药物基因组学及生物芯片应用

药物基因组学(Pharmacogenomics)主要阐明药物代谢、药物转运和药物靶分子的基因多态性与药物作用,包括疗效和毒副作用之间的关系。药物基因组学将在药学研究中,特别是药物作用机制、药物代谢、提高药物疗效及新药研发等方面发挥重要作用,并将从根本上改变药物临床治疗模式和新药开发方式。笔者通过对药物基因组学的研究内容的分析、阐明,讨论生物芯片与药物基因组学之间的关系,以及药物基因组学的发展前景。     

肿瘤药物基因组学研究进展

药物基因组学对于解释药物反应的个体差异及开展个体化用药具有重要意义。近年来药物基因组学新技术在肿瘤药物治疗方面的进展和应用鉴定出多种影响肿瘤药物治疗的遗传变异,深刻影响肿瘤治疗的药物研发及个体化治疗。本文通过举例说明近期肿瘤药物基因组学重要研究进展的临床应用评价及面临的挑战,对肿瘤药物基因组学的发展及其临床应用进行综述。     

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。     

药物基因组学与合理用药研究进展

目的介绍药物基因组学及其在临床制定治疗方案中的应用。方法根据有关文献 ,综合分析、归纳总结药物基因组学和临床药物基因组学的发展、研究内容及与个体化用药的关系。结果药物基因组学研究表明 ,基因多态性与药物作用多样性之间的关系非常密切。结论药物基因组学为安全、有效和合理用药提供了理论依据。     

药物基因组学与合理用药

目的 :介绍药物基因组学及其在临床制定药物治疗方案中的应用。方法 :依据有关文献分析、归纳、总结药物基因组学的发展、研究内容及与个体化给药的关系。结果 :药物基因组学研究基因的多态性与药物作用多样性之间的关系。结论 :药物基因组学为安全、合理用药提供理论依据     

药物基因组学及生物芯片应用

药物基因组学主要阐明药物代谢、药物转运和药物靶分子的基因多态性与药物作用、包括疗效和毒副作用之间的关系。目前药物基因组学通常是指以快速增长的人类基因组中所有基因信息,指导新药开发的一个领域。药物基因组学有可能从根本上改变药物临床治疗模式和新药开发方式。生物芯片技术在药物基因组学研究中的应用,必将有助于设计针对靶点的更为有效的新型药物,提高临床疾病的诊断和治疗水平。     

药物基因组学在药物研发中的转化与应用

药物安全性和有效性是新药开发和临床用药的核心问题,也是药物基因组学研究的主要内容。目前,已阐明影响药物安全性有效性及个体化差异的首要因素是药物相关生物标记。近年来,药物基因组学各机构正式成立,各发达国家也纷纷出台各种规章,对药物研发中药物基因组学的应用进行规定。药物基因组学在上市药物的评价中已获得巨大的成功,并成功指导了数例肿瘤靶向药物从研发到上市的全过程,缩短了药物开发周期、降低了研究成本及毒副反应。     

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、     

心功能不全患者骨折术后使用地高辛的药学监护

80岁骨折术后男性患者,因心功能不全服用地高辛后,临床药师分析药物相互作用、生理病理状态对地高辛浓度的影响,计算群体药代动力学参数,预测药物浓度。临床药师干预患者地高辛的治疗方案,减少不良反应的发生,使临床用药更安全、有效、合理。     

影响地高辛作用的相关因素

目的总结影响地高辛作用的相关因素。方法通过检索中国医院数字图书馆1990-2010年文献,对影响血清地高辛浓度及地高辛作用的因素进行汇总分析。结果影响地高辛作用的因素很多,包括患者年龄、性别、服药时间、病理状况、用药剂量、取样时间以及联合应用的药物都对地高辛的血清浓度有影响。结论地高辛有效浓度范围比较窄,药效学、药动学个体差异大,影响地高辛作用的因素很多,应注意监测地高辛血药浓度及不良反应,适时调整地高辛剂量,以确保患者的治疗安全、合理、有效。     

