喹诺酮类药物与碳青霉烯类药物之间的交叉耐药性和泛耐药性的研究

目的研究由喹诺酮类和碳青霉烯类药物诱导的耐药性铜绿假单胞菌之间的交叉耐药,以及与庆大霉素(CN)、头孢哌酮/舒巴坦(SCF)之间的交叉耐药情况。方法用左氧氟沙星(LEV)和亚胺培南(IPM)分别诱导3株铜绿假单胞菌菌株(1株为标准菌株,2株为野生菌株),使之耐药,通过检测LEV、IPM、CN、SCF对该菌株的最低抑菌浓度(MIC),与未耐药菌株的MIC进行对比,观察药物间的交叉耐药情况。并通过对2005—2008年的铜绿假单胞菌耐药情况的分析,进一步观察上述药物间的交叉耐药情况。结果LEV、IPM、CN、SCF对由LEV诱导耐药的铜绿假单胞菌标准菌株的MIC值分别为32、16、16、32μg/ml,野生菌株的MIC值分别为16、8、8、64μg/ml和8、16、16、32μg/ml;LEV、IPM、CN、SCF对由LEV诱导耐药的铜绿假单胞菌标准菌株的MIC值分别为16、16、128、64μg/ml,野生菌株的MIC值分别为8、8、8、64μg/ml;和4、16、8、64μg/ml。结论由LEV、IPM诱导耐药的铜绿假单胞菌菌株,对LEV、IPM、CN、SCF均产生了不同程度的耐药性。提示喹诺酮类与碳青霉烯类药物的滥用都可能导致广泛的细菌交叉耐药。     

Inter-ethnic differences in drug response: Implications for drug development and complying with drug regulation

Abstract

The two key components of the pharmacology of a drug—dose–concentration (pharmacokinetic) and/or concentration–response (pharmacodynamic) relationships—are often influenced by genetic variations. These account for a substantial fraction of variability in dose–response or drug response, not only between individuals, but also between different ethnic groups. The approval of ‘BiDil’ for the treatment of cardiac failure in self-identified black patients is a spectacular example of inter-ethnic differences in drug response and regulatory awareness of ethnicity of the study population. Drug development programs are increasingly undertaken globally to reduce costs, shorten timeframes, and address issues concerning global prescribing. Regulatory authorities have responded to this globalization of drug development by promulgating guidelines that recommend sponsors of new drugs to explore the role of genetic variations, and potential differences in drug response, between different ethnic populations. They may refuse to accept an application, or require bridging studies, when such differences are anticipated but not adequately addressed. These bridging studies may include (i) pharmacokinetic studies, (ii) pharmacodynamic studies, (iii) dose–response studies, and/or (iv) in extreme cases, pivotal phase III studies in order to extrapolate efficacy and/or safety data from one population to another.     

在线药学知识的配方软件设计及其应用

目的：提高医院门诊药学服务水平。方法：基于医院信息系统，采用PowerBuilder6．5开发语言，整合药学信息知识库，改进门诊配方软件。结果：构建了在线提供药学知识的门诊配方软件，减少了配方差错，提高了药师接受信息咨询的能力。结论：该软件具有快速、高效、综合、直观的特点．可满足门诊药学信息咨询的需求。     

Challenges and opportunities with modelling and simulation in drug discovery and drug development

The benefits of modelling and simulation at the pre-clinical stage of drug development can be realized through formal and realistic integration of data on physicochemical properties, pharmacokinetics, pharmacodynamics, formulation and safety. Such data integration and the powerful combination of physiologically based pharmacokinetic (PBPK) with pharmacokinetic-pharmacodynamic relationship (PK/PD) models provides the basis for quantitative outputs allowing comparisons across compounds and resulting in improved decision-making during the selection process. Such PBPK/PD evaluations provide crucial information on the potency and safety of drug candidates in vivo and the bridging of the PK/PD concept established during the pre-clinical phase to clinical studies. Modelling and simulation is required to address a number of key questions at the various stages of the drug-discovery and -development process. Such questions include the following. (1) What is the expected human PK profile for potential clinical candidate(s)? (2) Is this profile and its associated PD adequate for the given indication? (3) What is the optimal dosing schedule with respect to safety and efficacy? (4) Is a food effect expected? (5) How can formulation be improved and what is the potential benefit? (6) What is the expected variability and uncertainty in the predictions?     

