药理学前沿

基因药理学本身不是一个新领域。药物反应的个体差异和基因的多态性多年来一直是个研究课题。目前已有可能在分子水平上观察药物反应中个体和基因间的关系。由于深入研究了药物代谢中细胞色素P-450的作用,已能分离和克隆这一族酶的特异亚型,以确定这些亚型对不同药物的反应,探讨其诱导的分子机制以及确定某一特定细胞色素的结构和基因位     

阿托伐他汀的基因多态性研究进展

阿托伐他汀是临床上广泛使用的调血脂药物,长期使用能够预防并减少动脉粥样硬化性心血管疾病（ASCVD）的发生,但阿托伐他汀的疗效具有显著的个体间差异,有些个体不能达到预期调脂目标值或出现严重的不良反应。这与个体间的遗传多样性有关,遗传变异可导致药物体内处置不同,从而导致临床疗效和不良反应有差异。对影响阿托伐他汀药物反应的药物代谢酶、药物转运体、药物作用靶点及与脂质代谢相关基因多态性加以综述,并从基因水平上探讨不同个体使用阿托伐他汀的药动学、药效学及不良反应易感性差别的原因。     

药物基因组学与个体化治疗

早在20世纪50年代,科学家就发现不同的遗传背景会导致药物作用的差异,特别是药物代谢酶基因的差异可以引起不同的药物不良反应。随着20世纪末人类基因组计划的完成以及基因组结构图的公布,揭露了人类基因组中存在着单核苷酸多态性（SNP）和拷贝数变异等大量的遗传变异,人体之间基因组差异至少有15％以上。这些了解使人们认识到基因参与了药物在体内作用的过程,基因多态性导致了药物反应的多样性,由此药物基因组学受到了极大的重视。药物基因组学通过对药效和不良反应的相关基因进行检测,     

Ⅱ相代谢及其酶的研究进展石淑亚,王连生简

以结合反应为特征的Ⅱ相药物代谢是机体处置药物重要环节,主要包括葡萄糖醛酸化、乙酰化、甲基化、谷胱甘肽化、硫酸化等结合反应。不同基团对应的结合反应均由多个同类基因或超基因家族介导催化完成。Ⅱ相代谢反应都具有各自不同的反应特征与各自不同的功能意义。Ⅱ相药物代谢酶活性受联合用药影响会导致临床药物相互作用,其基因多态性一方面会影响内源性物质的代谢,可能导致某些疾病发生率升高,同时也会影响外源性物质的代谢,引起药物疗效的改变或毒性反应的发生。     

遗传药理学:个体化用药的科学依据

遗传药理学的研究进展为基因导向性个体化用药提供了理论依据遗传药理学主要在基因水平研究药物反应相关蛋白的多态性等,来揭示药物治疗中疗效和不良反应差异的遗传特征,鉴别基因序列中的差异。遗传药理学是以药物效应及安全性为目标,研究药物代谢酶(影响药物的代谢,如细胞色素P450)、药物转运蛋白(影响药物的吸收、分布和排泄,如P-糖蛋白)以及药物作用受体或靶位(影响药物反应的敏感性,如β肾上腺素受体)等药物反应相关蛋白基因突变与药效及安全性之间的关系,而这些基因突变是不同个体产生不同药物效应的根本原因。1.药物代谢酶关于药物代…     

药物基因组学与免疫抑制剂

近年随着药物基因组学（Pharmacogenomics，PG）的发展，研究不同个体间药物代谢动力学（Pharmacokinetics，PK）和药物效应动力学（Pharmacodynomics，PD）差异的分子遗传机制越来越受到人们的重视，许多科学家认为编码药物代谢酶、药物转运体和药物作用靶点的基因序列的不同是引起同一种药物相似剂量在不同个体间产生不同反应的主要原因。尽管年龄、体重、器官功能、药物相互作用、疾病状况等许多非遗传因素也会造成药物反应的个体差异，但是20％～95％药物反应和处置的个体差异却是遗传因素引起，而且将伴随人的一生。     

药物基因组学与临床合理用药

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,在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高潮.药物基因组学[1]是以提高药物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征,以及基因变异所致的不同病人对药物的不同反应,即应用已获得的遗传信息预测药物治疗结果(治疗作用和毒副作用),阐明决定药物反应个体差异的根本机理,将从根本上改变临床药物治疗模式和新药开发方向.本文简述药物基因组学对药物效应、药物不良反应和新药临床评价等方面的影响,希望对我们从事医院临床药学研究工作的同仁有参考价值.     

