遗传药理学与高血压药物治疗进展

遗传药理学对于解释药物反应的个体差异并进行个体化用药具有重要意义。近年来其新技术在高血压治疗等方面的临床应用引起了广泛关注。本文结合本临床评价中心实践经验,从药代动力学和药效动力学方面对与高血压治疗相关的基因多态性研究进展,及其对高血压个体化治疗的影响进行综述。可以认为基因芯片技术等药物基因组学的新发展,必将对高血压等疾病的个体化治疗发挥更显著的促进作用。     

药物基因组学及其在合理用药中的应用

药物基因组学 (ｐｈａｒｍａｃｏｇｃｎｏｍｉｃｓ)是 2 0世纪 90年代末发展起来的基于功能基因组学 (ｆｕｎｃｔｉｏｎａｌｇｅｎｏｍｉｃｓ)与分子药理学的一门科学。它从基因水平研究基因序列的多态性与药物效应多样性之间的关系 ,即 :研究基因本身及其突变体对不同个体药物作用效应差异的影响 ,以此为平台开发药物 ,指导合理用药 ,提高用药的安全性和有效性 ,避免不良反应 ,减少药物治疗的费用和风险[1,2 ] 。1　药物基因组学的研究内容与方法药物基因组学是基于药物反应的遗传多态性提出来的 ,遗传多态性是药物基因组学的基础。药物遗…     

环孢素A的药物基因组学与个体化用药的研究现状及进展

环孢素（CsA）作为一种新型强效免疫抑制剂,近年来广泛应用于器官移植术后的抗排斥反应治疗。由于其治疗指数狭窄,个体间差异大,如何在临床合理使用CsA-直是广大学者关注的热点。CsA的生物利用度和代谢主要受药物代谢酶CYP3A和转运蛋白P-糖蛋白（P-gp）的影响,而不同个体间CYP3A与多药耐药基因（MDR1）基因多态性则是CYP3A酶和P-gP产生活性差异的分子机制。此外,合并用药、饮食结构等非遗传因素也是影响CsA疗效的重要原因,本文就近年来CsA药物基因组学研究进展结合非遗传因素予以综述,为临床个体化用药提供参考,确保患者安全合理用药。     

基于药物基因组学指导转移性结直肠癌化疗药物个体化用药的研究现状

转移性结直肠癌患者的化疗反应存在较大的个体差异,这种差异可能由遗传和药物的相互作用等因素引起。基于药物基因组学指导转移性结直肠癌患者化疗方案的个体化用药有助于确保化疗疗效,降低药物不良反应。本文通过系统梳理转移性结直肠癌患者化疗药物基因组学相关内容及临床用药指南,并简要介绍了中药联合化疗药物在其治疗中的临床应用情况,以期为转移性结直肠癌患者的个体化治疗提供用药参考建议。     

抗精神病药物的基因组学研究进展

目的从药物基因组学的角度出发,试析抗精神病药物剂量的个体差异与药物反应的遗传多态性之间的关系。方法查阅近几年的相关文献,从而综述抗精神病药物基因组学的研究进展。结果 5-羟色胺受体、多巴胺受体、5-羟色胺转运蛋白、p-糖蛋白、儿茶酚氧位甲基转移酶、细胞色素P450酶、G蛋白等的基因多态性与抗精神病药物的药效及药动学差异有直接关系。结论基因表型与药物之间存在明显的关系,但受多种基因之间相互作用的影响,某一种基因的独立作用尚不能肯定。但是,从基因多态性的角度考虑个体之间的差异,是未来实现用药个体化,提高药物疗效,减少药物不良反应的重要途径。     