华法林药物基因组学的研究推动其个体化医疗的进程

药物基因组学可以帮助人们更好地认识药物与机体之间的相互作用。华法林是临床上广泛使用的香豆素类口服抗凝血药,其狭窄的抗凝治疗指数范围和抗凝不当所致的并发症一直困扰着临床医师,如何合理使用已经成为一个难题。近年来,随着药物基因组学的快速发展,研究发现药动学和药效学多个相关基因的多态性造成了个体差异,影响了华法林的使用剂量。本文综述了药物基因组学研究在华法林用药中的国内外最新进展,为华法林个体化医疗提供参考依据。     

药物基因组学与个性化药物设计研究进展

药物基因组学是采用基因组学的信息和研究方法，通过分析DNA的遗传变异和监测基因表达谱，以阐明药物反应差异的遗传学本质。这不仅有利于根据药物代谢和药物反应的遗传学特点指导合理用药，而且有利于开发和设计新的药物。综述药物基因组学研究进展，论述与药物开发和临床用药相关的药物代谢的基因组学原理，给出CYP450、药物转运蛋白等实例，概述药物基因组学的一些潜在的用途，预测药物基因组学的发展和临床应用前景。     

临床药物个体化治疗技术体系研究进展

临床药物个体化治疗是精准医疗的重要组成部分,代表现代医学的最新发展趋势,旨在保障患者用药安全、有效和经济。近年来随着分子生物学、基因组学和生物信息学技术的进步,临床药物个体化治疗已开始利用药物基因组学、治疗药物监测等技术获得一些良好的治疗效果,新兴的类器官技术也在肿瘤药物治疗领域崭露头角。综述临床药物个体化治疗技术体系研究进展,以期为相关研究和治疗提供参考。     

Inappropriate use of digoxin in the elderly: how widespread is the problem and how can it be solved?

Cardiovascular disease is ubiquitous within the elderly population and requires treatment with multiple types of medications. As with any cardiovascular pharmaceutical regimen, the risk versus the benefit of each medication must be strongly considered. This is particularly true where, for various reasons, adverse effects are more often prevalent and pronounced. Over the years, it has been documented that digoxin is a frequently prescribed medication in elderly populations. Although this drug can be beneficial when used in the appropriate setting, recent data would suggest that inappropriate administration of digoxin is common and not without potentially serious consequences. Currently, the use of digoxin can be advocated to control heart failure in atrial fibrillation and when added to ACE inhibitors and diuretics in those patients with symptomatic heart failure related to systolic left ventricular dysfunction. It is likely that the excessive use of digoxin in elderly populations as discussed in this review is perhaps based on the prevalence of diastolic heart failure in the elderly as well as other co-morbid conditions that may mimic heart failure signs and symptoms. Since the elderly appear to be at high risk for digoxin toxicity, the inappropriate use of this medication to treat these conditions could result in significant and unnecessary morbidity. It is proposed that echocardiography should be performed in most elderly patients when congestive heart failure is suspected. This simple diagnostic tool, along with a careful history and medical examination, would hopefully prevent the misinterpretation of confusing clinical findings and would help to identify the patients with normal systolic function or valvular disease such as critical aortic stenosis, where digoxin treatment would not be warranted. If it is necessary to administer digoxin, then the likelihood of significant toxicity can be greatly reduced by using an algorithm to calculate the appropriate dosage, which takes into consideration the patient's gender, bodyweight and creatinine clearance. Although it is probable that the indications for digoxin use to treat congestive heart failure will continue to evolve, at the present time most would recommend using this agent in symptomatic heart failure related to a reduction in left ventricular systolic function or when associated with atrial fibrillation.     

