药物基因组学在新药临床试验及个体化用药中的应用

药物安全性和有效性评价是药物临床试验和个体化用药的核心,也是药物基因组学研究的主要内容。药物基因组学研究贯穿于药物 研发、上市评价和临床应用整个过程, 根据药物代谢酶、转运体、受体相关基因多态性对用药者进行分层分析,评价与药物体内的处置过程、 安全性、有效性个体差异的相关性。综述药物基因组学在新药临床试验、个体化用药中的应用研究新进展。     

孕烷X受体的研究进展

核受体是一类高度保守的配体依赖性转录因子家族,在哺乳动物发育、繁殖、免疫应答、心血管功能、组织生长、肿瘤形成、外源物清除及糖类和脂质代谢等生理过程中发挥重要作用。机体对外源物质的清除主要是由孕烷X受体等核受雄介导的。孕烷X受体最早是作为外源物感受器而被研究的,可以被大多数亲脂性药物等外源性化合物及一些内源性化合物如胆汁酸等结构差异很大的配体激活,进而与视黄醇类X受体等形成异源二聚体,结合在ER6、XREM等DNA元件上,调控下游靶基因（包括一相代谢酶、二相结合酶及药物转运体等基因）的表达。此外,孕烷X受体在能量代谢和免疫反应中也有重要作用,参与某些代谢疾病的发生发展,且已在动物模型中被证明是Ⅱ型糖尿病、血脂异常、肥胖症和动脉粥样硬化等代谢疾病治疗的有效靶标。我们主要就其发现、结构、组织分布、作用方式、自身表达的调节等方面的最新研究进行综述。     

肺癌铂类化疗所致周围神经毒性与SNP相关性研究

目前肺癌发病率与死亡率均居恶性肿瘤首位,铂类药物已广泛应用于肺癌等多种癌症的治疗。然而,铂类药物化疗取得较佳疗效的同时,往往由于严重的毒副反应而限制了其使用剂量,从而难以达到最佳疗效。其中,铂类药物化疗所引起的周围神经毒性(peripheral neurotoxicity,PN)十分常见。与此同时,临床中周围神经毒性的发生存在较大的个体性差异,其药物代谢相关基因的单核苷酸多态性(single nucleotide polymorphism,SNP)的遗传变异可能是引起PN发生个体差异的重要原因之一。本文就DNA修复酶、药物代谢酶、转运体等相关基因的SNP与铂类化疗引起的PN之间的相关性作一综述。     

基因多态性与药物的效能

长期以来,人们就认识到不同的个体对同一种药物的反应存在着差异,这直接影响着药物的疗效和不良反应。本文从药物代谢基因、药物受体相关基因、药物转运基因和疾病通路基因等方面论述了基因多态性与药物效能的关系。有关这方面的研究,为开发安全、有效的药物,指导临床个性化合理用药,减少毒、副作用,提供了新的思路。     

CCH1或MID1基因缺失对白念珠菌药物耐受性及致病性的影响

CCH1和MID1基因编码的钙闸门是外源钙进入细胞内的重要通道,Ca2+作为细胞内重要的第2信使分子,其浓度的升高可激活相应的途径参与各种细胞反应过程。该研究将利用钙通路CCH1和MID1基因的单缺失菌株,并构建其相应的回补菌株,研究CCH1或MID1基因缺失后对白念珠菌药物耐受性和致病性的影响作用。通过药物平板敏感性试验和微量液基稀释法比较不同菌株对唑类药物敏感性的变化,进一步添加钙通道阻滞剂和钙离子螯合剂来分析钙离子浓度变化对药物作用的影响,结果发现CCH1或MID1基因的缺失明显对氟康唑和伊曲康唑表现出敏感性,且药物作用受到钙离子浓度变化的调节。最后建立小鼠感染模型分析不同菌株的毒力变化差异,确定CCH1或MID1基因的缺失显著减弱了白念珠菌的致病性。     