治疗药物监测与药物基因组学

目的将药物基因组学应用到临床合理用药,为临床个体化给药提供依据。方法查阅文献,总结治疗药物监测在临床实践中发现的问题,并阐述药物基因组学等学科的发展与特点。结果基因多态性是药物治疗效果因人而异的最重要因素。通过药物基因组学研究,实现临床个体化药物治疗,是治疗药物浓度监测的进一步延伸和充实。药物基因组学应用到临床合理用药,弥补了以往只根据血药浓度进行个体化给药的不足,也为以前无法解释的药效学现象找到了答案。结论将来的临床药物治疗模式应以遗传药理学、药物基因组学为导向,结合血药浓度监测,来指导特定药物对特定患者的合理使用。     

心血管药物代谢酶及其遗传药理学研究进展

目的:为心血管药物的临床合理应用和个体化给药提供参考。方法:检索近年来国内、外遗传药理学和药物基因组学在心血管药物代谢酶研究方面的论文,对其进行分析、归纳和总结。结果与结论:药物代谢酶的基因多态性是心血管药物疗效和不良反应产生个体差异的重要原因,是个体化给药的依据。     

药物基因组学在晚期非小细胞肺癌治疗中的应用

药物基因组学以药物效应及安全性为目标,将基因的多态性与药物效应个体多样性紧密的联系在一起。药物基因组学研究不同于以往的基因研究,不是以发现新基因,阐明作用机制为目标,而是通过研究遗传因素对药物效应的影响,针对不同个体携带的基因型,给予不同的药物或剂量,以达到个体化治疗的目的。目前药物基因组学的研究主要是单核苷酸多态性（SNP）的研究,随着对药物作用机制分子水平的深入阐明,药物基因组学在抗癫痫药物、     

基因多态性与临床合理用药

药物基因组学(pharmacogcnomics)是以药物效应和安全为主要目标,研究药物体内过程差异的基因特性,以及基因变异所致的不同患者对药物的不同反应,从而研究开发新的药物和合理用药方法的一门新学科。它从基因水平研究基因序列的多态性与药物效应多样性之间的关系,研究基因及其突变体对不同个体药物作用效应差异的影响,并以此为平台指导药物合理应用,为提高药物的安全性和有效性,减少不良反应,为实现个体化医疗提供了理论依据和技术支持。     

遗传药理学在临床安全用药中的作用

本文介绍了个体遗传多态性以及遗传药理学在安全用药中的作用。加深对药理效应和药物代谢个体差异的遗传因素及个体化用药的了解,从而提高临床疗效,减少药物不良反应。     

Adverse drug reactions: role of pharmacogenomics.

Adverse drug reactions (ADRs) are a significant cause of morbidity and mortality. The majority of ADRs can be considered common disorders with considerable clinical variability (clinical phenotype) in which many different genes are involved together with environmental variables. Pharmacogenomics is the study of how genes affect the individual response to drugs. There is some evidence that in the future the use of pharmacogenomics could help to reduce ADRs, as it aims to predict which patients are likely to respond to a particular drug and which patients are likely to have significant ADRs. In this article some examples of genetic polymorphisms affecting drug kinetics, drug toxicity and hypersensitivity related to ADRs are illustrated.     

EUDRAGENE: European collaboration to establish a case-control DNA collection for studying the genetic basis of adverse drug reactions

Type B adverse drug reactions (ADRs) are often serious, limit the usefulness of drugs that are otherwise effective, and increase the risks of drug development as they often lead to postmarketing withdrawal. There is evidence that susceptibility to at least some Type B ADRs is under strong genetic influence. Identifying genes in which variation influences susceptibility has obvious practical value for genetic testing and might also make it easier to screen molecules likely to cause ADRs at an early stage of the drug development process. Research in this area is hampered by the lack of a resource in which to study genetic determinants of susceptibility to Type B ADRs. As serious Type B ADRs are rare, case-control designs are the most frequently-used approach. The EUDRAGENE collaboration seeks to develop a resource using an international collaboration. This will provide a basis for adverse drug susceptibility genome association-wide studies using tag single nucleotide polymorphisms, or a direct approach using putative functional polymorphisms.     