心脑血管药物基因组学与个体化治疗研究进展

心脑血管疾病是威胁人类健康的主要疾病,而药物基因组学与个体化治疗的研究和发展为这类疾病的治疗提供了新的思路。药物基因组通过研究药物效应与基因多态性之间的关系,为实现个体化治疗提供理论依据。本文从临床上最常用的抗凝药、抗高血压药、血小板聚集抑制剂和调节血脂药等药物出发,概述了心脑血管药物基因组学研究进展。     

Making digoxin therapeutic drug monitoring more effective

Digoxin is an important drug in the treatment of patients with either congestive heart failure or atrial arrhythmia. Because of its narrow therapeutic range, digoxin serum concentrations are commonly monitored in both inpatients and outpatients. However, with the costs of health care skyrocketing, there is debate whether such therapeutic drug monitoring (TDM) is cost-effective. To reduce the number of samples drawn too soon after a previous dose and in an effort to improve digoxin TDM at this teaching hospital, a new dosing and monitoring policy was initiated. This policy involved uniform digoxin dosing at 5 p.m. (1700 h) for all inpatients and serum drug measurements at 7 a.m. (0700 h) the next day. By coordinating the time of dosing to be greater than 12 h prior to serum digoxin analysis, the number of inappropriate digoxin serum determinations have been reduced. This new protocol has increased the effectiveness of the toxicology laboratory and enhanced the efficiency of the house staff. Other issues concerning digoxin TDM are also addressed. These findings can be generalized to all drugs that are monitored at any hospital and can result in a significant cost savings and decrease the time spent analyzing inappropriate data.     

Antiarrhythmic agents: drug interactions of clinical significance.

The management of cardiac arrhythmias has grown more complex in recent years. Despite the recent focus on nonpharmacological therapy, most clinical arrhythmias are treated with existing antiarrhythmics. Because of the narrow therapeutic index of antiarrhythmic agents, potential drug interactions with other medications are of major clinical importance. As most antiarrhythmics are metabolised via the cytochrome P450 enzyme system, pharmacokinetic interactions constitute the majority of clinically significant interactions seen with these agents. Antiarrhythmics may be substrates, inducers or inhibitors of cytochrome P450 enzymes, and many of these metabolic interactions have been characterised. However, many potential interactions have not, and knowledge of how antiarrhythmic agents are metabolised by the cytochrome P450 enzyme system may allow clinicians to predict potential interactions. Drug interactions with Vaughn-Williams Class II (beta-blockers) and Class IV (calcium antagonists) agents have previously been reviewed and are not discussed here. Class I agents, which primarily block fast sodium channels and slow conduction velocity, include quinidine, procainamide, disopyramide, lidocaine (lignocaine), mexiletine, flecainide and propafenone. All of these agents except procainamide are metabolised via the cytochrome P450 system and are involved in a number of drug-drug interactions, including over 20 different interactions with quinidine. Quinidine has been observed to inhibit the metabolism of digoxin, tricyclic antidepressants and codeine. Furthermore, cimetidine, azole antifungals and calcium antagonists can significantly inhibit the metabolism of quinidine. Procainamide is excreted via active tubular secretion, which may be inhibited by cimetidine and trimethoprim. Other Class I agents may affect the disposition of warfarin, theophylline and tricyclic antidepressants. Many of these interactions can significantly affect efficacy and/or toxicity. Of the Class III antiarrhythmics, amiodarone is involved in a significant number of interactions since it is a potent inhibitor of several cytochrome P450 enzymes. It can significantly impair the metabolism of digoxin, theophylline and warfarin. Dosages of digoxin and warfarin should empirically be decreased by one-half when amiodarone therapy is added. In addition to pharmacokinetic interactions, many reports describe the use of antiarrhythmic drug combinations for the treatment of arrhythmias. By combining antiarrhythmic drugs and utilising additive electrophysiological/pharmacodynamic effects, antiarrhythmic efficacy may be improved and toxicity reduced. As medication regimens grow more complex with the aging population, knowledge of existing and potential drug-drug interactions becomes vital for clinicians to optimise drug therapy for every patient.     