药物代谢酶基因型与药物反应相关性研究近况

药物代谢酶的基因多态性是引起药物反应个体差异的重要原因。进行药物代谢酶基因型与药物反应的相关性研究有助于根据个体的基因型确定临床给药方案,最大程度地提高药物的疗效,并有效减少不良反应发生率,实现基因导向个体化药物治疗。综述药物代谢酶基因型与药物反应相关性研究的近况,为个体化药物治疗提供指导。     

临床个体化用药中的药物基因组学考虑

虽然引起药物反应个体差异的原因很多,但遗传因素起相当重要的作用。药物代谢酶、转运药物的蛋白质、受体和其它药物靶体的遗传多态性与药物效应、毒性的个体差异密切相关。药物基因组学是利用已知的基因组学理论,研究遗传因素对药物反应的影响,即研究药物动力学和药效学差异的基因特征,以及基因变异所致的不同个体对药物的不同反应。深入研究遗传因素与临床合理用药之间的重要关系,确定引起个体对药物处置和疗效差异的遗传学特征,将为个体化合理用药提供强有力的科学依据。本文简要介绍药物在血浆中结合的蛋白质的基因多态性和与高血压相关的药物基因组学在临床个体化合理用药中的意义。     

miRNA与药物反应个体差异

目前关于药物反应个体差异研究集中在药物代谢和药物靶点基因的单核苷酸多态性位点(SNPs)和其他基因突变(例如拷贝数的变化)的表型效应,而仅分析DNA序列不能完全解释药物反应个体差异.miRNA的发现,为其提供了新的研究方向.miRNA是一类内源性的非编码小RNA,其与靶基因mRNA3'非翻译区(3'UTR)互补结合,引起mRNA切割或翻译抑制,从而在转录后水平下调基因表达.miRNA可负调控大量人类基因的表达,其中包括许多药物疗效相关基因.越来越多的研究结果表明,miRNA是导致药物反应个体差异的又一重要因素.本文从miRNA调控药物代谢、药物转运和药物靶点,miRNA及其结合位点多态性等方面对miRNA在药物反应个体差异中所起作用进行综述.     

Creation and first 20 years of the society for the stimulus properties of drugs (SSPD).

Clinical observations and novels in the 19th century recognized that memory of some events can be retrieved only under the influence of the same drug condition that was present during the event. This dissociative effect of drugs probably reflects the same drug effects that were later called the discriminative stimulus effects of drugs. The Society for Stimulus Properties of Drugs (SSPD) was founded in 1978 as a forum for communications and periodic meetings on this drug effect. During its early years many of its members were psychologists, but subsequent to that time the most frequent research application has been for the pharmacological purpose of identifying new drugs that have the same discriminative stimulus attributes as a prototype training drug. The majority of members have been in the United States, but several major international meetings have been in Europe. The methods used by the society's members involve both neuropharmacological and psychological processes, allowing them to make unique contributions to the study of both mind and brain.     

Graphene nano-ribbon based high potential and efficiency for DNA,cancer therapy and drug delivery applications

In this article, graphene oxide Nano ribbons (GONRs) and its high potential for using in medical fields have been reviewed. Recently, Graphene Nano ribbons (GNRs) has been a field of interest in biological methods and disease treatment such as drug delivery, DNA applications, and photothermal cancer therapies. GNRs demonstrate more efficient properties rather than other graphene-based Nanomaterials due to their larger surface area. These novel properties made them into a remarkable substitute material for biological fields as they have different cytotoxic effects and almost nontoxic to human health and the environment. In this study, some of the significant effects of GNRs such as Geno toxicity effects in human mesenchymal stem cells, DNA assembly, drug delivery agents, and the use of PEGylated GNRs in photothermal cancer therapy has been investigated.     

Iontophoretic delivery of nonpeptide drugs: formulation optimization for maximum skin permeability

Although the technique of transdermal iontophoretic drug delivery has been known for many years, its use has been limited clinically to those applications for which a brief drug delivery period is adequate (e.g., delivery of pilocarpine in the diagnosis of cystic fibrosis). For most therapeutic applications, however, it is necessary to have an extended, if not continuous, drug delivery regimen. The use of iontophoresis has been limited in these applications by side effects, primarily skin trauma, associated both with the current density and the total amount of current passed. A mechanism for these side effects will be proposed and techniques to mitigate them will be presented. Many of these techniques involve ways in which the drug formulation can be designed to maximize the fraction of current carried by the drug species. These methods include the following: control of the pH in the bulk solution and in the boundary layer without using conventional buffers; taking advantage of polarization effects; and enhancing the permselectivity of skin. In this way, the therapeutic dose or optimal infusion rate of drug can be achieved with the minimum current and, therefore, the minimum number of side effects.     

Drug Repurposing Based on Drug–Drug Interaction

Given the high risk and lengthy procedure of traditional drug development, drug repurposing is gaining more and more attention. Although many types of drug information have been used to repurpose drugs, drug–drug interaction data, which imply possible physiological effects or targets of drugs, remain unexploited. In this work, similarity of drug interaction was employed to infer similarity of the physiological effects or targets for the drugs. We collected 10 835 drug–drug interactions concerning 1074 drugs, and for 700 of them, drug similarity scores based on drug interaction profiles were computed and rendered using a drug association network with 589 nodes (drugs) and 2375 edges (drug similarity scores). The 589 drugs were clustered into 98 groups with Markov Clustering Algorithm, most of which were significantly correlated with certain drug functions. This indicates that the network can be used to infer the physiological effects of drugs. Furthermore, we evaluated the ability of this drug association network to predict drug targets. The results show that the method is effective for 317 of 561 drugs that have known targets. Comparison of this method with the structure-based approach shows that they are complementary. In summary, this study demonstrates the feasibility of drug repurposing based on drug–drug interaction data.     

