%;胆汁15例,阳性率5.3%。屎肠球菌对青霉素、氨苄西林、环丙沙星、左氧氟沙星、红霉素和四环素的耐药率已接近或达到90%,而粪肠球菌对青霉素和氨苄西林仍保持100%敏感性。未发现肠球菌对万古霉素、利奈唑胺和替加环素耐药。结论:革兰阳性球菌中肠球菌是引起医院感染的重要病原菌之一,肠球菌引起的感染性疾病的治疗一定要以药敏结果为指导合理选用抗生素。     

中国药品数据保护制度的政策立场与执行调适

我国现行的药品数据保护法律制度是根据TRIPS协议精神构建的。当前药品数据保护主要运用于药品注册审批管理领域。食品药品监督管理部门在执行药品数据保护制度时,遭遇到是否保护非首次提交的药品数据、监管机构能否使用保藏的药品数据、药品数据提交的豁免、药品数据的质量及保护造成的成本等方面的困扰。面对法律的概括性和医药注册管理实际状况,有必要在药品数据保护制度执行中采取具有可行性的调适措施,以促进医药知识产权保护水平的提高,规范中国的制药产业发展。     

An Integrated Workflow for Proteome-Wide Off-Target Identification and Polypharmacology Drug Design

Polypharmacology,which focuses on designing drugs to target multiple receptors,has emerged as a new paradigm in drug discovery.To rationally design multi-target drugs,it is fundamental to understand protein-ligand interactions on a proteome scale.We have developed a Proteome-wide Off-target Pipeline （POP） that integrates ligand binding site analysis,protein-ligand docking,the statistical analysis of docking scores,and electrostatic potential calculations.The utility of POP is demonstrated by a case study,in which the molecular mechanism of anti-cancer effect of Nelfinavir is hypothesized.By combining structural proteome-wide off-target identification and systems biology,it is possible for us to correlate drug perturbations with clinical outcomes.     

抗癌药物阿霉素的荧光发射光谱分析

利用蒽环类抗癌药物阿霉素的自发荧光可反映药物在细胞中的分布和相对剂量,利用特异性荧光探针Ｈｏｅｃｈｓｔ３３３４２（Ｈｏ．３３３４２）可标记活细胞ＤＮＡ,从而反映细胞所处周期时相及染色体的形态变化,但是在阿霉素和Ｈｏ．３３３４２共存在的细胞中,用ＭＰＶＩＩ型显微荧光分光光度计对药的的自发荧光和Ｈｏ．３３３４２的发射芝光进行光谱分析的结果表明：在紫外激发下,药物自我荧光与Ｈｏ．３３３４２荧光之间存在干     

G蛋白偶联受体的共同激活机制

G蛋白偶联受体(G protein-coupled receptor, GPCR)构成人体中最庞大的膜蛋白家族,也是最重要的一类药物靶 标。随着GPCR结构解析技术的突破,目前已破解八十余个受体的400多个结构,揭示出GPCR复杂多样的配体结合模式和 跨膜信号转导机制。近年来,残基相互作用计算已实现对GPCR构象变化的精细描述,揭示出A家族GPCR存在共同的激活 机制。文章简要回顾GPCR激活机制研究的方法和创新点,并对A家族GPCR共同激活机制如何推动功能研究和药物研发进行展望。