Pharmacogenomic-guided rational therapeutic drug monitoring: conceptual framework and application platforms for atypical antipsychotics

Atypical antipsychotic agents such as aripiprazole, clozapine, olanzapine, quetiapine and ziprasidone offer many advantages over conventional neuroleptics. These agents reduce negative symptoms of schizophrenia, are effective in treatment refractory cases, and have a markedly lower incidence of extrapyramidal symptoms and tardive dyskinesia. However, there is considerable patient-to-patient variability in therapeutic dose requirements of atypical antipsychotics and the propensity for side effects. Hence, the initial excitement since the introduction of atypical antipsychotics in late 1980s is now shifting towards a focus on individualization of pharmacotherapy and elucidation of the mechanistic basis of interindividual variability in drug response with use of pharmacokinetic and pharmacodynamic biomarkers. Pharmacogenomics, introduced in late 1990s, is the study of variability in drug response using information from the entire genome of a given individual patient. Both pharmacogenomics and conventional therapeutic drug monitoring (TDM) share the similar goal of improving pharmacotherapy through better explanation of individual variability in drug response. Hence, pharmacogenomic biomarkers offer a unique opportunity to complement and expand the scope of traditional TDM in clinical psychopharmacology. Importantly, pharmacogenomics enables the investigation of factors distal to drug exposure in the plasma compartment (e.g. drug targets at the biophase), thereby providing a more complete portrayal of sources of variability in psychotropic drug response. We discuss (1). the definitions for biomarkers and surrogate endpoints in the context of pharmacogenomics, (2). genetic variations in isozyme-specific atypical antipsychotic metabolism in vivo, (3). selected examples of pharmacogenomic variability in pertinent drug targets and, (4). the anticipated roadmap from implementation of pharmacogenomics to changes in healthcare and therapeutic policy. In addition, a conceptual framework that outlines the theoretical advantages of pharmacogenomics-guided TDM is presented using recent clinical applications as precedence.     

Digoxin toxicity in the aged. Characterising and avoiding the problem.

Digoxin is one of the most frequently prescribed drugs, particularly in the elderly population where there is an increased prevalence of atrial fibrillation and cardiac failure. The drug has a narrow therapeutic range and has gained a reputation for producing adverse effects in older patients. The more frail elderly patients with coexistent disease, often taking other treatments, are more at risk from digoxin toxicity due to inappropriate dosing, noncompliance, or increased sensitivity to digoxin resulting from pharmacokinetic or pharmacodynamic interactions. Application of basic pharmacological principles may be helpful in anticipating these problems. Elderly patients more commonly receive digoxin than younger patients, which in part accounts for the higher rates of toxicity in this group. Numerous components contribute to the development of toxicity, and diagnosis of toxicity is difficult in this age group. The measurement of serum concentrations can contribute to the clinical diagnosis. A major problem is the accurate diagnosis of digoxin toxicity which may have numerous nonspecific clinical manifestations, many of which are related to coexisting disease in elderly patients. This diagnostic imprecision is well recognised but has been helped by the introduction of serum digoxin measurement. However, reliance on serum concentrations should not replace clinical judgement, since these do not always correlate with toxicity. The apparently decreasing incidence of toxicity over recent years probably reflects several factors: the improvement in digoxin formulations, awareness of digoxin pharmacology, utilisation of serum concentrations, and the realisation that digoxin withdrawal is a viable proposition in elderly patients. Greater knowledge about the causes and prevention of digoxin toxicity should further reduce the morbidity and mortality arising from digoxin overdose, especially in the elderly population.     

常见药物转运体基因多态性对药动学影响及研究进展

药物转运体在体内药物的吸收（absorption）、分布（distribution）、代谢（metabolism）及排泄（excretion）的过程（ADME）中发挥着关键的作用。转运体在各组织器官的不同分布以及其基因多态性,导致某些药物的吸收、分布、代谢和排泄过程产生明显的个体差异。随着药物基因组学的快速发展,关于转运体基因多态性的研究报道越来越多。本文对近年来人体主要药物转运体基因多态性在药动学和药效学中的影响研究进行综述。