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,國家衛(wèi)生部 全國合理用藥監(jiān)測系統(tǒng) 孫忠實 2011,10,27,海口,藥物基因組學與受體阻滯劑的安全性 Pharmacogenomics and Sefaty of beta-blockrs,WHO實況報道 第317號2011年9月,心血管病是全球范圍造成死亡的最主要原因：與其 它任何原因相比，心血管病每年造成的死亡最多。2008年估計有1730萬人死于心血管病，占全球死亡的30%。在這些死亡中，估計有730萬死于冠心病，620萬死于中風。 80%以上的心血管病死亡發(fā)生在低收入和中等收入國家，男性和女性的發(fā)生率幾乎持平。到2030年，幾乎有2360萬人將死于心血管病，主要死于心臟病和中風。預計它們將繼續(xù)成為死亡的一個主要原因。,2,WHO:The top 10 causes of deathUpdated June 2011,3,美國醫(yī)療中的不良事件, Estimated 100,000 deaths per year (in 1994; Lazarou et al 1998); 6th leading cause of death in the US; Experienced by approximately 7% of patients (2.2 million) per year; Medication-related health problems account for an estimated 3% to 7% of hospital admissions (Pirmohamed M, et al 2004); During their hospital stay, 15% of patients experienced adverse drug reactions (Davies, et al 2009); Increased patient non-compliance。,4,為什么藥物療效不一樣?,5,為什么藥物的無效率如此之高?,Disease Drug Class Poor/Non Responders(%)Cancer (breast, lung, brain)Various70 100DiabetesSulfonylureas25 50AsthmaBeta-2 agonist40 75OA/RANSAID, COX-220 50Duodenal UlcerProton pump20 90HypertensionThiazides50 75Beta-blockers20 30ACE inhibitors10 30Angiotensin IIs10 30HyperlipidemiaHMGCoA reductase inhibitors 30 75DepressionSRRIs20 40Tricyclics25 50MigraineSerotonin25 50BPHSteroid 5a-reductase40 100,6,7,為什么藥物的無效率如此之高?,所用藥物無效而浪費財力巨大Ineffective Therapies Waste Money,8,Cost of Ineffectiveness to Healthcare System$390 million $1.2 billion$345 million $575 million$2.3 billion $5.8 billion$3.8 billion $8.8 billion$560 million $1.0 billion,Major Drug Hypertension Drugs ACE Inhibitors Heart Failure Drugs Beta Blockers Anti Depressants SSRIs Cholesterol Drugs StatinsAsthma Drugs Beta-2-agonists,藥物不良反應多與基因變異相關(guān),Over 16( 60%) of the 27 drugs most frequently cited in ADRs are metabolized by at least 1 enzyme with an inherited DNA variant known to cause poor metabolism!Pharmacogenomics 2003;Lazarou et al (JAMA 1998),9,PGx個體化給藥的熱點:波立維,10,11,Pharmacogenomics = drug therapy + genetic diagnostic test,什么是藥物基因組學?,+,Pharmacogenetics: the study of how genetic differences among individuals cause varied responses to a drug,Pharmacogenomics: Study of the effect of variation in multiple genes, or Is the Whole Genome Application of Pharmcogenetics.目前已將二者統(tǒng)一稱為PGx.,藥物基因組學與藥物基因?qū)W的區(qū)別,12,Prevalence of Use in 2006 for Drugs withPharmacogenomic Biomarker Information in the Product Labeling,Pharmacotherapy 2008;28(8):992998,13,不良反應與藥酶變異相關(guān)最多的藥物,DrugTreatment Enzyme Genotype Frequency,Fluoxetine antidepressant CYP1A2/CYP2D6 2-6/3-10Imipramine antidepressant CYP1A2/CYP2D6 12/3-10%Isoniazid antituberculosis NAT 50-59%Metoprolol Beta-blocker CYP2D6 3-10%Naproxen NSAID CYP2C9 2-6%Phenytoin Anticonvulsant CYP1A2 12%Piroxicam NSAID CYP1A2 12%S-Ibuprofen NSAID CYP1A2 12%S-Warfarin Anticoagulant CYP2C9 2-6%Theophylline Brochodilator CYP1A2 12%,From