Pharmacogenomics does not only bring the connection of genes, medicines and diseases, but also become a powerful tool for clinical pharmacists. Pharmacogenomics is commonly used in clinical practice, especially in the implementation of genetic-test results for guiding rational use of medicines. The genotyping results of genes can provide good individualized medication guidance for patients, which can be confirmed by clinical use of the clopidogrel and warfarin. As a member of the clinical treatment team, clinical pharmacists should take advantage of pharmaceutical and pharmacogenomics information to promote rational use of medicines.
Key words:
Pharmacogenomics
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Genetic test
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Clinical pharmacists
药物基因组学的核心内容是发现基因、药物和疾病间的相互关系。患者的遗传因素除了影响药物药动学和药效学外,还决定着疾病对药物的易感性以及药物的不良反应。从最初的6-磷酸葡萄糖脱氢酶基因缺陷导致的服用伯氨喹啉溶血到如今的全基因范围内的分析,药物基因组学的发展突飞猛进。截至2016年,经美国食品药品监督管理局(FDA)批准的所有药物中,130余种药物其说明书上已有药物基因组学信息,用于指导不同基因型患者正确服用该药物。随着药物基因组学的发展,遗传多态性已经从传统的基因组水平扩展到了表观遗传水平,从研究基因组单核苷酸多态性(single nucleotide polymorphisms,SNPs)发展到基因拷贝数变异(copy number variation,CNV)等多个方面。随着基因组测序技术以及相应分析方法的发展,使得药物基因组学研究对象从单一基因模型扩展到多基因模型。
临床药师需要的药物基因组学信息可以大致分4类:背景信息、患者信息、药品信息和指导信息。临床药师既要坚信药物基因组学信息能在医疗实践中起到作用,也要认识到仅仅知道患者的基因型信息是不够的,还要知道如何成功地将这些信息应用到临床实践中去。美国的一项统计表明[12],药师在医院内提供包括关于调整剂量(98%)、药物信息(93%)和药动学(92%)等方面的各种药学服务。还有一项针对日本药师的调查显示,31%的调查对象听说过药物基因组学或遗传药理学;16.8%的调查对象知道日本国内药物基因组学检测是医疗保险报销范围内的项目;只有0.4%的调查对象能够基于患者药物基因组学的信息指导一些关于用药方面的问题;61.2%的调查对象表示愿意针对药物的药效或者不良反应做相关药物基因组学的检测[13]。美国卫生系统药师协会(American Society of Health-Systems Pharmacists,ASHP)认为药物基因组学检测能够提高医疗实践效果,如减少不良预后、降低治疗周期、减少治疗费用、减少药物治疗的副作用和保障患者安全。
药师在药物基因组学实践中有3个不同角色:研究者角色、教育者的角色、临床应用者的角色。研究者角色针对的是药师开发以药物基因组学为基础的治疗并在临床实践中进行评估的作用;教育者的角色是指药师对其他药师、临床医生和患者进行药物基因组学的教育;临床应用者角色则是药师利用药物基因组学信息给出建议或者参与患者的药物治疗过程[14]。在一个名为“佛罗里达大学健康个体化医疗项目(University of Florida Health Personalized Medicine Program)”的项目中,研究者详细地记录了药师根据基因型指导氯吡格雷治疗过程中职责和角色的转变情况[15]。文中强调了药师在该过程中所凸显的临床应用者的角色以及药物治疗领导者地位。ASHP和美国药师协会(American Pharmacists Association)都认可了药师在药物基因组学临床实践中的作用[16-17]。鉴于许多医疗机构没有资深的遗传药理学专家,这些组织呼吁医疗机构尽早地将药师安排到药品信息、治疗药物检测、用药系统、患者安全计划以及临床教育等相关工作领域中去,将药师培养成这些领域中的带头人。
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MALLALS,PHILLIPSE,CAROSIG,et al.HLA-B*5701 screening for hypersensitivity to abacavir[J].N Engl J Med,2008,358(6):568-579.
[本文引用:1]
[4]
MARTIN MA,HOFFMAN JM,FREIMUTH RR,et al.Clinical pharmacogenetics implementation consortium guidelines for HLA-B genotype and abacavir dosing:2014 update[J].Clin Pharmacol Ther,2014,95(5):499-500.
Abstract Top of page Abstract ACKNOWLEDGMENTS CONFLICT OF INTEREST Supporting Information The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA-B Genotype and Abacavir Dosing were originally published in April 2012. We reviewed recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplementary Material online and included additional resources for applying CPIC guidelines to the electronic health record. Up-to-date information can be found at PharmGKB ( TODO: clickthrough URL http://www.pharmgkb.org ). Clinical Pharmacology & Therapeutics (2014); 95 5, 499 500. doi: 10.1038/clpt.2014.38
XIN HW,LIU HM,LI YQ,et al.Association of CYP3A4*18B and CYP3A5*3 polymorphism with cyclosporine-related liver injury in Chinese renal transplant recipients[J].Int J Clin Pharmacol Ther,2014,52(6):497-503.
