抗血小板药物临床个体化给药中存在的问题及其研究进展

目的:了解抗血小板药物临床个体化给药中存在的问题及其研究进展。方法:查阅近年来国内外相关文献,从药物相互作用、基因多态性和血小板功能监测方面对抗血小板药物在临床个体化给药中存在的问题进行归纳和总结。结果:药物相互作用和基因多态性均导致抗血小板药物疗效差异,且血小板功能监测对临床的获益尚不能证实。结论:掌握影响抗血小板药物疗效的因素,有助于抗血小板药物的个体化给药,以最大程度地减少抗血小板效应不足导致的血栓性事件或抗血小板效应过度导致的出血性事件。     

血小板高反应性的遗传因素及其药物治疗策略的研究进展

抗血小板药物是目前治疗缺血性心脏病的常用药物,主要包括氯吡格雷、阿司匹林,但易发生氯吡格雷抵抗、阿司匹林抵抗,而它们同属于抗凝治疗后血小板高反应性的范畴。遗传因素对血小板高反应性的影响至关重要。目前对血小板高反应性的治疗策略主要以个体化抗血小板治疗为主,常用的药物包括替格瑞洛、αIIbβ3拮抗剂、中药。总结了血小板高反应性的遗传因素和治疗策略的研究进展,旨在为血小板高反应性的治疗提供临床参考。     

抗血小板药物致胃肠道出血的防治进展

抗血小板聚集是血栓栓塞性疾病防治的重要措施,但由抗血小板药物引发的胃肠道损害临床常见。本文就阿司匹林与氯吡格雷等抗血小板药物导致胃肠道出血的研究现状及其防治的研究进展作一综述。     

临床药师参与１例冠心病伴假性血小板减少症诊治病例分析

摘 要抗血小板药物在冠心病患者的治疗中十分重要,但伴血小板重度减少往往限制了抗血小板药物的应用。因此,临床中应及时准确辨别血小板减少的原因以指导临床抗血小板药物的应用。本案例中临床药师通过分析１例老年冠心病患者出现血小板减少的原因,排除药源性血小板减少,明确为ＥＤＴＡ依赖性假性血小板减少症,及时恢复抗血小板治疗,避免误停抗血小板药物而导致心血管不良事件的发生。     

氯氮平的基因遗传多态性研究进展

氯氮平是非典型抗精神分裂的代表药物,在治疗精神分裂疾病中起到重要作用,临床实践发现,不同个体对氯氮平的反应有较大差异,研究表明,遗传因素是导致氯氮平疗效产生个体差异的重要原因之一。本文就氯氮平的基因遗传多态性研究进展进行综述。     

抗血小板药物研制与临床应用进展

目的:为抗血小板药物的研制与临床应用提供参考。方法:该文就抗血小板药物的研制及临床应用进展作一述评。结果:动脉粥样斑块脱落后血小板黏附、活化和聚集,形成附壁血栓是导致心肌梗死、缺血性脑卒中的主要原因。血小板的活化、释放、黏附和聚集等在这一病理过程中起重要作用。结论:抗血小板药物在动脉血栓的预防和治疗中有着重要的地位。     

临床药师参与1例多因素导致血小板减少诊治的药学实践

通过1例多因素导致血小板减少患者的病例,探讨抗凝药、抗血小板药、感染及抗菌药物对患者血小板的影响及处理方法。以专家共识及指南为依据,结合相关文献,对多因素影响患者血小板减少的问题进行详细阐述及分析。该老年患者肾功能不全,透析时使用肝素及低分子肝素;合并急性冠状动脉综合征,使用尿激酶抗栓,氯吡格雷抗血小板;合并重症感染,使用头孢哌酮舒巴坦抗感染。以上任何一种情况都可能导致血小板消耗,引起血小板减少。患者出现血小板减少后,经过暂停抗凝抗栓及抗血小板药物,停用头孢哌酮舒巴坦,改为美罗培南抗感染,血小板逐步显著回升。对于各种复杂原因导致的血小板减少,医务工作者应尽快寻找可能的所有原因并按照指南及专家共识进行相关处理。     

