药物基因组学与新药开发

药物基因组学是建立在人类基因组计划之上的一门新兴学科 ,在基因芯片技术、遗传标记技术以及功能蛋白质组学的推动下 ,药物基因组学发展非常迅速。它的学科范畴将逐步涵盖人类基因组的研究、病原生物基因组的研究以及药物产生基因的研究。生物医学工程中药物基因组学在实现个体化用药的同时也为新药开发开辟了新的领域 ,将推动整个制药工业的发展。     

国外药物基因组学的开发动态

药物基因组学是药物研究的新方法之一,并逐步成为发现新的药物治疗靶点,鉴定先导化合物,研究其药理作用、代谢规律及不良反应的有效方法之一.以基因多态性为基础建立的药物基因组学是一门研究影响药物吸收、转运、代谢、清除、作用等个体差异的基因特性即决定药物行为和敏感性的全部基因的新学科.现简述药物基因组学的研究概况和国外的开发动态.     

药物基因组学及其在合理用药中的应用

本文介绍了药物基因组学的概念 ,综述了药物基因组学在合理用药、新药开发、临床前药理研究等方面的应用及其研究方法。药物基因组学可以改善病人用药 ,使用药更有效、更安全 ,同时也给新药研究提供了很大机遇     

参与的是新药开发的重要环节

当申办者要求各区域与会者推荐适合的国家时,范大超最自然不过地发出"拿到中国来做"的呼声——"这次的试验是否能在亚洲的参与国家中加入中国?""的确,我们也曾经考     

药物基因组学的应用研究

介绍药物基因组学的概念、研究内容、应用前景。通过研究遗传因素(基因型)与药物反应相互关系，以提高药物的疗效及安全性为目标，研究影响药物吸收、转运、代谢、消除等个体差异的基因特性，以及相同药物对基因变异所致的不同患者产生不同疗效和不良反应发生率，并据此开发新药和进行个体化给药。     

药物基因组学研究概况

目的介绍药物基因组学的研究目的、内容和方法，指导用药的安全性及合理用药。方法对近年国内外发表的文献作分析、归纳，总结了药物基因组学的概念，了解遗传基因多态性与药物对机体影响差异之间的关系。结果与结论药物基因组学在促进合理用药、推动新药开发、降低医疗保健费用开支等方面具有广泛意义。     

浅谈药物基因组学的研究及应用

目的：介绍药物基因组学的概念，研究和应用趋势，为医药卫生人员提供新的理念。方法：以国内外有影响和有代表性的献为依据，对药物基因组学的概念，研究及应用进行综述。结果：药物基因组学的研究及应用，将极大地推动药物研发进程，并在指导合理用药和市场化策略等方面发挥根本性作用。结论：药物基因组学将对21世纪医学产生深远影响。     

药物基因组学在临床试验中的应用

随着药物基因组学的发展,其在新药研发中逐渐被应用。新药研发是一个高投入、高风险、长周期的过程,药物基因组学在药物靶点的发现、临床前研究、临床研究以及新药上市后不良反应监测方面有重要作用。在Ⅰ～Ⅳ期临床试验中,根据基因型对受试者进行分层分析,可以减少受试者纳入人数,尽可能地减少毒性反应,节省高昂的临床研究成本,缩短上市所需时间。但是,药物基因组学在临床试验中的应用尚处于早期阶段,还面临着许多问题,随着各种新技术的研究和应用,药物基因组学在新药研发上将有更为广阔的前景。     

药物安全性和新药开发

20 0 1年 8月降胆固醇药物Balcol (cerivastatin ,西立伐他丁 )因不良反应而撤出市场 ,Bayer公司的股价随即跳水 ,一下子跌落 18%。Bayer公司的这一遭遇证明药物的安全性并非小事 ,它对一家企业的利益 ,甚至对其资本价值都有重大影响。Sanofi-Synthelabo则从相反的角度证实了同样的道理。该公司的抗血小板凝聚药物Plavix(Clopidogrel,氯吡格雷 )在减少动脉粥样硬化病人心脏病发作率及血管疾病危险方面效果较阿司匹林仅胜一筹 ,因它不会引起胃肠道出血 ,由此它成了“重磅炸弹” ,使该公司 2 0 0 2年的销售总额猛增 14 .8%。1　不良副作用…     

Pharmacogenomics and drug response

Following pioneer work in the early 20th century, the era of molecular pharmacogenomics started with the cloning of a polymorphic gene encoding the drug-metabolizing enzyme cytochrome P450-2D6. Today, recent conceptual and methodological advances in genomics allow a much broader approach to elucidating inheritance patterns in drug response and identification of functional polymorphisms, that affect drug response, has become a key issue. Despite recent euphoria about potential applications of pharmacogenomic principles, currently available pharmacogenomic data have had modest overall impact on the routine of drug therapy. Most data were derived from single gene approaches for select drug metabolizing enzymes with extreme phenotypes. Data on genetic determinants of drug distribution, absorption and response, however, are scarce and it seems that most events in the dose-response cascade follow a complex interplay of environmental factors with several genes encoding proteins in multiple pathways. Thus, there is great need for clinical studies on genotype-phenotype and gene environment interactions, based on multiple gene approaches. Major challenges also relate to practical aspects of clinical pharmacogenomic studies, e.g. appropriate data handling, selection of appropriate study designs and control groups and issues of prediction accuracy. To move to a clinically useful and predictive level in pharmacogenomics, much work remains to be completed. Nevertheless, it can be anticipated that for select drugs, pharmacogenomics may lead to a shift from the current strategy of developing medications for a statistically optimized fraction of patients to a strategy that aims to provide tailored medications for genetically diverse patients.     