Abstract OBJECTIVE: The purpose of this study was to investigate the associations between CYP3A4*18B and CYP3A5*3 polymorphism and cyclosporine-related liver injuries in Chinese renal transplant recipients. METHODS: We genotyped 339 renal transplant recipients treated with a triple immunosuppressive regimen including cyclosporine for CYP3A4*18B and CYP3A5*3 polymorphism using the polymerase chain reaction restriction fragment length polymorphism assay. RESULTS: The incidence of liver injury in the study population was 36.9% (125/339). At 1 month after transplantation, the trough concentration of cyclosporine (C0) in the group with CYP3A4*1/*1(GG alleles) was significantly higher than in the group with CYP3A4*18B/*1 8B(AA alleles) (p < 0.05). At 3 months after transplantation, the C0 in the group with CYP3A4*1/*1 and group with CYP3A4*1/*18B was markedly higher than in the group with CYP3A4*18B/*18B (p < 0.05). The GG genotypes of CYP3A4*18B were more common in the liver injury group compared with the control group (p < 0.05). Univariate logistic regression analysis showed that subjects carrying the GG genotypes had a 5.136- and 2.528-fold higher risk of developing cyclosporine-related liver injury than those with the AA and GA genotypes. When adjusted for sex, the risk of the CYP3A4*18B genotypes was OR = 4.969 for GG compared to AA (p = 0.030), and OR = 2.634 for GG compared to GA (p = 0.025). However, no association was observed between CYP3A5*3 polymorphisms with cyclosporine-related liver injury. CONCLUSIONS: These results suggested that the wild type of CYP3A4*18B is a risk factor for the development of cyclosporine- related liver injuries in Chinese renal transplant recipients.
CHENW,ZHENGR,BAADE PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
<p>With increasing incidence and mortality, cancer is the leading cause of death in China and is a major public health problem. Because of China's massive population (1.37 billion), previous national incidence and mortality estimates have been limited to small samples of the population using data from the 1990s or based on a specific year. With high-quality data from an additional number of population-based registries now available through the National Central Cancer Registry of China, the authors analyzed data from 72 local, population-based cancer registries (2009-2011), representing 6.5% of the population, to estimate the number of new cases and cancer deaths for 2015. Data from 22 registries were used for trend analyses (2000-2011). The results indicated that an estimated 4292,000 new cancer cases and 2814,000 cancer deaths would occur in China in 2015, with lung cancer being the most common incident cancer and the leading cause of cancer death. Stomach, esophageal, and liver cancers were also commonly diagnosed and were identified as leading causes of cancer death. Residents of rural areas had significantly higher age-standardized (Segi population) incidence and mortality rates for all cancers combined than urban residents (213.6 per 100,000 vs 191.5 per 100,000 for incidence; 149.0 per 100,000 vs 109.5 per 100,000 for mortality, respectively). For all cancers combined, the incidence rates were stable during 2000 through 2011 for males (+0.2% per year; P =鈥.1), whereas they increased significantly (+2.2% per year; P CA Cancer J Clin 2016;66:115鈥132. 漏 2016 American Cancer Society.</b></p>
YINM,RENX,ZHANGX,et al.Selective killing of lung cancer cells by miRNA-506 molecule through inhibiting NF-kappaB p65 to evoke reactive oxygen species generation and p53 activation[J].Oncogene,2015,34(6):691-703.
The tumor suppressor p53, nuclear factor-κB (NF-κB) and reactive oxygen species (ROS) have crucial roles in tumorigenesis, although the mechanisms of cross talk between these factors remain largely unknown. Here we report that miR-506 upregulation occurs in 83% of lung cancer patients (156 cases), and its expression highly correlates with ROS. Ectopic expression of miR-506 inhibits NF-κB p65 expression, induces ROS accumulation and then activates p53 to suppress lung cancer cell viability, but not in normal cells. Interestingly, p53 promotes miR-506 expression level, indicating that miR-506 mediates cross talk between p53, NF-κB p65 and ROS. Furthermore, we demonstrated that miR-506 mimics inhibited tumorigenesis in vivo, implicating that miR-506 might be a potential therapeutic molecule for selective killing of lung cancer cells.
KOBAYASHIY,TOGASHIY,YATABEY,et al.EGFR exon 18 mutations in lung cancer:molecular predictors of augmented sensitivity to afatinib or neratinib as compared with first- or third-generation TKIs[J].Clin Cancer Res,2015,21(23):5305-5313.
Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18. Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC90s) of first-generation (1G; gefitinib and erlotinib), second-generation (2G; afatinib, dacomitinib, and neratinib), and third-generation TKIs (3G; AZD9291 and CO1686) were determined. Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%. Transfected Ba/F3 cells grew in the absence of IL3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC90s of 1G and 3G TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by >11-50-fold), whereas IC90s of afatinib were only 3- to 7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5-25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (鈭80%) than to 1G TKIs (35%-56%) by compilation of data in the literature. Lung cancers harboring exon 18 mutations should not be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits cannot detect all exon 18 mutations. Clin Cancer Res; 21(23); 5305-13. 2015 AACR.
SMIT EF,BAASP.Lung cancer in 2015:bypassing checkpoints,overcoming resistance,and honing in on new targets[J].Nat Rev Clin Oncol,2016,13(2):75-76.
Lung-cancer treatment paradigms continue to advance as we exploit our growing understanding of the genetic basis of both tumorigenesis and therapy resistance. Moreover, ongoing developments with targeted therapies are improving patient outcomes, with two new drugs approved in 2015 for non-small-cell lung cancer and many others showing promise.