Challenges and opportunities with modelling and simulation in drug discovery and drug development

The benefits of modelling and simulation at the pre-clinical stage of drug development can be realized through formal and realistic integration of data on physicochemical properties, pharmacokinetics, pharmacodynamics, formulation and safety. Such data integration and the powerful combination of physiologically based pharmacokinetic (PBPK) with pharmacokinetic–pharmacodynamic relationship (PK/PD) models provides the basis for quantitative outputs allowing comparisons across compounds and resulting in improved decision-making during the selection process. Such PBPK/PD evaluations provide crucial information on the potency and safety of drug candidates in vivo and the bridging of the PK/PD concept established during the pre-clinical phase to clinical studies. Modelling and simulation is required to address a number of key questions at the various stages of the drug-discovery and -development process. Such questions include the following. (1) What is the expected human PK profile for potential clinical candidate(s)? (2) Is this profile and its associated PD adequate for the given indication? (3) What is the optimal dosing schedule with respect to safety and efficacy? (4) Is a food effect expected? (5) How can formulation be improved and what is the potential benefit? (6) What is the expected variability and uncertainty in the predictions?     

Evaluation of drug–drug interactions with fesoterodine

Purpose  To assess drug–drug interactions of fesoterodine with cytochrome P450 (CYP) 3A4 inhibitor (ketoconazole), inducer (rifampicin), and substrates (ethinylestradiol and levonorgestrel). Methods  Effects of ketoconazole 200 mg twice daily and rifampicin 600 mg twice daily on fesoterodine 8 mg once daily were investigated in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) based on 5-hydroxymethyl tolterodine (5-HMT) pharmacokinetics (principal active fesoterodine metabolite and CYP3A4 substrate). Effects of fesoterodine 8 mg versus placebo once daily on ethinylestradiol and levonorgestrel were investigated based on oral contraceptive pharmacokinetics and on pharmacodynamic effects on progesterone, luteinizing hormone, follicle-stimulating hormone, and estradiol plasma levels. Results  Compared with fesoterodine alone, coadministration of fesoterodine with ketoconazole resulted in increases in mean 5-HMT maximum concentration in plasma (C_max; from 3.0 to 6.0 ng/mL in EMs and from 6.4 to 13.4 ng/mL in PMs) and mean area under the plasma concentration time curve (AUC; from 38.2 to 88.3 ng h/mL in EMs and 88.3 to 217.2 ng h/mL in PMs). Coadministration of festerodine with rifampicin resulted in decreases in mean 5-HMT C_max (from 5.2 to 1.5 ng/mL in EMs and from 6.8 to 1.9 ng/mL in PMs) and mean AUC (from 62.4 to 14.4 ng h/mL in EMs and from 87.8 to 19.6 ng h/mL in PMs). Fesoterodine did not affect oral contraceptive pharmacokinetics or pharmacodynamics or the suppression of ovulation. Conclusions  Fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors. Coadministration of CYP3A4 inducers with fesoterodine may produce subtherapeutic 5-HMT exposures. No dose adjustment is necessary for concomitant use of fesoterodine with oral contraceptives. Funding for this study was provided by Schwarz Biosciences GmbH, and Pfizer Inc.     

败血症患者细菌耐药情况分析及用药对策

目的 分析败血症患者的细菌耐药情况及用药对策,为进一步规范临床用药提供依据。方法 回顾性分析本院2012年5月～2013年10月临床确诊的160例败血症住院患者的临床资料,考察其病原菌的分布,采用Kirby—Bauer纸片扩散法进行药敏试验,最终结果 以美国临床实验室标准委员会（NCCLS）标准判断。结果 共检出细菌112株,革兰氏阳性菌74株（66．1％）、革兰氏阴性菌38株（33．9％）,前者以金黄色葡萄球菌为主,占34．8％,后者以大肠埃希菌为主,占13．4％。对常用的抗菌药物均呈现出较高的耐药率,只有万古霉素和亚胺培南分别对金黄色葡萄球菌和大肠埃希菌敏感性高。结论 开展细菌耐药性监测、控制耐药菌株发展,可为临床合理应用抗菌药物提供依据。     