DNA甲基化与原发性高血压的研究进展

原发性高血压(简称高血压病)是遗传和环境因素相互作用所导致的一种复杂性疾病.近年来的研究发现,高血压病的发生和发展与DNA甲基化密切相关.11β-HSD-2、ECE-1和AT1b等基因发生甲基化和去甲基化会影响代谢酶和受体的表达,从而通过肾素-血管紧张素-醛固酮系统激活以及肾性水钠潴留等途径引起高血压的发生,这可能是高血压发病的一个重要分子机制.基因组低甲基化(如:高同型半胱氨酸所引起的)会诱发AT1b、ECE-1等受体和代谢酶基因发生去甲基化,从而参与高血压病的发生.深入了解DNA甲基化调控在原发性高血压发病过程中的分子机制及药物代谢酶和受体基因甲基化状态的改变对高血压患者降压疗效的影响,将为临床制定合理化的用药方案提供依据.     

药物代谢酶及转运体与前列腺癌药物治疗

药物代谢酶是催化体内摄入的各种药物进行生物转化的一系列重要酶,属于生物转化酶系中的一类.虽然药物生物转化的主要场所在肝脏,但在肝外组织(如前列腺)亦存在,而且可影响药物在局部的生物转化率.药物转运体在药物的跨膜转运中发挥了重要的作用,影响了药物在体内的药代动力学进程,药物转运体在组织中分布广泛;本文着重阐述这些药物代谢酶及转运体在治疗前列腺癌药物中的作用,及它们在前列腺中的特异性表达,同时讨论了在不同的治疗策略中与药物代谢酶及转运体相关的靶向作用.     

CYP3A4基础与临床研究进展

细胞色素P4503A4(CYP3A4)是存在人类肝脏及肠道中的一种主要的细胞色素CYP450酶,约占成人肝脏CYP450酶总量的25%左右。临床中约有50%的药物是通过其代谢,并且其基因位点突变也与其多种疾病相关,知晓CYP3A4的表达水平和不同功能的遗传学基础,无论是对疾病的发病基础、临床药物的应用,会带来前所未有的启发,在药物应用过程中,通过对基因组学的认识,从而可以在基因层面了解个体代谢差异产生的原因,调整药物用量,提高疗效,最终使药物副作用降到最低限。目前对CYP3A4的研究渐趋于成熟,已逐渐阐明了其药物间相互作用的机制,它能够被多种药物竞争性抑制或者诱导,并受到某些蛋白受体的调控影响,可改变药物的药代动力学,增强或降低药效,造成个体用药差异,这也是造成药物间相互作用的重要原因。然而CYP3A4基因多态性与基因导向治疗关系,还有待进一步深入研究。该文对CYP3A4基因多态性、分布以及与临床疾病及用药的研究现状作一综述。     

血栓病治疗药物-纤溶酶的生物来源

血栓病的干预方式包括抗血小板凝集、抗凝血和溶栓,对应临床应用的分别是抗血小板、抗凝血酶和纤溶酶溶栓药物;纤溶酶是主要的溶栓类药物,主要用于血栓发病后的治疗。纤溶酶种类多来自于生物体,更多来自于微生物的次级代谢。本文从作用方式、安全性和市场开发等方面总结了国内外纤溶酶的类别、研究现状和发展趋势,并对不同产纤溶酶的微生物菌株类别进行了总结,对不同来源的纤溶酶基因和氨基酸序列等信息进行了比较,发现不同物种的纤溶酶基因虽然有差异,但主要是丝氨酸蛋白酶类,氨基酸序列一致性比较高,说明丝氨酸蛋白酶活性功能区域是相对保守的。     

戒毒药物新进展

目前戒毒药物的作用靶点主要包括阿片受体、M受体、a2受体、DA2受体、NMDA受体以及钙离子通道等,与此相对应的戒毒药物均具有较好的疗效,但长期使用会形成心理、躯体依赖及耐受性,停用时出现明显的戒断症状。中药戒毒有较好的发展前途,尤其在控制稽延症状方面优于西药阿片受体类及非阿片受体类。查阅近年来国内外公开发表的有关文章,按戒毒药物的性质分类汇总,并对近年来戒毒药物的研究进展作以综述。     

Pharmacogenomics of Drug Metabolizing Enzymes and Transporters:Relevance to Precision Medicine

The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision med-icine, pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual’s particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacoge-nomics of phase-I drug metabolizing enzymes and transporters. Substantial frequency differences in key variants of drug metabolizing enzymes and transporters, as well as their possible functional consequences, have also been discussed across geographic regions. The current effort illustrates the common presence of variability in drug responses among individuals and across all geographic regions. This information will aid health-care professionals in prescribing the most appropriate treatment aimed at achieving the best possible beneficial outcomes while avoiding unwanted effects for a particular patient.     