Generic and therapeutic substitutions: are they always ethical in their own terms?

Cost containment-driven drug substitution, whether generic or therapeutic, is defined as switching to another drug because it is cheaper. So far, such substitutions have drawn their public legitimacy from the general belief that they would not compromise the clinical interests of patients and certainly not violate their right to decline them if they did. This article does not enter the debate on whether or not such substitutions must give exclusive priority to the patient’s interests and choices in order to be ethical. Indeed, it acknowledges the plurality of views on this matter. It simply argues that when such substitutions involve a cheaper drug that is known to have different effects and side effects, or even a drug whose effects and side effects are unknown, they are potentially deleterious to the patient, and that no competent and well-informed patient would ever consent to them. Such substitutions are thus unethical in their very own terms.     

中药川芎化学成分及其生理活性研究的回顾与展望

近15年来自川芎中分离确定的生物碱、酚、有机酸和不饱和内酯有40多个,其中包括10个新化合物。初步研究发现某些化合物有明显的药理作用。盐酸四甲基吡嗪在中国广泛用于缺血性脑血管病的治疗。     

Untoward effects of fenfluramine in autistic children

Several recent studies have described the benefits of fenfluramine for the symptomatic treatment of infantile autism. No large surveys of side effects of this drug have been reported in autistic children. To evaluate the untoward effects of fenfluramine in children with autism, 12 subjects were systematically studied. Medication was administered in a double-blind, placebo-controlled cross-over study. Parents were trained in monitoring untoward effects. These observations were compiled in detailed daily notes. In addition, four cases describing unusual effects found in a sample of 170 patients treated with fenfluramine are also reported. In the initial 2 weeks of active drug listlessness, food refusal, and stomach upset were frequently seen. A different pattern of untoward effects was seen in the final 14 weeks of treatment. Irritability, agitation, and crying along with continued food refusal were noted. The subjects lost 2.1% of body weight during active drug phase, but there was a rebound weight gain during the subsequent placebo phase. A thorough understanding of fenfluramine's side effects and adverse reactions is necessary so as to differentiate them from the multiple symptoms inherent in the syndrome of autism.     

抗组胺药物应用进展

抗组胺药物治疗过敏性疾病已广泛地应用于临床。由于第 1代抗组胺药物嗜睡的不良反应而影响了它的临床应用 ,2 0世纪 80年代后生产的第 2代抗组胺药物具有H1受体选择性高、无镇静作用与组胺作用分离等特点 ,称非镇静抗组胺药 (NSA)。但第 2代抗组胺药仍有一些不良反应 ,尤以心脏的毒性作用 ,这与抗组胺药物相互作用、药动学、以及药物的分子结构有关。 1997年新型抗组胺药物———非索非那定 (fexofenadine)问世 ,它是作用快、疗效高、相对安全低毒的抗组胺药。非索非那定的开发 ,为寻找既无中枢镇静作用 ,也无心脏毒性的抗组胺药物开辟了新的途径     

Endocannabinoids and drug dependence

Drug dependence is a chronically relapsing disorder, manifested as an intense desire for the drug, with impaired ability to control the urges to take the drug, even at the expense of serious adverse consequences. These behavioral abnormalities develop gradually during repeated exposure to a drug of abuse, and can persist for months or years after discontinuation of use, suggesting that this addiction can be considered a form of drug-induced neural plasticity. Many neurotransmitters, including gamma-aminobutyric acid (GABA), glutamate, acetylcholine, dopamine, serotonin and endogenous opioid peptides, have been implicated in the effects of the various drugs of abuse. Dopamine has been consistently associated with the reinforcing effects of most of them. There is, in addition, a growing body of evidence that the endogenous cannabinoid system might participate in the motivational and dopamine-releasing effects of several drugs of abuse. This review will discuss the latest advances on the mechanisms of cannabinoid dependence and the possible role of the endocannabinoid system in the treatment of addiction, not only to marijuana but also to the other common illicit drugs.     

Pharmacy-based computer system for monitoring and reporting drug interactions

A pharmacy-based computer system for monitoring and reporting drug interactions is described, and physicians' responses to patient management suggestions generated by the system are reported. Using information from a commercially available drug-interaction database, a pharmacist chose 41 potentially interacting drug combinations to include in the pharmacy's automated system. A warning notice appears on the computer screen if one of these drug combinations is prescribed. Pharmacists who encounter these notices while entering medication orders telephone the prescribing physician if the combination represents a Class I interaction (immediate onset, major severity, established documentation); for Class II interactions, which have a delayed onset, a copy of the warning notice and suggestions for patient management are placed in the prescribing physician's mailbox. The system was evaluated during a three-month period in 1985 to determine physicians' responses to the patient management suggestions. A total of 927 patients had 1004 potentially interacting drug combinations prescribed for them. Changes in drug dosage were made in 44% of these instances, and in 75%, patients were monitored for the development of adverse clinical effects. A computerized drug-interaction monitoring system can help increase physicians' awareness of possibly interacting drug combinations and provide them with useful information about the clinical management of patients for whom such drug combinations have been prescribed.