HIV Pharmacogenomics

Pharmacogenomics classically focuses on host nuclear genetic polymorphisms that can be used to predict adverse drug reactions (ADRs). Because ADRs are defined as any noxious, unintended, and undesired drug effects, loss of efficacy due to the development of antiretroviral drug resistance and both acute and cumulative adverse effects of antiretroviral therapy can be considered ADRs. In order to address these types of antiretroviral-associated ADRs, pharmacogenomic testing methods have expanded to include molecular assays that characterize extranuclear genetic material (e.g. HIV and mitochondrial genomes), as well as the host nuclear genetic material. Recent molecular advances permit high resolution resistance testing that detects loss of therapeutic efficacy through the use of phenotypic, genotypic and/or virtual phenotypic resistance testing. These assays use complex technical and interpretative methods to improve the therapeutic efficacy of antiretroviral therapy. The resistance assays demonstrate the utility of pharmacogenomic testing for patients undergoing lifelong and complex antiretroviral therapies. Future applications of antiretroviral-directed pharmacogenomic tests range from quantitative detection of mitochondrial depletion as an early surrogate marker for drug toxicity, to qualitative analysis of host immune haplotypes, and metabolic/transporter genetic polymorphisms for predicting disease progression.In summary, pharmacogenomic testing for HIV-positive patients provides proof of principle that these tests can be used clinically to improve outcomes for patients undergoing complex and sustained drug regimens.     

Pharmacogenomics of cardiovascular drugs and adverse effects in pediatrics

Individual response to medication is highly variable. For many drugs, a substantial proportion of patients show suboptimal response at standard doses, whereas others experience adverse drug reactions (ADRs). Pharmacogenomics aims to identify genetic factors underlying this variability in drug response, providing solutions to improve drug efficacy and safety. We review recent advances in pharmacogenomics of cardiovascular drugs and cardiovascular ADRs, including warfarin, clopidogrel, β-blockers, renin-angiotensin-aldosterone system inhibitors, drug-induced long QT syndrome, and anthracycline-induced cardiotoxicity. We particularly focus on the applicability of pharmacogenomic findings to pediatric patients in whom developmental changes in body size and organ function may affect drug pharmacokinetics and pharmacodynamics. Solid evidence supports the importance of gene variants in CYP2C9 and VKORC1 for warfarin dosing and in CYP2C19 for clopidogrel response in adult patients. For the other cardiovascular drugs or cardiovascular ADRs, further studies are needed to replicate or clarify genetic associations before considering uptake of pharmacogenetic testing in clinical practice. With the exception of warfarin and anthracycline-induced cardiotoxicity, there is lack of pharmacogenomic studies on cardiovascular drug response or ADRs aimed specifically at children or adolescents. The first pediatric warfarin pharmacogenomic study indeed indicates differences from adults, pointing out the importance and need for pediatric-focused pharmacogenomic studies.     

Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy

Most medications exhibit wide interpatient variability in their efficacy and toxicity. For many medications, these interindividual differences result in part from polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters, and/or drug targets (eg, receptors, enzymes). Pharmacogenomics is a burgeoning field aimed at elucidating the genetic basis of differences in drug efficacy and toxicity, using genome-wide approaches to identify the network of genes that govern an individual's response to drug therapy. For some genetic polymorphisms, such as thiopurine S-methyltransferase (TPMT), monogenic traits have a marked effect on the pharmacokinetics of medications, such that individuals who inherit an enzyme deficiency must be treated with markedly different doses of the affected medications (eg, 5-10% of the standard thiopurine dose). This review uses the TPMT polymorphism and thiopurine therapy (eg, azathioprine, mercaptopurine) to illustrate the potential of pharmacogenomics to elucidate genetic determinants of drug response, and optimize the selection of drug therapy for individual patients.     

Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications

Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters, as well as drug metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.     

Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications

Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters, as well as drug metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.