mipomersen通过第2项Ⅲ期临床试验

Isis公司的降脂反义类药物的第一个化合物mipomersen通过了第2项临床试验，明显降低杂合型家族性高胆固醇血症（heFH）病人的LDL一胆固醇（LDL－C）水平。Mipomersen是一种反义寡核苷酸，与载脂蛋白B（apoB）mRNA结合阻止胆固醇和载甘油三酯蛋白的合成。它可能是hoFH（一种罕见和致命的遗传疾病，患者的胆固醇水平极高）病人的新降脂替代药物。     

Mipomersen治疗纯合性家族性高胆固醇血症的Ⅲ期研究达到主要终点

Genzyrne和Isis公司宣布，Mipomersen（Ⅰ）用于治疗纯合性家族性高胆固醇血症（hoFH）的Ⅲ期临床达到主要终点，患者用药26周后，低密度脂蛋白胆固醇水平下降了25％，     

新降脂药Mipomersen取得Ⅲ期临床试验结果

Genzyme和Isis公司于2010年8月4日公布新降脂药Mipomersen的两项Ⅲ期临床试验结果,患者用药后能够降低其低密度脂蛋白（LDL-C）水平,有望用于治疗纯合型家族性高胆固醇血症（hoFH）以及严重高胆固醇血症。     

新型反义降胆固醇药物Mipomersen进入第二项Ⅲ期临床

2008年8月6日，Genzyme和Isis制药公司宣布开始mipomersen治疗杂合性家族性高胆固醇血症（heFH）的第二项Ⅲ期临床。Mipomersen是第二代反义药物，可以降低体内载脂蛋白B—100的含量（载脂蛋白B—100是合成运送胆固醇的关键蛋白）。Ⅱ期临床试验表明mipomersen注射治疗可以明显降低体内胆固醇及其他致动脉粥样硬化的脂类的含量，且优于其他降脂药物。     

新型降脂药——依折麦布的研究进展

依折麦布是一种新型胆固醇吸收的选择性抑制剂，在单独用药或与他汀类药物联用时，都能稳定降低血浆低密度脂蛋白胆固醇水平，为临床治疗高脂血症和动脉粥样硬化提供了新的选择。本文综述了依折麦布的作用机制、药动学特性及其在临床应用中的最新进展。     

新型胆固醇吸收抑制剂依泽替米贝

依泽替米贝是新型选择性胆固醇吸收抑制剂,现对其作用机制、药动学及临床单独使用或与他汀类药物联用治疗高胆固醇血症的研究进展进行综述.     

新型选择性胆固醇吸收抑制剂依泽麦布

依泽麦布为一种新型口服调血脂药物，它能选择性抑制肠道对胆固醇和相关植物甾醇的吸收。单独应用或与他汀类药物合用，均能降低具有冠心病风险患者的血清胆固醇水平。本文主要对其作用机制、药代动力学、临床疗效和安全性进行综述。     

抗癫痫新药瑞替加滨

瑞替加滨为神经元钾离子通道开放剂,是一种具有全新作用机制的抗癫痫药,临床上用于成人癫痫部分发作的辅助治疗。文中对瑞替加滨的作用机制、药效学、药代动力学、药物相互作用、临床评价和安全性等进行综述。     

普罗布考对高密度脂蛋白胆固醇代谢的影响及其作用机制

普罗布考是一种调脂药 ,其在降脂同时显著降低了血浆HDL C含量却能抗动脉粥样硬化。高密度脂蛋白 胆固醇 (HDL C)在体内的代谢过程目前尚未清楚 ,有研究表明普罗布考通过促进胆固醇逆向转运途径而抗动脉粥样硬化。文章综述普罗布考对体内HDL C代谢的影响及其作用机制。     

他汀类药物的非降脂作用

他汀类药物又称羟甲基戊二酸单酰辅酶A(HMG-CoA)还原酶抑制药.其主要机制是抑制胆固醇合成途径的HMG-CoA还原酶,阻止该酶催化产物甲羟戊酸的合成.临床应用显示此药具有安全有效的调整胆固醇和甘油三酯水平的作用;同时发现该药还具有诸多非降脂作用,如有抗骨质疏松、抗炎、抗肿瘤、抗病毒,降低脂蛋白(a)等作用.显示出临床多方面的应用价值.     

Drug affinity responsive target stability and its application: Review北大核心CSCD

A drug target refers to specific molecules that exist within tissue cells and interact with a drug to produce the drug effect. More than 98% of drug targets belong to protein. The interactions between a drug and the target in cells play a key role in the drug effect. How to use various methods to find and confirm the new target of a drug is one of the important challenges facing researchers. Drug affinity responsive target stability (DARTS) is a new technique based on the principle that when a small molecule compound binds to a protein, the interaction stabilizes the target protein's structure so that it becomes protease resistant. This technique is universally applicable to drug screening and target identification because it requires no modification of the drug and is independent of the mechanism of drug action. This paper reviews the discovery of DARTS method, technical principles, methodology and its applications in researches.     