Current aspects of the mechanism of action of calcium antagonists in patients with diabetes mellitus]

The review summarizes recent data about the use of calcium channel blockers for the treatment of cardiovascular complications in patients with diabetes mellitus. It is shown that disturbances of Ca ion homeostasis play an important role in the pathogenesis of such diabetic complications as cardiomyopathy, microangiopathy, hypertension and the use of modern calcium channel antagonists for their treatment seems to be quite justified. However, despite definite positive effects of such treatment, these drugs should be used with care, especially if combined with derivatives of sulphonylurea as activators of the beta-cell function. Calcium channel blockers may intervene in the mechanism of the activity of beta-cells in which activation of the calcium channels is an obligatory link for triggering insulin secretion. Nevertheless, according to most of the authors, in such cases Ca antagonists can be recommended in moderate doses under continuous control of the hormonal status of the patient.     

Antioxidant effects and the therapeutic mode of action of calcium channel blockers in hypertension and atherosclerosis

Drugs currently known as calcium channel blockers (CCB) were initially called calcium antagonists because of their ability to inhibit calcium-evoked contractions in depolarized smooth muscles. Blocking the entry of calcium reduces the active tone of vascular smooth muscle and produces vasodilatation. This pharmacological property has been the basis for the use of CCBs in the management of hypertension and coronary heart disease. A major question is whether drugs reducing blood pressure have other effects that help prevent the main complications of hypertension, such as atherosclerosis, stroke, peripheral arterial disease, heart failure and end-state renal disease. Experimental studies that focus on this question are reviewed in the present paper.     

Membrane transport metabolons

In this review evidence from a wide variety of biological systems is presented for the genetic, functional, and likely physical association of membrane transporters and the enzymes that metabolize the transported substrates. This evidence supports the hypothesis that the dynamic association of transporters and enzymes creates functional membrane transport metabolons that channel substrates typically obtained from the extracellular compartment directly into their cellular metabolism. The immediate modification of substrates on the inner surface of the membrane prevents back-flux through facilitated transporters, increasing the efficiency of transport. In some cases products of the enzymes are themselves substrates for the transporters that efflux the products in an exchange or antiport mechanism. Regulation of the binding of enzymes to transporters and their mutual activities may play a role in modulating flux through transporters and entry of substrates into metabolic pathways. Examples showing the physical association of transporters and enzymes are provided, but available structural data is sparse. Genetic and functional linkages between membrane transporters and enzymes were revealed by an analysis of Escherichia coli operons encoding polycistronic mRNAs and provide a list of predicted interactions ripe for further structural studies. This article supports the view that membrane transport metabolons are important throughout Nature in organisms ranging from bacteria to humans.     

Membrane transport metabolons

In this review evidence from a wide variety of biological systems is presented for the genetic, functional, and likely physical association of membrane transporters and the enzymes that metabolize the transported substrates. This evidence supports the hypothesis that the dynamic association of transporters and enzymes creates functional membrane transport metabolons that channel substrates typically obtained from the extracellular compartment directly into their cellular metabolism. The immediate modification of substrates on the inner surface of the membrane prevents back-flux through facilitated transporters, increasing the efficiency of transport. In some cases products of the enzymes are themselves substrates for the transporters that efflux the products in an exchange or antiport mechanism. Regulation of the binding of enzymes to transporters and their mutual activities may play a role in modulating flux through transporters and entry of substrates into metabolic pathways. Examples showing the physical association of transporters and enzymes are provided, but available structural data is sparse. Genetic and functional linkages between membrane transporters and enzymes were revealed by an analysis of Escherichia coli operons encoding polycistronic mRNAs and provide a list of predicted interactions ripe for further structural studies. This article supports the view that membrane transport metabolons are important throughout Nature in organisms ranging from bacteria to humans.     

