Nuclear imaging with radiolabeled odor molecules in patients with olfactory disorder

Smell loss originates from peripheral disorders, like intranasal obstruction and olfactory cell injury, as well as central pathway diseases. Information derived from electrophysiological and psychophysical tests are useful for identifying loss of smell, but not for discriminating between central and peripheral deficits. This is because conventional imaging modalities are unable to deliver information about functional olfactory performance. Although functional imaging is able to show abnormal changes in central olfactory pathways, it seems that it is only possible to observe such abnormalities in olfactory cell dysfunction. We hypothesize that the scanning of peripheral olfactory systems by radiolabeled odor molecules may specifically reveal olfactory dysfunction and may be useful for differentiating peripheral from central olfactory disorders.     

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。     

Use of radiolabeled compounds in drug metabolism and pharmacokinetic studies

As part of the drug discovery and development process, it is important to understand the fate of the drug candidate in humans and the relevance of the animal species used for preclinical toxicity and pharmacodynamic studies. Therefore, various in vitro and in vivo studies are conducted during the different stages of the drug development process to elucidate the absorption, distribution, metabolism, and excretion properties of the drug candidate. Although state-of-the-art LC/MS techniques are commonly employed for these studies, radiolabeled molecules are still frequently required for the quantification of metabolites and to assess the retention and excretion of all drug related material without relying on structural information and MS ionization properties. In this perspective, we describe the activities of Isotope Chemistry at AstraZeneca and give a brief overview of different commonly used approaches for the preparation of (14)C- and (3)H-labeled drug candidates. Also various drug metabolism and pharmacokinetic studies utilizing radiolabeled drug candidates are presented with in-house examples where relevant. Finally, we outline strategic changes to our use of radiolabeled compounds in drug metabolism and pharmacokinetic studies, with an emphasis on delaying of in vivo studies employing radiolabeled drug molecules.     

Microequilibrium of drug molecules]

Protonation macro-, micro-, and submicro constants are physico-chemical parameters of crucial importance, concerning the fate of bio-, drug, and narcotic drug molecules in the body and in protic solvents. The most important characteristics, relationships, applications and biological significance of these parameters are reviewed, using acetylcysteine and cysteine, as examples. The mucolytic effect of acetylcysteine, an active principle in numerous drugs, is interpreted in terms of protonation state of the molecule and its thiolate site. Microscopic protonation constants of acetylcysteine, data that have not previously appeared, are also reported.     

Antiviral drug resistance

Almost 30 years ago it was proposed that the selection for antiviral drug resistance should be used as an indicator of antiviral drug activity. In addition to discriminating between cellular toxicity and specific activity directed against a viral target, drug resistant mutants have been used to confirm the mechanism of action of antiviral drugs, to discover the functions of several viral proteins and to provide insights into viral evolution and fitness. Drug resistance has also become a standard component of both the preclinical and clinical drug development process. For HIV and increasingly for other viruses drug resistance testing has become standard-of-care in clinical practice. A few selected examples are provided to illustrate each of these points.     

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。     

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。     

Cell adhesion molecules for targeted drug delivery

Rapid advancement of the understanding of the structure and function of cell adhesion molecules (i.e., integrins, cadherins) has impacted the design and development of drugs (i.e., peptide, proteins) with the potential to treat cancer and heart and autoimmune diseases. For example, RGD peptides/peptidomimetics have been marketed as anti-thrombic agents and are being investigated for inhibiting tumor angiogenesis. Other cell adhesion peptides derived from ICAM-1 and LFA-1 sequences were found to block T-cell adhesion to vascular endothelial cells and epithelial cells; these peptides are being investigated for treating autoimmune diseases. Recent findings suggest that cell adhesion receptors such as integrins can internalize their peptide ligands into the intracellular space. Thus, many cell adhesion peptides (i.e., RGD peptide) were used to target drugs, particles, and diagnostic agents to a specific cell that has increased expression of cell adhesion receptors. This review is focused on the utilization of cell adhesion peptides and receptors in specific targeted drug delivery, diagnostics, and tissue engineering. In the future, more information on the mechanism of internalization and intracellular trafficking of cell adhesion molecules will be exploited for delivering drug molecules to a specific type of cell or for diagnosis of cancer and heart and autoimmune diseases.     

葡萄球菌中红霉素对克林霉素诱导型耐药的检测及耐药性分析

目的:了解诱导型克林霉素耐药的葡萄球菌的耐药状况及发生率.方法:用常规方法对2007年1月～2009年12月各种临床标本进行培养,MicWalK 40微生物鉴定仪进行鉴定及药物的敏感性试验检测,红霉素诱导克林霉素耐药试验采用双纸片法进行.结果:350株葡萄球菌中结构型克林霉素耐药葡萄球菌有112株,占32.0%,诱导型克林霉素耐药的葡萄球菌有36株,占10.3%,36株诱导型克林霉素耐药的葡萄球菌对利奈唑胺、万古霉素、奎奴普汀/达福普宁均100.0%敏感.结论:葡萄球菌对克林霉素的耐药主要是结构型耐药,利奈唑胺、万古霉素、奎奴普汀/达福普宁对克林霉素诱导型葡萄球菌有良好体外抗菌活性.     

抗病毒药物耐药及耐药机制研究进展

目前临床应用的抗病毒药物达40多种，为病毒引起的疾病的治疗发挥了重大作用。与临床其他抗感染药物一样，抗病毒药物长期应用易产生耐药性．降低疗效，成为临床治疗及新药开发的重要问题。本文就抗艾滋病毒药物、抗乙型肝炎病毒药物、抗流感病毒药物及抗疱疹病毒药物耐药性及耐药机制研究进行综述。     

Radionuclide therapy of cancer with radiolabeled antibodies

Radioimmunotherapy (RIT) using radiolabeled monoclonal antibodies (MAbs) directed against tumor-associated antigens has evolved from an appealing concept to one of the standard treatment options for patients with non-Hodgkin's lymphoma (NHL). Inefficient localization of radiolabeled MAbs to nonhematological cancers due to various tumor-related factors, however, limits the therapeutic efficacy of RIT in solid tumors. Still, small volume or minimal residual disease has been recognized as a potentially suitable target for radiolabeled antibodies. Several strategies are being explored aimed at improving the targeting of radiolabeled MAbs to solid tumors thus improving their therapeutic efficacy. In this review, various aspects of the application of radiolabeled MAbs as anti-cancer agents are discussed, and the clinical results of RIT in patients with hematological and various solid cancers (colorectal, ovarian, breast and renal carcinomas) are reviewed.     

真菌对临床抗真菌药物的耐药机制

真菌感染,尤其是深部真菌感染的发病率近年来呈上升趋势,抗真菌药物的大量使用引起了真菌耐药曰益严重,严重影响了抗真菌药物治疗的效果,也增加了危重患者的病死率,因此对真菌耐药机制的研究十分必要.本文依据常用抗真菌药物的药物种类,分别总结论述了近年来真菌耐药机制研究的新进展.