2011年住院患者抗菌药物使用及耐药情况分析

目的通过对2011年住院患者抗菌药物使用及耐药情况的分析,以期提高对抗菌药物的合理使用水平。方法统计2011年住院患者抗菌药物使用的相关数据,使用限定日剂量值(DDD值)分析方法,并结合抗菌药物耐药情况进行分析。结果我院的微生物样本送检率较低,抗菌药物选用未严格按照药敏结果。革兰氏阳性菌对万古霉素、利奈唑胺、呋喃妥因、复方新诺明的耐药性均小于30%,其他均高于65%。亚胺培南、美罗培南对铜绿假单胞菌的耐药率分别为37.8%和43.5%。两个碳青霉烯类鲍曼不动杆菌的耐药率分别为66.7%和72.3%,高于平均水平。结论我院须加强抗菌药物使用的管理,进一步提高抗菌药物分级管理水平,减缓细菌耐药性的发生。     

Interaction of the antiviral drug telaprevir with renal and hepatic drug transporters

Telaprevir is a new, direct-acting antiviral drug that has been approved for the treatment of chronic hepatitis C viral infection. First data on drug-drug interactions with co-medications such as cyclosporine, tacrolimus and atorvastatin have been reported recently. Drug transporting proteins have been shown to play an important role in clinically observed drug-drug interactions. The aim of this study was therefore to systematically investigate the potential of telaprevir to inhibit drug transporting proteins. The effect of telaprevir on substrate uptake mediated by drug transporters located in human kidney and liver was investigated on a functional level in HEK293 cell lines that over-express single transporter. Telaprevir was shown to exhibit significant inhibition of the human renal drug transporters OCT2 and MATE1 with IC(50) values of 6.4μM and 23.0μM, respectively, whereas no inhibitory effect on OAT1 and OAT3 mediated transport by telaprevir was demonstrated. Liver drug transporters were inhibited with an IC(50) of 2.2μM for OATP1B1, 6.8μM for OATP1B3 and 20.7μM for OCT1. Our data show that telaprevir exhibited significant potential to inhibit human drug transporters. In view of the inhibitory potential of telaprevir, clinical co-administration of telaprevir together with drugs that are substrates of renal or hepatic transporters should be carefully monitored.     

Engineering biodegradable polyester particles with specific drug targeting and drug release properties

Poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) microspheres and nanoparticles remain the focus of intensive research effort directed to the controlled release and in vivo localization of drugs. In recent years engineering approaches have been devised to create novel micro- and nano-particles which provide greater control over the drug release profile and present opportunities for drug targeting at the tissue and cellular levels. This has been possible with better understanding and manipulation of the fabrication and degradation processes, particularly emulsion-solvent extraction, and conjugation of polyesters with ligands or other polymers before or after particle formation. As a result, particle surface and internal porosity have been designed to meet criteria-facilitating passive targeting (e.g., for pulmonary delivery), modification of the drug release profile (e.g., attenuation of the burst release) and active targeting via ligand binding to specific cell receptors. It is now possible to envisage adventurous applications for polyester microparticles beyond their inherent role as biodegradable, controlled drug delivery vehicles. These may include drug delivery vehicles for the treatment of cerebral disease and tumor targeting, and co-delivery of drugs in a pulsatile and/or time-delayed fashion.     

1例肺脓肿患者抗感染治疗引发药物热、紫癜型药疹病例分析

目的探讨临床药师参与1例肺脓肿患者抗感染治疗引发药物热、紫癜型药疹临床治疗的作用。方法临床药师分析引发药物热的抗菌药物并总结其发生特点,为临床诊断此类药物热提供一定参考;针对患者的紫癜型药疹,采用Naranjo评定法分析可疑药物及其不良反应等级,对患者进行个体化用药监护。结果通过药学监护,临床药师阻止了药物不良反应的恶化,减轻了患者的痛苦,提高了患者用药疗效。结论临床药师通过参与患者个体化药学监护,为医护人员提供互补的药学专业知识,提高药物治疗的安全性和有效性。     

: prevalence and association with drug use

In a cross-sectional study, we have investigated the prevalence of self-reported symptoms and their association with medicinal drug use in elderly people. Data from the Kungsholmen Project were used, a population-based study of elderly people aged 75 years and over in Stockholm, Sweden. The study sample comprised 1800 persons. Information on the occurrence of 22 different symptoms and the actual drug use was obtained at interviews with the participants. The relation of symptoms to age, gender and housing, and their association with drug use was analysed using logistic regression. The most commonly reported symptoms were pain and tiredness. In general, symptoms were more common in women and at higher ages. Many of the associations between symptoms and drug use reflected established treatments. However, some were suggestive of inappropriate treatment or dosage; for example, the association between tiredness and the use of anxiolytics and hypnotics-sedatives.     