WALTER AO,SJIN RT,HARINGSMA HJ,et al.Discov-ery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC[J].Cancer Discov,2013,3(12):1404-1415.
Abstract Patients with non-small cell lung cancer (NSCLC) with activating EGF receptor (EGFR) mutations initially respond to first-generation reversible EGFR tyrosine kinase inhibitors. However, clinical efficacy is limited by acquired resistance, frequently driven by the EGFR(T790M) mutation. CO-1686 is a novel, irreversible, and orally delivered kinase inhibitor that specifically targets the mutant forms of EGFR, including T790M, while exhibiting minimal activity toward the wild-type (WT) receptor. Oral administration of CO-1686 as single agent induces tumor regression in EGFR-mutated NSCLC tumor xenograft and transgenic models. Minimal activity of CO-1686 against the WT EGFR receptor was observed. In NSCLC cells with acquired resistance to CO-1686 in vitro, there was no evidence of additional mutations or amplification of the EGFR gene, but resistant cells exhibited signs of epithelial-mesenchymal transition and demonstrated increased sensitivity to AKT inhibitors. These results suggest that CO-1686 may offer a novel therapeutic option for patients with mutant EGFR NSCLC. SIGNIFICANCE: We report the preclinical development of a novel covalent inhibitor, CO-1686, that irreversibly and selectively inhibits mutant EGFR, in particular the T790M drug-resistance mutation, in NSCLC models. CO-1686 is the fi rst drug of its class in clinical development for the treatment of T790M-positive NSCLC, potentially offering potent inhibition of mutant EGFR while avoiding the on-target toxicity observed with inhibition of the WT EGFR. 脗漏2013 AACR.
PEDERSEN CA,SCHNEIDER PJ,SCHECKELHOFF DJ.ASHP National survey of pharmacy practice in hospital settings:prescribing and transcribing-2013[J].Am J Health Syst Pharm,2014,71(11):924-942.
Abstract Results of the 2001 ASHP national survey of pharmacy practice in hospital settings that pertain to prescribing and transcribing are presented. A stratified random sample of pharmacy directors at 1091 general and children's medical-surgical hospitals in the United States was surveyed by mail. SMG Marketing Group, Inc., supplied data on hospital characteristics; the survey sample was drawn from SMG's hospital database. The response rate was 49.0%. During 2001, nearly all hospitals are estimated to have pharmacy and therapeutics (P&T) committees that meet an average of seven times per year. It is estimated that more than 90% of P&T committees are responsible for formulary development and management, drug policy development, adverse-drug-reaction review, and medication-use evaluation. More than 90% of hospitals use clinical and therapeutic, cost, and pharmacoeconomic information in the formulary management process, while nearly two thirds consider quality-of-life issues. Nearly 70% use clinical practice guidelines in the formulary management process, and 78% have a medication-use evaluation program designed to improve prescribing. Pharmacists in more than 75% of hospitals provide consultations on drug information, dosage adjustments for patients with renal impairment, antimicrobials, and pharmacokinetics. Further, a majority of hospitals ensure accurate transcription of medication orders by clarifying illegible orders before transcription or entry into medication administration records (MARs), using standardized prescriber order forms, requiring prescribers to countersign all oral orders, and reconciling MARs and pharmacy patient profiles at least daily. In 2001, large hospitals are most likely to use prescriber order-entry systems to improve patient safety and are least likely to require the reentry of medication orders into the pharmacy computer system. The 2001 ASHP survey results suggest that pharmacists in hospital settings have positioned themselves well to improve the prescribing and transcribing components of the medication-use process.
OBARAT,ABES,SATOHM,et al.Awareness regarding clinical application of pharmacogenetics among Japanese pharmacists[J].Pharmgenomics Pers Med,2015,8(1):35-41.
Taku Obara,1ndash;3 Shinya Abe,4 Michihiro Satoh,1 Sergio Ramoacute;n Gutieacute;rrez Ubeda,5 Shoko Yoshimachi,4 Teruaki Goto4 1Department of Pharmacy, Tohoku University Hospital, Sendai, 2Division of Molecular Epidemiology, Environment and Genome Research Center, Tohoku University Graduate School of Medicine, Sendai, 3Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, 4Tsuruha Holdings, Sapporo, 5Department of Geriatric Behavioral Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan Abstract: Advances in pharmacogenetic analysis technology have accelerated the movement to incorporate pharmacogenetic analysis data into medicine. Therefore, pharmacists will soon have to provide guidance and raise pharmaceutical questions regarding prescriptions based on patient pharmacogenomic information. The objective of this study was to clarify Japanese pharmacists#39; awareness of pharmacogenetics. We conducted a postal questionnaire survey among 372 pharmacists belonging to Tsuruha Holdings. Available data were collected from 268 pharmacists (male [n=133], lt;40 years old [n=170], drugstore pharmacists [n=182]). Of the pharmacists, 19.0% of the population were aware of the Ethical Guidelines for Human Genome/Gene Analysis Research in Japan, 31.0% of the population had heard either or both the terms ldquo;pharmacogenomicsrdquo; and ldquo;pharmacogeneticsrdquo;, and 16.8% of the population were aware that health insurance covered pharmacogenomic tests performed before prescription in Japan. Only 0.4% indicated that they could raise pharmaceutical questions regarding prescriptions based on patients#39; pharmacogenomic information, and 61.2% of the population indicated a preference to undertake pharmacogenomic tests to predict the efficacy or adverse reactions of a drug. We found a need for actions to improve the awareness of pharmacists about pharmacogenetics and create an environment in which pharmacists are able to provide appropriate medical service based on pharmacogenomic information. Keywords: pharmacogenomics/pharmacogenetics, awareness, pharmacist
BROCK TP,FAULKNER CM,WILLIAMS DM,et al.Continuing-education programs in pharmacogenomics for pharmacists[J].Am J Health Syst Pharm,2002,59(8):722-725.