Photoalteration of calcium channel blockade in the cardiac Purkinje fiber.

Organic compounds that block calcium channel current (calcium antagonists) are important tools for the characterization of this channel. However, the practically irreversible nature of this block restricts the usefulness of this group of drugs. In this paper, we investigate the influence of light on calcium channel blockade by several organic compounds. Our results show that inhibition of calcium channel current by two dihydropyridine derivatives that contain an o-nitro moiety (nisoldipine and nifedipine) can be rapidly reversed by illumination. The energy range important to this reaction is for light wavelengths between 320 and 450 nm. Calcium channel inhibition by two other dihydropyridine derivatives (nicardipine and nitrendipine) as well as by D600, is not modulated by illumination. These results indicate that the photosensitivity of certain dihydropyridine calcium channel blockers make these compounds useful as reversible blockers of this channel.     

Phenethyl nicotinamides, a novel class of Na(V)1.7 channel blockers: Structure and activity relationship

The Na(V)1.7 ion channel is an attractive target for development of potential analgesic drugs based on strong genetic links between mutations in the gene coding for the channel protein and inheritable pain conditions. The (S)-N-chroman-3-ylcarboxamide series, exemplified by 1, was used as a starting point for development of new channel blockers, resulting in the phenethyl nicotinamide series. The structure and activity relationship for this series was established and the metabolic issues of early analogues were addressed by appropriate substitutions. Compound 33 displayed acceptable overall in vitro properties and in vivo rat PK profile.     

T-type calcium channels and tumor proliferation

The role of T-type Ca2+ channels in proliferation of tumor cells is reviewed. Intracellular Ca2+ is important in controlling proliferation as evidenced by pulses, or oscillations, of intracellular Ca2+ which occur in a cell cycle-dependent manner in many tumor cells. Voltage-gated calcium channels, such as the T-type Ca2+ channel, are well suited to participate in such oscillations due to their unique activation/inactivation properties. Expression of the T-type Ca2+ channels has been reported in numerous types of tumors, and has been shown to be cell cycle-dependent. Overexpression of the alpha1 subunit of T-type Ca2+ channels in human astrocytoma, neuroblastoma and renal tumor cell lines enhanced proliferation of these cells. In contrast, targeting of the alpha1 subunit of the T-type calcium channel via siRNA decreased proliferation of these cells. A Ca2+ oscillatory model is proposed involving potassium channels, Ca2+ stores and Ca2+ exchangers/transporters. A review of T-type channel blockers is presented, with a focus on mibefradil-induced inhibition of proliferation. The development of newer blockers with higher selectivity and less potential side effects are discussed. The conclusion reached is that calcium channel blockers serve as a potential therapeutic approach for tumors whose proliferation depends on T-type calcium channel expression.     

The diversity of mechanisms of the ion channels blockade as a way towards designing new pharmacological agents

Dysfunctions of glutamatergic synaptic neurotransmission often accompany various CNS disorders. Action of excessive glutamate, which causes excitotoxic effects by neuron depolarization and massive calcium influx can lead to cell death. Despite obvious importance of development of anti-glutamic neuroprotectors, among great number of known antagonists of ionotropic glutamate receptors only memantine is used in medicinal practice. One of the sources of numerous side effects caused by glutamate receptor antagonists is that the drugs usually inhibit receptors, which mediate both normal and pathological CNS processes. A possible approach to overcoming the problem is to develop the drugs whose action is enhanced in potentially pathological conditions such as high-frequency activation, high glutamate concentration, depolarized membrane, etc. Action of many classes of antagonists depends on pattern of receptor activation and on membrane voltage. In the present work, we discuss several peculiarities of channel blocking mechanisms from the viewpoint of neuroprotector development. In particular, we compare channel blockers which demonstrate different types of interaction with the channel gating machinery, we consider different types of voltage dependence and consider action of channel blockers, which can permeate through the channel. We conclude that meticulous analysis of the mechanism of action of the glutamate receptor channel antagonists could help to approach predicting of in vivo action using in vitro data.