Autoradioluminography,a powerful and reliable tool for drug development: Accelera's experience

A deeper understanding of the pharmacokinetic and pharmacodynamic properties of a drug candidate is a pivotal component of drug discovery and development. Autoradiography is an excellent technique allowing exploiting the advantages of the use of radioisotopes in the drug disscovery field. The introduction of phosphor imaging technology has revolutionized the handling of drug distribution studies providing high‐resolution images. Specifically, quantitative whole‐body autoradioluminography is employed for preclinical study where the aim is to obtain information about the route of elimination and tissue distribution of a drug candidate. Autoradioluminography is also the technique of choice pursued to deal with all the issue that it is possible to encounter in all stage of drug development (ie, site‐specific drug localization and retention, drug‐drug interactions, penetration into specific target, specific tissue binding, crossing of brain blood barrier, and placental transfer). The purpose of this review is to give a picture of how autoradiography is employed in our laboratory as a key tool for advances in the assessment of the drug disposition and to validate new experimental models.     

A novel approach for the control of drug release rate through hydrogel membrane: I. Effect of drug immobilization on drug release rate by copolymerization method.

Precise control of drug release rate in hydrogel drug delivery systems to better mimic physiological condition is a challenging research topic in development of Advanced Drug Delivery Systems. One of the major issues with bioresponsive drug delivery systems is the excessive 'leakage' of drug while the system is in the 'off' state, which leads to shortening of the device life-time and potential overdose problem for the patient. In the present study, a new approach, based on partition effects, termed drug immobilization via copolymerization, is proposed to control the drug release rate of membrane-based drug delivery systems. In this method, a certain level of drug is pre-immobilized in the membrane through copolymerization. The immobilized drug contributes to the overall chemical potential of drug molecules in the membrane but their mobility is restricted, hence will not be released. At equilibrium, the amount of drug from donor that dissolved in the membrane is reduced due to contribution of immobilized drug, resulting in an effective reduction in partition coefficient and hence the release rate. The testing of the method by bovine serum albumin (BSA) as a model drug confirmed the controllability of the method: almost 35% reduction of the drug leakage in the 'off-state' was observed when 20mg BSA was immobilized in the pH-sensitive hydrogel membrane. The mathematical model of the drug partition in the membrane was modified to describe the new partition phenomenon (mobile drug and immobilized drug in the membrane) in this study.     

搭建培训平台 传播先进理念以提高我国新药研发创新能力

随着全球新药研发速度的减缓、研发成本的上升以及投资回报的降低,越来越多的跨国制药公司开始把目光投向具有成本和资源优势的中国,中国已成为全球新药研发战略中不可或缺的重要组成部分。然而,中国的制药产业长期处于低端复制状况,研发理念落后,专业人才缺乏,这些已经成为限制中国新药研发创新能力的瓶颈。要想提高我国新药研发创新能力,实现我国由制药大国走向制药强国的历史转变,就必须建立新药研发培训平台,传播先进理念,为中国培养高端的熟悉整个药品研发产业链条的专业人才。     

药品技术审评时限纳入法规的合理性讨论

目的 探讨将药品技术审评时限写入法规中的合理性问题.方法 通过分析人用药品注册技术要求国际协调会（ICH）成员国美国、日本及欧盟在法律中对药品技术审评时限的规定,并对美国、日本药品实际审评时限作简要统计.结合我国药品审评现状,进一步分析我国将药品技术审评时限写入法规中是否合理.结果与结论 药品技术审评是一项复杂的技术工作,其考虑因素的复杂性远非法定时限的简单切割.所以,将药品技术审评时限写入《药品注册管理办法》中有欠妥之处.     

Is it possible to more accurately predict which drug candidates will cause idiosyncratic drug reactions?