The Notes section welcomes the following types of contributions: (1) practical innovations or solutions to everyday practice problems, (2) substantial updates or elaborations on work previously published by the same authors, (3) important confirmations of research findings previously published by others, and (4) short research reports, including practice surveys, of modest scope or interest. Notes should be submitted with AJHP's manuscript checklist. The text should be concise, and the number of references, tables, and figures should be limited.
OWUSU-OBENGA,WEITZEL KW,HATTON RC,et al.Emerging roles for pharmacists in clinical implementation of pharmacogenomics[J].Pharmacotherapy,2014,34(10):1102-1112.
Pharmacists are uniquely qualified to play essential roles in the clinical implementation of pharmacogenomics. However, specific responsibilities and resources needed for these roles have not been defined. We describe roles for pharmacists that emerged in the clinical implementation of genotype-guided clopidogrel therapy in the University of Florida Health Personalized Medicine Program, summarize preliminary program results, and discuss education, training, and resources needed to support such programs. Planning for University of Florida Health Personalized Medicine Program began in summer 2011 under leadership of a pharmacist, with clinical launch in June 2012 of a clopidogrel- CYP2C19 pilot project aimed at tailoring antiplatelet therapies for patients undergoing percutaneous coronary intervention and stent placement. More than 1000 patients were genotyped in the pilot project in year 1. Essential pharmacist roles and responsibilities that developed and/or emerged required expertise in pharmacy informatics (development of clinical decision support in the electronic medical record), medication safety, medication-use policies and processes, development of group and individual educational strategies, literature analysis, drug information, database management, patient care in targeted areas, logistical issues in genetic testing and follow-up, research and ethical issues, and clinical precepting. In the first 2聽 years of the program (1 year planning and 1 year postimplementation), a total of 14 different pharmacists were directly and indirectly involved, with effort levels ranging from a few hours per month, to 25 30% effort for the director and associate director, to nearly full-time for residents. Clinical pharmacists are well positioned to implement clinical pharmacogenomics programs, with expertise in pharmacokinetics, pharmacogenomics, informatics, and patient care. Education, training, and practice-based resources are needed to support these roles and to facilitate the development of financially sustainable pharmacist-led clinical pharmacogenomics practice models.
REISS SM.Integrating pharmacogenomics into pharmacy practice via medication therapy management[J].J Am Pharm Assoc,2011,51(6):e64-74.
To explore the application and integration of pharmacogenomics in pharmacy clinical practice via medication therapy management (MTM) to improve patient care. Department of Health & Human Services (HHS) Personalized Health Care Initiative, Food and Drug Administration (FDA) pharmacogenomics activity, and findings from the Utilizing E-Prescribing Technologies to Integrate Pharmacogenomics into Prescribing and Dispensing Practices Stakeholder Workshop, convened by the American Pharmacists Association (APhA) on March 5, 2009. Participants at the Stakeholder Workshop included diverse representatives from pharmacy, medicine, pathology, health information technology (HIT), standards, science, academia, government, and others with a key interest in the clinical application of pharmacogenomics. In 2006, HHS initiated the Personalized Health Care Initiative with the goal of building the foundation for the delivery of gene-based care, which may prove to be more effective for large patient subpopulations. In the years since the initiative was launched, drug manufacturers and FDA have begun to incorporate pharmacogenomic data and applications of this information into the drug development, labeling, and approval processes. New applications and processes for using this emerging pharmacogenomics data are needed to effectively integrate this information into clinical practice. Building from the findings of a stakeholder workshop convened by APhA and the advancement of the pharmacist's collaborative role in patient care through MTM, emerging roles for pharmacists using pharmacogenomic information to improve patient care are taking hold. Realizing the potential role of the pharmacist in pharmacogenomics through MTM will require connectivity of pharmacists into the electronic health record infrastructure to permit the exchange of pertinent health information among all members of a patient's health care team. Addressing current barriers, concerns, and system limitations and developing an effective infrastructure will be necessary for pharmacogenomics to achieve its true potential. To achieve integration of pharmacogenomics into clinical practice via MTM, the pharmacy profession must define a process for the application of pharmacogenomic data into pharmacy clinical practice that is aligned with MTM service delivery, develop a viable business model for these practices, and encourage and direct the development of HIT solutions that support the pharmacist's role in this emerging field.
American Society of Health-Systems Pharmacists.ASHP statement on the pharmacist's role in clinical pharmaco-genomics[J].Am J Health Syst Pharm,2015,72(7):579-581.