剪切诱导血小板聚集机制及其治疗进展

血小板的活化在与心脑血管疾病相关的生理止血以及病理血栓形成方面发挥关键作用。抗血小板聚集的药物研究也是当前研究的热点。但目前抗血小板药物疗法的最大挑战是病理性血小板反应与生理性血小板反应相互重叠,从而可能导致严重的出血风险。近年来研究发现,血流剪应力是血小板活化聚集的重要诱发因素之一。利用生理与病理血流力学环境的差异而开发出剪应力选择的抗血小板聚集疗法或许会成为治疗心脑血管疾病更为安全的疗法。本文对近年来剪切诱导血小板聚集的机制进行总结,并对现有的化合物及传统中药抗剪切诱导血小板聚集效应及机制进行总结,旨在为活血化瘀中药的生物药理学研究提供参考。     

抗血小板药物致上消化道出血的临床分析及泮托拉唑的预防作用

目的分析并研究抗血小板药物导致上消化道出血的临床情况,并且探讨泮托拉唑的预防作用。方法选择我院在2014年1月至2015年12月收治的采用抗血小板药物治疗的患者124例作为本研究的研究对象,将所有患者随机方法分为观察组和对照组,每组患者62例。对于对照组患者单纯选择采用抗血小板药物进行治疗,观察组患者在采用抗血小板药物治疗的同时为患者配合使用泮托拉唑进行干预,比较本研究两组患者治疗以后,患者出现上消化道出血的发生率。同时对于本研究患者上消化道出血的相关情况进行病例分析,分析患者出现上消化道出血的原因。结果比较本研究两组患者上消化道出血的发生率,观察组患者的发生率明显低于对照组,两组之间差异明显,P <0.05,差异明显,具有统计学意义;对于抗血小板药物致上消化道出血进行临床分析,其最常见的病因是急性胃黏膜病变,消化性溃疡也是导致患者出现上消化道出血的一个主要的病因,而抗血小板药物导致上消化道出血的临床表现多样,使用泮托拉唑能够起到有效的预防作用。结论临床患者在使用抗血小板药物进行治疗时,容易导致患者出现,上消化道出血症状,特别是对于胃黏膜病变和消化性溃疡患者,为患者选择采用泮托拉唑进行干预,可以起到有效的预防作用,值得推广使用。     

抗血小板药物的研究进展

抗血小板药可抑制血小板聚集,进而抑制动脉中血栓形成,是防治动脉血栓性疾病的重要治疗药物。随着心脑血管疾病发病率逐年增加,临床对抗血小板药物的应用、疗效和不良反应的研究越来越多。为获得更好的抗血小板效果,目前临床急需一种抗血小板药物或药物组合,能达到提高抗血小板效果,同时降低药物副作用、减少药物抵抗发生概率、降低术后出血再栓塞风险的目的,以适合更广泛的人群。按药物作用机制,抗血小板药分为如下几类：①环氧酶抑制剂：代表药物阿司匹林,具有强烈的抗血小板聚集作用;②二磷酸腺苷受体拮抗药（ADPR - A）：代表药物噻氯匹定、氯吡格雷、普拉格雷;③血小板膜糖蛋白（GP）Ⅱb／Ⅲa 受体抑制剂：代表药物阿昔单抗、依替非巴肽、替罗非班;④磷酸二酯酶抑制剂：代表药物双嘧达莫、西洛他唑,通过激活血小板腺苷环化酶（cAMP）或抑制磷酸二酯酶对 cAMP 的降解作用,使血小板内 cAMP 浓度增高而产生抗血小板作用;⑤5-羟色胺受体拮抗剂：代表药物沙格雷酯,可以特异性地与5- HT2受体结合,抑制血小板的聚集。本文对近年较有潜力的或已上市的几类抗血小板药物的临床研究进展进行综述。     

Gender differences in the membrane transport of endogenous and exogenous compounds

Gender differences have been well described in pharmacokinetics and contribute to the interindividual variation in drug disposition, therapeutic response, and drug toxicity. Sex-related differences in the membrane transport of endogenous substrates and xenobiotics have been reported in various organs of the body including kidney, liver, intestine, and brain. These gender-related differences in transport systems could also contribute to interindividual variability in pharmacokinetics and pharmacodynamics. This review will focus on current knowledge of gender-associated differences in the transport of endogenous and exogenous compounds in a variety of body organs and will discuss the implications and the clinical significance of these observations.     

Genetic basis of drug metabolism.