Pharmacogenomics and drug development

It is generally anticipated that pharmacogenomic information will have a large impact on drug development and will facilitate individualized drug treatment. However, there has been relatively little quantitative modeling to assess how pharmacogenomic information could be best utilized in clinical practice. Using a quantitative model, this review demonstrates that efficacy is increased and toxicity is reduced when a genetically-guided dose adjustment strategy is utilized in a clinical trial. However, there is limited information available regarding the genetic variables affecting the disposition or mechanism of action of most commonly used medications. These genetic factors must be identified to enable pharmacogenomic testing to be routinely used in the clinic. A recently described murine haplotype-based computational genetic analysis method provides one strategy for identifying genetic factors regulating the pharmacokinetics and pharmacodynamics of commonly used medications.     

药物基因组学与安全用药

由于人类基因组计划的实施,特别是目前较为精确的人类基因组全序列的初步绘制,以及大量单核苷酸多态性 (single-nucleotide polymorphisms,SNPs)的检测与发现,以基因水平研究药物反应个体差异的药物基因组学在生物技术和医药工业界掀起了前所未有的热潮.     

Pharmacogenomics in anticoagulant drug development

The emergence of pharmacogenomic-guided anticoagulant drug development has unraveled novel approaches in the management of patients and ensured individualized therapy to one and all. Gene expression profiling will be useful in the diagnoses of various diseases, in preclinical phases of drug development and in developing markers for adverse drug reactions and desired pharmacological effects. Hence, the adverse drug reactions can be avoided by withdrawing a particular drug. Through cheminformatics, decisions could be made in anticoagulant drug discovery, tailored to the individual needs of the patient at the right dosage and right time. As the human genome is now completely mapped, gene-based single nucleotide polymorphism will be valuable in the diagnosis of diseases. In this review, various polymorphism of coagulation factors will be discussed. Newer anticoagulant drugs could be withdrawn from drug discovery and development pipelines should they exhibit hepatic metabolism requiring CYP450 enzymes known to manifest single nucleotide polymorphism resulting in adverse drug reactions. Pharmacogenomics and cheminformatics should be incorporated in the current study designs of prospective clinical trials. Pharmacogenomic and pharmacogenetic data should be included in the Investigational New Drug (IND) applications, which would enable the FDA to better understand its true impact on pharmacoeconomics. Pharmacogenomics will eventually revolutionize anticoagulant drug development and future practice of medicine.     

Pharmacogenomics to predict drug response

From theory to proof-of-concept, pharmacogenomics promises to improve future general healthcare in a number of ways. By identifying individuals who will respond to a particular drug treatment compared to those who have a low probability of response, pharmacogenomic test development hopes to aid the physician in prescribing the optimal medication for each patient. This approach promises faster relief from symptoms, a lowering of side effect risks and a reduction in healthcare costs. Pharmacogenomic tests used by the pharmaceutical companies themselves can be used to help identify suitable subjects for clinical trials, aid in interpretation of clinical trial results, find new markets for current products and speed up the development of new treatments and therapies. This type of approach should also see fewer compounds failing during later phases of development. The questions we are faced with as we enter the new millennium, however, are if and when the promises of pharmacogenomnics in improving healthcare will be fulfilled. Currently, there are only a handful of pharmacogenomic tests and associated products which are commercially available and it remains to be seen what impact these will have on the market and on healthcare in general.     

Pharmacogenomics and drug response in cardiovascular disorders

There are a total of 17 families of drugs that are used for treating the heterogeneous group of cardiovascular diseases. We propose a comprehensive pharmacogenomic approach in the field of cardiovascular therapy that considers the five following sources of variability: the genetics of pharmacokinetics, the genetics of pharmacodynamics (drug targets), genetics linked to a defined pathology and its corresponding drug therapies, the genetics of physiologic regulation, and environmental-genetic interactions. Examples of the genetics of pharmacokinetics are presented for phase I (cytochromes P450) and phase II (conjugating enzymes) drug-metabolizing enzymes and for phase III drug transporters. The example used to explain the genetics of pharmacodynamics is glycoprotein IIIa and the response to antiplatelet effects of aspirin. Genetics linked to a defined pathology and its corresponding drug therapies is exemplified by ADRB1, ACE, CETP and APOE and drug response in metabolic syndrome. The examples of cytochrome P450s, APOE and ADRB2 in relation to ethnicity, age and gender are presented to describe genetics of physiologic regulation. Finally, environmental-genetic interactions are exemplified by CYP7A1 and the effects of diet on plasma lipid levels, and by APOE and the effects of smoking in cardiovascular disease. We illustrate this five-tiered approach using examples of cardiovascular drugs in relation to genetic polymorphism.     

Pharmacogenomics: integration into drug discovery and development

To deliver on the promise of personalized medicine requires the integration of pharmacogenomics into the discovery and development of medicines. Over the last few years the pharmaceutical industry has been building considerable resources to achieve that. However, this requires new skill sets, capabilities and infrastructures which have not been a traditional part of the industry's efforts. In this article we describe how the integration of genetics and pharmacogenomics data has begun to deliver success and illustrate the challenges that the new science and technologies bring and how these challenges can be addressed in order to deliver on the promise.