The article offers information for the members of the American Society of Health-System Pharmacists (ASHP) concerning the role of pharmacists in clinical pharmacogenomics. The ASHP stresses the important role of pharmacogenomic testing in improving medication-related outcomes across the continuum of care in all health-system practice settings. The Clinical Pharmacogenetics Implementation Consortium is mentioned.
MCCULLOUGH KB,FORMEA CM,BERG KD,et al.Assessment of the pharmacogenomics educational needs of pharmacists[J].Am J Pharm Educ,2011,75(3):51.
To evaluate the self-perceived knowledge and confidence of inpatient and outpatient pharmacists in applying pharmacogenomics information to clinical practice.A 19-question multiple-choice, electronic needs-assessment survey instrument was distributed to 480 inpatient and outpatient pharmacists in a large, academic, multi-campus healthcare system.The survey response rate was 64% (303). Most respondents (85%) agreed that pharmacists should be required to be knowledgeable about pharmacogenomics, and 65% agreed that pharmacists should be capable of providing information on the appropriate use of pharmacogenomics testing. Sixty-three percent felt they could not accurately apply the results of pharmacogenomics tests to drug-therapy selection, dosing, or monitoring.Pharmacists believe pharmacogenomics knowledge is important to the profession, but they lack the knowledge and self-confidence to act on the results of pharmacogenomics testing and may benefit from pharmacogenomics education.
SWEN JJ,NIJENHUISM,DE BOERA,et al.Pharmacoge-netics:from bench to byte——an update of guidelines[J].Clin Pharmacol Ther,2011,89(5):662-673.
Currently, there are very few guidelines linking the results of pharmacogenetic tests to specific therapeutic recommendations. Therefore, the Royal Dutch Association for the Advancement of Pharmacy established the Pharmacogenetics Working Group with the objective of developing pharmacogenetics-based therapeutic (dose) recommendations. After systematic review of the literature, recommendations were developed for 53 drugs associated with genes coding for CYP2D6, CYP2C19, CYP2C9, thiopurine-S-methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), vitamin K epoxide reductase (VKORC1), uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), HLA-B44, HLA-B*5701, CYP3A5, and factor V Leiden (FVL).
LEE KC,MA JD,HUDMON KS,et al.A train-the-trainer approach to a shared pharmacogenomics curriculum for US colleges and schools of pharmacy[J].Am J Pharm Educ,2012,76(10):193.
Abstract OBJECTIVE: To assess pharmacy faculty trainers' perceptions of a Web-based train-the-trainer program for PharmGenEd, a shared pharmacogenomics curriculum for health professional students and licensed clinicians. METHODS: Pharmacy faculty trainers (n=58, representing 39 colleges and schools of pharmacy in the United States and 1 school from Canada) participated in a train-the-trainer program consisting of up to 9 pharmacogenomics topics. Posttraining survey instruments assessed faculty trainers' perceptions toward the training program and the likelihood of their adopting the educational materials as part of their institution's curriculum. RESULTS: Fifty-five percent of faculty trainers reported no prior formal training in pharmacogenomics. There was a significant increase (p<0.001) in self-reported ability to teach pharmacogenomics to pharmacy students after participants viewed the webinar and obtained educational materials. Nearly two-thirds (64%) indicated at least a "good" likelihood of adopting PharmGenEd materials at their institution during the upcoming academic year. More than two-thirds of respondents indicated interest in using PharmGenEd materials to train licensed health professionals, and 95% indicated that they would recommend the program to other pharmacy faculty members. CONCLUSION: As a result of participating in the train-the-trainer program in pharmacogenomics, faculty member participants gained confidence in teaching pharmacogenomics to their students, and the majority of participants indicated a high likelihood of adopting the program at their institution. A Web-based train-the-trainer model appears to be a feasible strategy for training pharmacy faculty in pharmacogenomics.
MURPHY JE,GREEN JS,ADAMS LA,et al.Pharmaco-genomics in the curricula of colleges and schools of pharmacy in the United States[J].Am J Pharm Educ,2010,74(1):7.
To assess the breadth, depth, and perceived importance of pharmacogenomics instruction and level of faculty development in this area in schools and colleges of pharmacy in the United States.A questionnaire used and published previously was further developed and sent to individuals at all US schools and colleges of pharmacy. Multiple approaches were used to enhance response.Seventy-five (83.3%) questionnaires were returned. Sixty-nine colleges (89.3%) included pharmacogenomics in their PharmD curriculum compared to 16 (39.0%) as reported in a 2005 study. Topic coverage was <10 hours for 28 (40.6%), 10-30 hours for 29 (42.0%), and 31-60 hours for 10 (14.5%) colleges and schools of pharmacy. Fewer than half (46.7%) were planning to increase course work over the next 3 years and 54.7% had no plans for faculty development related to pharmacogenomics.Most US colleges of pharmacy include pharmacogenomics content in their curriculum, however, the depth may be limited. The majority did not have plans for faculty development in the area of pharmacogenomic content expertise.
CHENL,QINS,XIEJ,et al.Genetic polymorphism analy-sis of CYP2C19 in Chinese Han populations from different geographic areas of mainland China[J].Pharmacogenomics,2008,9(6):691-702.