The unexpected occurrence of idiosyncratic drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use or failure to release/withdrawal. This leads to considerable uncertainty in drug development and has led to attempts to try to predict a drug's potential to cause such reactions. It appears that most idiosyncratic drug reactions are due to reactive metabolites; however, many drugs that form reactive metabolites are associated with a very low incidence of idiosyncratic drug reactions. Therefore. screening drug for their ability to generate reactive metabolites is likely to cause the rejection of many good drug candidates. There is evidence to suggest that an idiosyncratic drug reaction is more likely if there is some "danger signal'. Thus drugs that cause some degree of cell stress or damage may be more likely to lead to a high incidence of idiosyncratic drug reactions. The exact nature of the putative danger signals is unknown. However, a screen of the effects of drugs known to be associated with a high incidence of idiosyncatic reactions using expression genomics and proteomics may reveal a pattern or patterns of mRNA and protein expression that predict which drugs will cause a high incidence of idiosyncratic drug reactions. Although idiosyncratic drug reactions are not usually detected in animal tests because they are just as idiosyncratic in animals as they are in humans, it is likely that drug reactive metabolites would also cause similar cell stress in animals. It is more likely that in most cases it is differences in the immune response to the reactive metabolites that determine which individuals will develop an idiosyncratic reaction. If the expression of certain proteins in animals treated with a drug candidate could be used as a screening method to predict a drug's potential to cause a high incidence of idiosyncratic drug reactions, it would greatly facilitate the development of safer drugs.     

药物毒理学技术方法研究进展

药物是否安全和有效是药物研发成功与否的决定性因素。就药物研发的整个流程而言,毒性是终止药物研发的重要原因之一。药物毒理学研究贯穿于新药发现阶段、临床前安全性评价和上市后跟踪监督的全过程,因此药物的毒理学研究至关重要。简要综述了药物毒理学研究过程中所涉及的技术方法以及研究新动向,并主要介绍了组学技术的发展。     

我国结核病耐药状况及其变化趋势分析

目的:了解结核病总体耐药、初始耐药和获得性耐药状况及其变化趋势,为改进结核病防治措施提供参考。方法:对国内1995～2005年结核病耐药监测结果进行综合评价,应用SPSS软件进行统计学分析。结果:1995～2005年我国人群结核耐药趋势总体呈下降趋势,总耐药率为24．8％。在耐药病例中,初始耐药率为20．6％,获得性耐药率为44．3％,获得性耐药率显著高于初始耐药率。不同抗结核药物的耐药顺序为:初始耐药异烟肼(15．3％)>链霉素(10．6％)>利福平(8．1％)>乙胺丁醇(4．2％);获得性耐药异烟肼(35．1％)>利福平(26．1％)>链霉素(23．3％)>乙胺丁醇(11．3％)。耐多药率中,1～4种耐药率按年份均呈缓慢下降趋势。耐药率排序为:单药>2药>3药>4药,耐多药率显著高于耐单药率。结论:我国人群结核耐药趋势总体呈缓慢下降趋势,但与发达国家相比,仍属高耐药水平,面临的形势依然十分严峻。     

Simulation of drug use and urine screening patterns

Urine drug screens are used extensively in substance-abuse treatment, especially methadone maintenance treatment programs, as well as criminal-justice and clinical research settings. While positive urinalysis generally indicates drug use, no information is provided about the context or pattern of use. A computer generated model was created to examine the influence of drug use patterns and drug screen schedules upon urine test results. The results indicate that (1) when urine testing is performed at a rate of eight times per year, the probability of testing positive in a given month is little better than 50-50 even for daily use, (2) infrequent drug use is difficult to detect regardless of drug testing frequency, and (3) the benefits of more frequent drug testing are greatest with moderate drug use. The data presented provide a guide for clinicians to match drug screen schedules to frequency or pattern of suspected drug use.     

Tailoring drug therapy based on genotype

Polymorphisms in genes encoding drug metabolizing enzymes, drug transporters, and drug targets can influence drug effects and contribute to inter-individual differences in drug response. Genotype for drug metabolizing enzymes and drug transporters can influence drug disposition in the body (pharmacokinetics), whereas genotype for drug targets may influence sensitivity to a drug (pharmacodynamics). In some cases, response to a particular drug is contingent on genotype for both drug disposition and drug target proteins. For example, warfarin dose requirements are influenced by both cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex 1 (VKORC1) genotypes. The goal of pharmacogenetics is to maximize drug effectiveness while limiting drug toxicity, based on an individual's DNA. Over 80 drugs now contain genetic information in their FDA-approved labeling. In addition to influencing warfarin dose requirements, genotype contributes to the efficacy of clopidogrel in coronary artery disease, risk for hypersensitivity reactions to abacavir in the treatment of human immunodeficiency virus, risk for statin-induced myopathy, and responses to numerous other drugs. Genetic information is routinely integrated into decisions regarding cancer chemotherapy and treatment for human immunodeficiency virus. Clinical implementation of pharmacogenetics is becoming a reality in other therapeutic areas, such as for patients requiring dual antiplatelet therapy following coronary artery stent implantation. In the future, it is possible that individuals will be broadly genotyped so that genetic information can guide drug therapy decisions throughout their lifetime.