Pharmacogenomic:Social, Ethical and Clinical Dimensions, M. Rothstein, ed.,2005 Gus Rosania,14,常用藥物與相關(guān)藥酶基因多態(tài)性,15,25%重要處方藥是經(jīng)2D6代謝,16,CYP 2D6誘導劑,DexamethasoneRifampin,17,2D6的抑制劑,18,美托洛爾說明書明確提示確有較多的藥物相互作用,Known clinically significant potent inhibitors of CYP2D6 are antidepressants such as fluoxetine, paroxetine or bupropion, antipsychotics such as thioridazine, antiarrhythmics such as quinidine or propafenone, antiretrovirals such as ritonavir, antihistamines such as diphenhydramine, antimalarials such as hydroxychloroquine or quinidine, antifungals such as terbinafine and medications for stomach ulcers such as cimetidine.,19,美托洛爾說明書明確提示確受到PGx的影響,Metoprolol tartrate is extensively metabolized by the cytochrome P450 enzyme system in the liver. The oxidative metabolism of Lopressor (metoprolol tartrate) is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers.,20,藥物相互作用的典型病例分析-1,52歲男性,經(jīng)4位醫(yī)師依據(jù)不同病情共處方8種藥:對乙酰氨基酚,西咪替丁,可待因,紅霉素,布洛芬,美托洛爾,帕羅西汀及替沃噻噸,其中有4種藥物發(fā)生了嚴重DDI;因可待因為前藥,經(jīng)CYP2D6轉(zhuǎn)化為嗎啡方有鎮(zhèn)痛作用;美托洛爾,帕羅西汀(低濃度)受CYP2D6代謝,而治療量帕羅西汀又可抑制CYP2D6;紅霉素為CYP3A4抑制劑,可增加帕羅西汀濃度,四藥形成惡性循環(huán)的DDI,結(jié)果是可待因無效,血壓急劇下降,減少心臟變力和變時作用,同時抑郁癥惡化,成為“抑郁綜合征”。,21,多用藥 多考慮,22,多用藥 多考慮,23,關(guān)于藥酶的基因多態(tài)性,P450酶的基因多態(tài)型（Genetic polymorphism）使藥物代謝存在著種族和個體差異,目前分為4種表型： 正常代謝型 (EM),又稱快代謝型（Extensive Metabolizer，占75-85%）; 活性缺乏型 (PM),又稱慢代謝型（Poor Metabolizer,占5-10%）;超速代謝型( UM)（Ultrarapid Metabolizer,占1-10%); 中間代謝型( IM)（Intermediate Metabolizer,占10- 15%)(此型介于EM與PM之間） 。,24,從基因型到表型（藥酶）,25,A:為顯性基因; a :為隱性基因,26,遺傳與代謝狀態(tài),27,藥物療效和毒性差異,基因組,基因多態(tài)性,藥物靶點,藥物轉(zhuǎn)運體,藥物代謝酶,基因,基因(組)決定藥物的效應,28,兩類藥物經(jīng)酶代謝的不同結(jié)果,29,2D6的基因多態(tài)性,CYP2D6s的等位基因(125個;2008年)與功能正常功能: CYP2D 6*1、 *33、*35;降低功能: CYP2D 6*2、 *9、*10、*17、*36、*41;增強功能: CYP2D 6*1N、 *2N、 *35N,N= *1、*2、*33 、*41;(為重復序列基因多態(tài)性); 全無功能: CYP2D6*3 、* 4、 *5 、*6 、* 7、 *8、 *11 、*12 、*13、 *14 、*15 、 * 16、 * 18、 19 * 、 * 20 、 * 21 、 * 38 、 * 40 、 * 42、 *43 、* 44 、* 56、 * 62,30,31,2D6等位基因在不同人群中的分布,CYP450 allele nomenclature committee database: http:/www.imm.ki.se/cypalleles,32,藥酶基因多態(tài)性與藥物濃度,(PM),(IM),(EM),(UM),33,-受體阻滯劑應用廣泛但風險卻很大,Blockers are among the most widely prescribed of all drug classes, with more than 120 million prescriptions in the United States in 2004; Are recommended as a first-line agent for various diseases, including heart failure, hypertension, and angina, as well as after myocardial infarction. However, -blocker therapy often produces variable responses among patients. Genetic differences may contribute to this variability in responses to -blockers. Pharmacotherapy.2007;27(6):874-887,34,腎上腺素能受體阻滯劑在心血管疾病中臨床應用的專家共識(2009) 中華醫(yī)學會心血管病學分會和中華心血管病雜志編輯委員會,不僅高度評價了受體阻滯劑的臨床地位和重要作用,更重要的是強調(diào)規(guī)范使用!為什么要強調(diào)規(guī)范使用? 認識上有誤區(qū); 使用率低; 應用不規(guī)范; 選藥不當. 遺憾地是“共識”未提及藥物基因組學對規(guī)范使用受體阻滯劑的重要作用,即提高療效、減少ADR所必需!,35,抗高血壓的藥物基因組學的過去、現(xiàn)在和未來Pharmacogenomics of antihypertensive drugs: past, present and future,21世紀將更加肯定高血壓藥物基因組學的臨床價值!