Abstract AIMS: Although many studies have been performed on CYP2C19, most of them have mainly examined the effects of the defective alleles CYP2C19(*)2 and CYP2C19(*)3. A comprehensive search for genetic polymorphisms of the CYP2C19 gene in the Chinese Han population has rarely been conducted. The present study was designed to determine the genetic basis of CYP2C19 polymorphisms. MATERIALS & METHODS: We investigated the 5 -regulatory region, all the exons and their surrounding introns of the CYP2C19 gene in 400 unrelated healthy Chinese Han volunteers from four different geographical locations, namely Shanghai, Shantou, Shenyang and Xi'an, with a sample of 100 subjects in each population, using direct sequencing. RESULTS: A total of 14 different CYP2C19 polymorphisms, including one novel variant (-2306G>A) in the enhancer region and a novel nonsynonymous one (905C>G, T302R) were identified. In addition, CYP2C19(*)1, (*)2, (*)3, (*)15 and (*)17 alleles showed frequencies of 69.7%, 24.7%, 3.3%, 1.2% and 1.2%, respectively, and CYP2C19(*)15 was the first detected in an Asian population. The frequencies of the prevalent defective alleles CYP2C19(*)2 and CYP2C19(*)3 in Chinese Han populations are similar to those in other Asians, and much higher than those reported in American European and other Caucasian populations. Haplotype analysis demonstrated CATCGG was the dominating haplotype with a frequency of 38.6% in the Chinese Han population. Furthermore, homology modeling analysis for CYP2C19 indicates that Thr302Arg could cause the displacement of heme. CONCLUSION: This is the first study that systematically screened the polymorphisms of the whole CYP2C19 gene in a large Chinese Han population. The results suggest that a few low frequent variants show significant differences among the four populations, while the prevalent polymorphisms show no differences. Therefore, our database provides important information on CYP2C19 polymorphisms in the Chinese population, and could be helpful for future personalized medicine studies in Asian populations generally.
SCOTT SA,SANGKUHLK,STEIN CM,et al.Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy:2013 update[J].Clin Pharmacol Ther,2013,94(3):317-323.
Cytochrome P450 (CYP)2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 loss-of-function alleles impair formation of active metabolites, resulting in reduced platelet inhibition. In addition, CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Guideline updates include emphasis on appropriate indication for CYP2C19 genotype-directed antiplatelet therapy, refined recommendations for specific CYP2C19 alleles, and additional evidence from an expanded literature review (updates at http://www.pharmgkb.org).
MIAOL,YANGJ,HUANGC,et al.Contribution of age,body weight,and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin:proposal for a new dosing regimen in Chinese patients[J].Eur J Clin Pharmacol,2007,63(12):1135-1141.
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WANG TL,LI HL,TJONG WY,et al.Genetic factors contribute to patient-specific warfarin dose for Han Chinese[J].Clin Chim Acta,2008,396(1/2):76-79.
A multiple regression model based on the genetic polymorphisms of VKORC1 , CYP2C9 , EPHX1 and the non-genetic factors of age and body weight can explain 40.2% of the variance in warfarin dose in Han Chinese patients. Translation of this knowledge into clinical guidelines for warfarin prescription may improve the safety and efficacy of warfarin treatment among Han Chinese.
LIX,LIUR,LUO ZY,et al.Comparison of the predictive abilities of pharmacogenetics-based warfarin dosing algori-thms using seven mathematical models in Chinese patients[J].Pharmacogenomics,2015,16(6):583-590.
Aim:This study is aimed to find the best predictive model for warfarin stable dosage.Materials & methods:Seven models, namely multiple linear regression (MLR), artificial neural network, regression tree, boosted regression tree, support vector regression, multivariate adaptive regression spines and random forest regression, as well as the genetic and clinical data of two Chinese samples were employed.Results:The average predicted achievement ratio and mean absolute error of the algorithms were ranging from 52.31 to 58.08 and 4.25 to 4.84 mg/week in validation samples, respectively. The algorithm based on MLR showed the highest predicted achievement ratio and the lowest mean absolute error.Conclusion:At present, MLR may be still the best model for warfarin stable dosage prediction in Chinese population. Original submitted 10 November 2014; Revision submitted 18 February 2015
CAVALLARI LH,NUTESCU EA.Warfarin pharmacogene-tics:to genotype or not to genotype,that is the question[J].Clin Pharmacol Ther,2014,96(1):22-24.
Genotype is well recognized to influence the dose of warfarin necessary for therapeutic anticoagulation. Recent randomized controlled trials evaluating the clinical utility of genotype-guided warfarin dosing have produced varying results. We review the design and results of the recent clinical trials, assess the impact of their findings on warfarin dosing, and examine unanswered questions related to clinical implementation of warfarin pharmacogenetics. <p> Clinical Pharmacology & Therapeutics (2014); 96 1, 22–24. doi:
DUNN A .Warfarin dosing by genotype did not improve time in therapeutic range[J].Ann Intern Med,2014,160(6):JC8.