The application of pharmacogenetics in identifying single nucleotide polymorphisms (SNPs) in DNA sequences that cause clinically significant alterations in drug-metabolizing enzyme activities is discussed. Recent advances in pharmacogenomic research have begun to elucidate the inherited nature of interindividual differences in drug-induced adverse reactions, toxicity, and therapeutic responses. In one particular area of study, variations in DNA sequences (i.e., genetic polymorphisms) explain some of the variability in drug-metabolizing enzyme activities which contribute to alterations in drug clearance and impact patients' response to drug therapy. Historical and current examples of several extensively studied SNPs include the genes encoding for glucose-6-phosphate dehydrogenase, N-acetyltransferase, and the superfamily of cytochrome P-450 (CYP) isoenzymes. Because CYP isoenzymes metabolize a large number of structurally diverse drugs and chemicals, most of the variant genotypes of the CYP2D6, CYP2C9, CYP2C19, and CYP3A families have been identified and studied. Individuals with aberrant genes for these enzymes may experience diminished efficacy or increased toxicity in response to certain drugs because of the different levels of activities associated with variant genotypes. The frequency of variant alleles for drug-metabolizing enzymes often differs among ethnic groups. Continued research in pharmacogenetics will further our understanding in interindividual differences in drug disposition. The application of this knowledge will ultimately help individualize drug dosing and drug therapy selection, predict toxicity or therapeutic failure, and improve clinical outcomes. Pharmacogenetics has elucidated the genetic basis for interindividual variability in drug response and will continue to play a key role in defining strategies to optimize drug therapy.     

Cytochrome P450 3A: genetic polymorphisms and inter-ethnic differences

Ethnicity is a demographic variable that plays an important role in interindividual variability of drug metabolism and response. The genetic variations of drug-metabolizing enzymes exhibiting interindividual differences of drug metabolism also show differences between populations. The reason for this is that the frequency of a polymorphism is found to differ between populations. The other reason is that different variants are seen in different populations. Most drugs are biotransformed in the body by cytochrome P450. The CYP3A isozymes are responsible for the metabolism of 50-60% of all currently prescribed drugs. Studies have shown that there is variability in CYP3A activity and also inter-ethnic differences in CYP3A-mediated drug metabolism. The purpose of this review is to focus on the genetic polymorphism and ethnic variations in CYP3A-mediated oxidative drug metabolism.     

Pharmacogenomics of importance for paclitaxel chemotherapy

Paclitaxel (Taxol) has a broad activity spectrum and is clinically used, often in combination with carboplatin, to treat breast, ovarian and lung cancer. The response to treatment and the severity of adverse drug reactions after chemotherapy varies greatly among individuals, and one of the most important factors responsible for these differences is now recognized to be the genetic variability. However, so far only genetic variants of ABCB1 have been indicated to be associated with response and pharmacokinetics of paclitaxel. Commercially, the patent on paclitaxel has expired; however, from a healthcare perspective, it would be beneficial to identify patients with risk of poor response or high risk of toxicity to reduce hospitalization costs. This article focuses on the pharmacogenomic background for paclitaxel response and interindividual variability.     

华法林个体差异的遗传药理学因素

华法林是临床上的常用药物,其临床反应有很大的个体差异及种族差异,用药剂量可以相差20倍左右,从而限制了其作为抗凝药物的应用。该文简要综述了遗传因素对华法林个体及种族间差异的影响,为临床华法林的个体化治疗提供了一定的理论指导。     

The pharmacogenetics of analgesia: toward a genetically-based approach to pain management

Interindividual differences in the experience of pain have been appreciated clinically for over a century. More recently, there has been a growing body of evidence demonstrating differences in analgesic response to various pharmacotherapies, although the source of this variability largely remains to be explained. To this end, basic science research is beginning to identify the allelic variants that underlie such antinociceptive variability using a multiplicity of animal models, and powerful genetic approaches are being exploited to accelerate this process. Although the vast majority of these studies have focused on the pharmacogenetics of opioids, owing to their prominent status as analgesics, the number of pharmacotherapies evincing genetically-based variability is rapidly expanding. In addition, analogous studies have been undertaken in humans, as a small but growing number of clinical trials have begun to evaluate prospectively the existence, if oftentimes not the origin, of interindividual differences in analgesic drug response. Importantly, with a few notable exceptions, such efforts have primarily identified differences in analgesic efficacy and/or potency between male and female human subjects. Looking toward the future development of one or more widely utilised, pharmacogenetic screens that would lead to modifications in treatment planning, at least with respect to the pharmacologic management of pain, this review will document the breadth of genetically-based variability in drug-mediated antinociception in animals. Specific examples in which the gene or genes underlying such variability have been postulated or identified will be given, while highlighting the effect of sex and its interactions with other genetic backgrounds. Finally, we will summarise and evaluate the literature on pharmacogenetic differences in human analgesic drug response, for which the influence of sex has served as one of the better studied and heuristically insightful examples.     