(The next decade should clearly define the clinical potential for hypertension pharmacogenomics.)Pharmacogenomics (2010) 11(4), 487491,36,歐洲心臟病協(xié)會2011年會(ESC Congress 2011),大會主題是“冠狀動脈疾病:從基因到預后(Coronary artery disease: From genetics to outcome )”; 充分表明醫(yī)藥界對基因影響藥物作用個體差異的高度重視,是未來醫(yī)藥學重點發(fā)展方向之一。27 Aug 2011 - 31 Aug 2011 , Paris France,37,美托洛爾受藥酶基因多態(tài)性的影響,The mean plasma half-life of the drug is 5.2 hours for extensive metabolizers and 21.6 hours for poor metabolizers,38,美托洛爾主經(jīng)2D6代謝/比索洛爾則否,39,美托洛爾主要被2D6代謝,美托洛爾70%80%依賴2D6代謝,共有3個代謝產(chǎn)物:O-去甲美托洛爾依賴2D6和3A4代謝,約占全部代謝的60%; -OH美托洛爾僅依賴2D6代謝,約占全部代謝的10%; N-去烷基美托洛爾僅依賴2D6代謝,約占全部代謝的10%;,Clin Pharmacokinetics 2009;48:689723,40,美托洛爾受藥酶基因多態(tài)性的影響顯著,41,攜帶PM者美托洛爾血濃度較EM高6.2倍,IM3.9倍Metoprolol and pharmacokinetic data according to the CYP2D6 genotype(91例白人,平均劑量47,5mg,平均療程12.6月),Pharmacogenetics 2002, 12:465472,42,Pharmacogenetics 2002, 12:465472,43,2D6基因多態(tài)性決定美托洛爾的作用,Plasma metabolic ratio of metoprolol/-OH-metoprolol: Cmax :PM:IM=3.9倍 (P 0.01) AUC: PM:EM=6.2倍(P 0.001) ADR:PM:EM=5倍為什么有些患者即使服用推薦劑量美托洛爾卻發(fā)生嚴重心動過緩、低血壓以及疲勞癥?為什么同服帕羅西汀、普羅帕酮等也出現(xiàn)上述病癥?,Pharmacogenetics 2002, 12:465472,44,2D6基因多態(tài)性對長期服用美托洛爾血濃度的影響與比索洛爾比較,共72例患者入選,其中美托洛爾俎38例;比索洛爾組40例(有6例交叉)至少用藥4周;患者2D6基因多態(tài)性檢測結(jié)果見下表:J Cardiovasc Pharmacol 2005;46:713720,45,72例患者2D6基因多態(tài)性的分布與分組根據(jù)有無2D6*10及其多態(tài)性,組,組,組,showed that normalized plasma concentration ofmetoprolol in patients homozygous for the reduced functionalallele was 3 times higher than in those with normal functional,46,結(jié)果:美托洛爾受2D6基因多態(tài)性影響顯著,而比索洛爾則否,J Cardiovasc Pharmacol 2005;46:713720,47,結(jié)果:美托洛爾受2D6基因多態(tài)性影響顯著組的血藥濃度較組高3倍,Het-PM,Hom-2D6*10,Heter-2D6*10,Hom-PM,J Cardiovasc Pharmacol 2005;46:713720,EM,showed that normalized plasma concentration of metoprolol in patients homozygous for the reduced functional allele was 3 times higher than in those with normal functional,*P0.01; #PUM;濃度相差60 倍,美托洛爾血藥濃度與CYP2D6基因多態(tài)性的關(guān)系,1.27,49,比索洛爾不受2D6基因多態(tài)性的影響,Heter-PM,EM,Hom-PM,Heter-2D6*10,Hom-2D6*10,J Cardiovasc Pharmacol 2005;46:713720,50,結(jié)果:美托洛爾受2D6基因多態(tài)性 影響顯著,而比索洛爾則否,J Cardiovasc Pharmacol 2005;46:713720,組與組*P75:1,Bisoprolol 天生麗質(zhì),Non-ISA,CIBIS CIBISIIITIBBSDECREASE,Balance Clearance,NHI price: Concor 5mg/片3. 03.5元,HypertensionAnginaCHF,75,實施PGx指導的個體化給藥的優(yōu)越性,1. Shift emphasis from reaction to prevention; 2. Select optimal therapy ( trial-and-error);3. Avoid adverse drug reactions ( drug safety);4. Increase patient compliance;5. Reduce time and cost of clinical trials;6. Revive drugs that are failing in clinical trials or were withdrawn from the market;7. Reduce the overall cost of healthcare,76,77,20世紀:千人一藥一量!,One drug fits all !One dose fits all !,21世紀:一人一藥一量“量體裁衣”給藥,78,21世紀人人持有基因身份證,79,2004年啟動醫(yī)師PGx的繼續(xù)教育FDA September 13-14, 2004,80,藥物基因組學的偉大意義,“If