Rheumatoid arthritis (RA) is a common autoimmune disease in which a heterogeneous course and different pathogenic mechanisms are implicated in chronic inflammation and joint destruction. Despite the diagnostic contribution of anti-citrullinated protein/peptide antibodies (ACPAs) and rheumatoid factors, about one-third of RA patients remain seronegative. ACPAs belong to a heterogeneous family of autoantibodies targeting citrullinated proteins, including myelin-basic protein, several histone proteins, filaggrin and fibrin, fibrinogen or vimentin. In addition to ACPAs, antibodies directed against other post-translationally modified-carbamylated proteins (anti-CarP) were detected in up to 30% of ACPA-negative patients. Using phage display technology, further autoantibodies were recently discovered as candidate biomarkers for seronegative RA patients. Furthermore, in clinical practice, ultrasound may reveal subclinical synovitis and radiographically undetected bone erosions. To improve diagnostic certainty in undifferentiated arthritis and seronegative patients, ultrasound imaging and several new biomarkers may help to identify at risk patients and those with early disease. In this commentary we summarize recent advances in joint ultrasound and future potential of serological biomarkers to improve diagnosis of RA.
TANG HL,SHI WL,LI XG,et al.Limited clinical utility of genotype-guided warfarin initiation dosing algorithms versus standard therapy:a meta-analysis and trial sequential analysis of 11 randomized controlled trials[J].Pharmaco-genomics J,2015,15(6):496-504.
In terms of inconsistent conclusions across all relevant randomized controlled trials (RCTs) and available meta-analyses, we aimed to use a meta-analysis and trial sequential analysis () to evaluate whether clinical utility of a genotype-guided initiation dosing algorithm could be better than that of a standard therapy regimen, and whether currently relevant evidence could be reliable and conclusive. Overall, 11 eligible RCTs involving 2677 patients were included for further analyses. Compared with fixed dose or clinically adjusted initiation dosing regimens, genotype-guided algorithms significantly increased time in therapeutic range, shortened time to first therapeutic international normalized ratio (INR) and time to stable doses, but did not show any marked improvements in excessive anticoagulation, bleeding events, thromboembolism, or all-cause mortality. Subgroup analyses revealed that, genotype-guided algorithms showed better control in the outcomes of time in therapeutic range or excessive anticoagulation than fixed-dose regimens rather than clinically adjusted regimens. Except for excessive anticoagulation, currently available evidence of all other outcomes was unreliable and inconclusive as determined with . Our findings suggest that genotype-guided initiation dosing algorithms have superiority in the improvement of surrogate quality markers for anticoagulation control, but that this does not translate into statistically significant differences in clinical outcomes, which is largely because of the insufficient sample size in the RCTs analyzed.The Pharmacogenomics Journal advance online publication, 14 April 2015; doi:10.1038/tpj.2015.16.
Selective killing of lung cancer cells by miRNA-506 molecule through inhibiting NF-kappaB p65 to evoke reactive oxygen species generation and p53 activation
EGFR exon 18 mutations in lung cancer:molecular predictors of augmented sensitivity to afatinib or neratinib as compared with first- or third-generation TKIs
ASHP National survey of pharmacy practice in hospital settings:prescribing and transcribing-2013
1
2014
... 临床药师需要的药物基因组学信息可以大致分4类:背景信息、患者信息、药品信息和指导信息.临床药师既要坚信药物基因组学信息能在医疗实践中起到作用,也要认识到仅仅知道患者的基因型信息是不够的,还要知道如何成功地将这些信息应用到临床实践中去.美国的一项统计表明[12],药师在医院内提供包括关于调整剂量(98%)、药物信息(93%)和药动学(92%)等方面的各种药学服务.还有一项针对日本药师的调查显示,31%的调查对象听说过药物基因组学或遗传药理学;16.8%的调查对象知道日本国内药物基因组学检测是医疗保险报销范围内的项目;只有0.4%的调查对象能够基于患者药物基因组学的信息指导一些关于用药方面的问题;61.2%的调查对象表示愿意针对药物的药效或者不良反应做相关药物基因组学的检测[13].美国卫生系统药师协会(American Society of Health-Systems Pharmacists,ASHP)认为药物基因组学检测能够提高医疗实践效果,如减少不良预后、降低治疗周期、减少治疗费用、减少药物治疗的副作用和保障患者安全. ...
Awareness regarding clinical application of pharmacogenetics among Japanese pharmacists
1
2015
... 临床药师需要的药物基因组学信息可以大致分4类:背景信息、患者信息、药品信息和指导信息.临床药师既要坚信药物基因组学信息能在医疗实践中起到作用,也要认识到仅仅知道患者的基因型信息是不够的,还要知道如何成功地将这些信息应用到临床实践中去.美国的一项统计表明[12],药师在医院内提供包括关于调整剂量(98%)、药物信息(93%)和药动学(92%)等方面的各种药学服务.还有一项针对日本药师的调查显示,31%的调查对象听说过药物基因组学或遗传药理学;16.8%的调查对象知道日本国内药物基因组学检测是医疗保险报销范围内的项目;只有0.4%的调查对象能够基于患者药物基因组学的信息指导一些关于用药方面的问题;61.2%的调查对象表示愿意针对药物的药效或者不良反应做相关药物基因组学的检测[13].美国卫生系统药师协会(American Society of Health-Systems Pharmacists,ASHP)认为药物基因组学检测能够提高医疗实践效果,如减少不良预后、降低治疗周期、减少治疗费用、减少药物治疗的副作用和保障患者安全. ...