The future prospects of pharmacogenetics in oral anticoagulation therapy

Coumarins are the mainstay of oral anticoagulation for the treatment and prophylaxis of thromboembolic disorders. They have a narrow therapeutic index and regular monitoring is therefore required to avoid serious adverse effects. There is wide interindividual variability in dosage requirements, which makes anticoagulation response unpredictable. Current dosing titrations are haphazard and inconvenient and poor initial control leads to morbidity, and occasional mortality, because of bleeding and further thromboembolism. Recent discoveries have helped to characterize the factors that contribute to the interindividual variability in responses to coumarins. Patient and environmental factors that affect anticoagulation response to coumarins include age, body size, dietary vitamin K status, concurrent disease and drug interactions. More recently, single nucleotide polymorphisms in the 2C9 isoform of cytochrome P450 (CYP2C9) and vitamin K epoxide reductase (VKOR) have been shown to make significant contributions to the variability in coumarin dosage requirements. Polymorphisms in other genes that mediate the actions of coumarins may also contribute to this variability. Racial and cultural differences influence dosage requirements, which can be explained, at least in part, by genetic and dietary factors. Incorporation of genetic and environmental factors could help in the prediction of more individualized loading and maintenance doses for safer anticoagulation therapy.     

How and why to screen for CYP2D6 interindividual variability in patients under pharmacological treatments

Cytochromes P450 are members of a superfamily of hemoproteins that catalyze a variety of oxidative reactions in the metabolism of endogenous and exogenous hydrophobic substrates. Fifty-eight cytochrome P450 (CYP) isoenzymes belonging to 18 families have been identified in human cells; the corresponding genes are highly polymorphic, and genetic variability underlies interindividual differences in drug response. The polymorphisms of CYP2D6 significantly affect the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. The number of functional CYP2D6 alleles per genome determines the existence of four different phenotypes, i.e. poor, intermediate, extensive, and ultrarapid metabolizers. CYP2D6 genetic variants include copy number variations, single nucleotide substitutions, frameshift and insertion/deletion mutations. This review reports some of the different methodological approaches used to screen for CYP2D6 variants and focuses on methods that have improved variation detection, from conventional techniques to more recent microarray technology and high throughput DNA sequencing. In addition, this review reports some results on clinical relevance of CYP2D6 polymorphisms and provides examples of variability in drug response associated with interindividual phenotypic differences.     

Candidate gene polymorphisms predicting individual sensitivity to opioids

Significant interindividual differences in opioid sensitivity can hamper effective pain treatment and increase the risk for substance abuse. Elucidation of the genetic mechanisms involved in the interindividual differences in opioid sensitivity would help establish personalized pain management. Studies using gene knockout mice have revealed that genes encoding some metabolic enzymes, opioid transporters, and opioid system signal transduction mediators may be candidate genes to predict appropriate kinds and doses of opioids for individuals. Recently, various databases on knockout mice, pharmacogenetics, and gene polymorphisms have been rapidly consolidated. Such information should aid in developing and improving the methods of predicting interindividual differences in opioid sensitivity. In the near future, it will be possible to predict the appropriate kinds and doses of opioids for individuals by analyzing genetic variations contributing to opioid sensitivity.     

Pharmacogenomics of asthma

Patient response to asthma therapy is consistently observed to be heterogeneous. Pharmacogenomics is the study of inherited differences in interindividual drug disposition and effects, with the goal of selecting the optimal drug therapy and dosage for each patient. This review will cover selected examples of gene polymorphisms that influence the outcome of asthma therapy, and whole-genome expression studies using microarray technology that have shown tremendous potential for benefiting asthma pharmacogenomics. The utility of the mouse as an experimental system for pharmacogenomic discovery will also be discussed in the context of asthma therapy.