Biophysics of cell membrane lipids in cancer drug resistance: Implications for drug transport and drug delivery with nanoparticles

In this review, we focus on the biophysics of cell membrane lipids, particularly when cancers develop acquired drug resistance, and how biophysical changes in resistant cell membrane influence drug transport and nanoparticle-mediated drug delivery. Recent advances in membrane lipid research show the varied roles of lipids in regulating membrane P-glycoprotein function, membrane trafficking, apoptotic pathways, drug transport, and endocytic functions, particularly endocytosis, the primary mechanism of cellular uptake of nanoparticle-based drug delivery systems. Since acquired drug resistance alters lipid biosynthesis, understanding the role of lipids in cell membrane biophysics and its effect on drug transport is critical for developing effective therapeutic and drug delivery approaches to overcome drug resistance. Here we discuss novel strategies for (a) modulating the biophysical properties of membrane lipids of resistant cells to facilitate drug transport and regain endocytic function and (b) developing effective nanoparticles based on their biophysical interactions with membrane lipids to enhance drug delivery and overcome drug resistance.     

新药研发中的me-too, me-better, me-new

文中根据作者对我国新药研发的认识和理解,提出了新药研发过程中me-too,me-better和me-new类新药的概念,并对新药研发过程中的这3类创新活动之间的关系、新药研发的创新程度与经济效益的关系,以及目前我国新药研发的途径选择做了简要的论述。     

Thinking with pleasure: Experimenting with drugs and drug research

Within the field of drug and alcohol studies, researchers think about pleasure or against it; we analyse, consider, investigate, invoke or ignore it. The philosophically inclined may think of pleasure or write on it, but in each of these scenarios pleasure is kept at an arm’s length while the researcher appears to remain unmoved – detached observers, objective scientists, conceptual experts, program directors, sharp critics, policy advocates – sober judges whose sovereignty is secured by the formal conventions of positivist research, established theory, institutional authority and/or disciplinary knowledge. This paper asks what happens when pleasure is allowed to emerge as a constitutive element in the relations of drug and alcohol research. What happens when we conceive our work as thinking with pleasure, rather than simply researching pleasure or thinking about it? I return to the later work of Foucault, reading it alongside conceptions of the experiment drawn from Science and Technology Studies, arguing that both the pleasures of drug consumption and drug research might be conceived more generatively as mutually implicated in events.     

Compliance with drug therapy.

Although no single method is ideal for measuring compliance the methods now available allow accurate assessment of compliance in most settings. Studies using new and more accurate methods of measuring compliance have shown poor compliance to be an even greater problem than was previously thought. Using these methods, efforts in the future should be directed at relating compliance to treatment outcome, and investigating whether manoeuvres aimed at improving compliance actually improve patient outcome.     

Targeted drug delivery with dendrimers: comparison of the release kinetics of covalently conjugated drug and non-covalent drug inclusion complex

Dendrimers have unique characteristics including monodispersity and modifiable surface functionality, along with highly defined size and structure. This makes these polymers attractive candidates as carriers in drug delivery applications. Drug delivery can be achieved by coupling a drug to polymer through one of two approaches. Hydrophobic drugs can be complexed within the hydrophobic dendrimer interior to make them water-soluble or drugs can be covalently coupled onto the surface of the dendrimer. Using both methods we compared the efficacy of generation 5 PAMAM dendrimers in the targeted drug delivery of methotrexate coupled to the polymer. The amine-terminated dendrimers bind to negatively charged membranes of cells in a non-specific manner and can cause toxicity in vitro and in vivo. To reduce toxicity and to increase aqueous solubility, modifications were made to the surface hydroxyl groups of the dendrimers. For targeted drug delivery, the dendrimer was modified to have a neutral terminal functionality for use with surface-conjugated folic acid as the targeting agent. The complexation of methotrexate within a dendrimer changes the water insoluble drug into a stable and readily water-soluble compound. When this dendrimer complexed drug, however, was placed in a solution of phosphate buffered saline, the methotrexate was immediately released and displayed diffusion characteristics identical to free methotrexate. Covalently coupled methotrexate dendrimer conjugates were stable under identical conditions in water and buffered saline. Cytotoxicity tests showed that methotrexate as the dendrimer inclusion complex had an activity identical to the free drug in vitro. In contrast, folic acid targeted dendrimer with covalently conjugated methotrexate specifically killed receptor-expressing cells by intracellular delivery of the drug through receptor-mediated endocytosis. This study demonstrates that while drug as a dendrimer inclusion complex is readily released and active in vitro, covalently conjugated drug to dendrimer is better suited for specifically targeted drug delivery.