Continuing-education programs in pharmacogenomics for pharmacists
1
2002
... 药师在药物基因组学实践中有3个不同角色:研究者角色、教育者的角色、临床应用者的角色.研究者角色针对的是药师开发以药物基因组学为基础的治疗并在临床实践中进行评估的作用;教育者的角色是指药师对其他药师、临床医生和患者进行药物基因组学的教育;临床应用者角色则是药师利用药物基因组学信息给出建议或者参与患者的药物治疗过程[14].在一个名为“佛罗里达大学健康个体化医疗项目(University of Florida Health Personalized Medicine Program)”的项目中,研究者详细地记录了药师根据基因型指导氯吡格雷治疗过程中职责和角色的转变情况[15].文中强调了药师在该过程中所凸显的临床应用者的角色以及药物治疗领导者地位.ASHP和美国药师协会(American Pharmacists Association)都认可了药师在药物基因组学临床实践中的作用[16-17].鉴于许多医疗机构没有资深的遗传药理学专家,这些组织呼吁医疗机构尽早地将药师安排到药品信息、治疗药物检测、用药系统、患者安全计划以及临床教育等相关工作领域中去,将药师培养成这些领域中的带头人. ...
Emerging roles for pharmacists in clinical implementation of pharmacogenomics
1
2014
... 药师在药物基因组学实践中有3个不同角色:研究者角色、教育者的角色、临床应用者的角色.研究者角色针对的是药师开发以药物基因组学为基础的治疗并在临床实践中进行评估的作用;教育者的角色是指药师对其他药师、临床医生和患者进行药物基因组学的教育;临床应用者角色则是药师利用药物基因组学信息给出建议或者参与患者的药物治疗过程[14].在一个名为“佛罗里达大学健康个体化医疗项目(University of Florida Health Personalized Medicine Program)”的项目中,研究者详细地记录了药师根据基因型指导氯吡格雷治疗过程中职责和角色的转变情况[15].文中强调了药师在该过程中所凸显的临床应用者的角色以及药物治疗领导者地位.ASHP和美国药师协会(American Pharmacists Association)都认可了药师在药物基因组学临床实践中的作用[16-17].鉴于许多医疗机构没有资深的遗传药理学专家,这些组织呼吁医疗机构尽早地将药师安排到药品信息、治疗药物检测、用药系统、患者安全计划以及临床教育等相关工作领域中去,将药师培养成这些领域中的带头人. ...
Integrating pharmacogenomics into pharmacy practice via medication therapy management
1
2011
... 药师在药物基因组学实践中有3个不同角色:研究者角色、教育者的角色、临床应用者的角色.研究者角色针对的是药师开发以药物基因组学为基础的治疗并在临床实践中进行评估的作用;教育者的角色是指药师对其他药师、临床医生和患者进行药物基因组学的教育;临床应用者角色则是药师利用药物基因组学信息给出建议或者参与患者的药物治疗过程[14].在一个名为“佛罗里达大学健康个体化医疗项目(University of Florida Health Personalized Medicine Program)”的项目中,研究者详细地记录了药师根据基因型指导氯吡格雷治疗过程中职责和角色的转变情况[15].文中强调了药师在该过程中所凸显的临床应用者的角色以及药物治疗领导者地位.ASHP和美国药师协会(American Pharmacists Association)都认可了药师在药物基因组学临床实践中的作用[16-17].鉴于许多医疗机构没有资深的遗传药理学专家,这些组织呼吁医疗机构尽早地将药师安排到药品信息、治疗药物检测、用药系统、患者安全计划以及临床教育等相关工作领域中去,将药师培养成这些领域中的带头人. ...
ASHP statement on the pharmacist's role in clinical pharmaco-genomics
1
2015
... 药师在药物基因组学实践中有3个不同角色:研究者角色、教育者的角色、临床应用者的角色.研究者角色针对的是药师开发以药物基因组学为基础的治疗并在临床实践中进行评估的作用;教育者的角色是指药师对其他药师、临床医生和患者进行药物基因组学的教育;临床应用者角色则是药师利用药物基因组学信息给出建议或者参与患者的药物治疗过程[14].在一个名为“佛罗里达大学健康个体化医疗项目(University of Florida Health Personalized Medicine Program)”的项目中,研究者详细地记录了药师根据基因型指导氯吡格雷治疗过程中职责和角色的转变情况[15].文中强调了药师在该过程中所凸显的临床应用者的角色以及药物治疗领导者地位.ASHP和美国药师协会(American Pharmacists Association)都认可了药师在药物基因组学临床实践中的作用[16-17].鉴于许多医疗机构没有资深的遗传药理学专家,这些组织呼吁医疗机构尽早地将药师安排到药品信息、治疗药物检测、用药系统、患者安全计划以及临床教育等相关工作领域中去,将药师培养成这些领域中的带头人. ...
Assessment of the pharmacogenomics educational needs of pharmacists
Contribution of age,body weight,and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin:proposal for a new dosing regimen in Chinese patients
Limited clinical utility of genotype-guided warfarin initiation dosing algorithms versus standard therapy:a meta-analysis and trial sequential analysis of 11 randomized controlled trials
, 辛华雯
