09基础研究与新药开发

基础研究与新药开发苏定冯药理学教研室基础研究与新药开发新药开发的形势和应对策略高血压基础研究和药物开发脑卒中基础研究和药物开发其他的基础研究和药物开发当前新药开发存在的问题现状：低水平重复：大学研究所药厂原因：利益驱使急功近利势单力薄后果：创新力度不大：无好药恶性竞争：多花钱治不好病应对：认识到社会不需要这么多药认识到中国不需要这么多药厂认识到创新或基础研究的重要性基础研究与新药开发新药开发的形势和应对策略高血压基础研究和药物开发脑卒中基础研究和药物开发其他的基础研究和药物开发S.J.Vane抗高血压药物发展历史前30年：交感抑制药利血平利尿药双克后20年：四大类目前：逾百种对抗高血压新药的要求确切有效，讲究器官保护；终生用药，讲究顺应性好；长效药物，讲究稳定血压；考虑国情，讲究价廉物美。尼群洛尔片单药用量：尼群地平20-40mg/d安替洛尔50-100mg/d复方含量：5mg+10mg复方用量：治疗：2-4片维持：1片协同作用的判定研究指标：血压血压波动性动脉压力感受性反射敏感性器官损伤指标概率相加法(q值法)OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOPa+PbPa×Pb概率相加法(q值法)q=P(a+b)/(Pa+Pb-Pa×Pb)0.85拮抗1.15协同Nit10mg/kgPA=0.6Ate10mg/kgPB=0.1Com10+10mg/kgPA+B=0.70.7/(0.6+0.1)–0.60.1=0.7/0.7–0.06=1.091:1Nit10mg/kgPA=0.6Ate20mg/kgPB=0.2Com10+10mg/kgPA+B=0.90.9/(0.6+0.2)–0.60.2=0.9/0.8–0.12=1.321:2Nit10mg/kgPA=0.6Ate30mg/kgPB=0.5Com10+30mg/kgPA+B=0.70.9/(0.6+0.5)–0.60.5=0.9/1.1–0.30=1.131:3Ate5/10SBPNit4/10A+N13/13q=1.43Ate3/10SBPVNit3/10A+N11/13q=1.66Ate5/10BRSNit6/10A+N13/13q=1.25长期治疗的协同作用Ate0/10LVWNit2/10A+N5/13q=1.92Ate6/10AWNit2/10A+N12/13q=1.36Ate3/10GSSNit4/10A+N12/13q=1.59长期治疗的协同作用对抗高血压新药的要求确切有效，讲究器官保护；终生用药，讲究顺应性好；长效药物，讲究稳定血压；考虑国情，讲究价廉物美。A10mg/kgPA=2/8B0.5mg/kgPB=1/7Com10+0.5mg/kgPA+B=3/83/8/(2/8+1/7)–2/81/7q=1.0910:0.5A10mg/kgPA=2/8B1mg/kgPB=2/7Com10+1mg/kgPA+B=5/7q=5/7/(2/8+2/7)–2/82/7=1.4510:1A10mg/kgPA=2/8B2mg/kgPB=5/8Com10+2mg/kgPA+B=6/8q=6/8/(2/8+5/8)–2/85/8=1.1810:2两类药物联用的选择利尿药钙拮抗药β阻断药RAS抑制药中国研究的复方制剂安替洛尔＋尼群地平安替洛尔＋氨氯地平厄贝沙坦＋氨氯地平坎地沙坦＋氨氯地平替米沙坦＋氨氯地平目前抗高血压药物开发之评价中药抗高血压药物仿制药Me-Too药创新药复方药改剂型药：透皮缓释定时长效药：周效疫苗基础研究与新药开发新药开发的形势和应对策略高血压基础研究和药物开发脑卒中基础研究和药物开发其他的基础研究和药物开发脑卒中的危害性发病率高致死率高致残率高年发病率2‰，中国每年新发200多万累计患病率5-7‰，现有病人700多万脑卒中是人口死亡的第二大原因，中国每年140万人死于脑卒中幸存者致残率很高，社会、家庭负担重。中国每年直接医疗费用374亿元G.A.Donnan,etal,Lancet371,1612(2008).29预防脑卒中的重要性脑卒中的发生率持续上升脑卒中的发生机制不清楚脑卒中一旦发生，病人非死即残缺乏有效的预防措施和理想的治疗方法加强脑卒中预防的基础研究非常紧迫，提出新的预防策略非常必要。4Arterialbaroreflex(ABR)BaroreflexSensitivity(BRS)一、ABR功能与脑卒中的发生动脉压力感受性反射Stroke-pronespontaneouslyhypertensiverats(SHR-SP）hemorrhageMale:9M;Female:13MinfarctionBRSisanimportantdeterminantforstroker=0.441P0.00010200400600-0.20.20.61.01.4BRS(ms/mmHg)Survivaltime(days)0100200300SBPDBPBP(mmHg)**0100200BRS-LBRS-HHP(ms)BRS0.3BRS0.3proportionsurvivingSinoaorticdenervation(SAD)SAD:sinoaorticdenervationSADonthehemodynamicandcerebralischemia0100200ShamSADSBP(mmHg)**00.40.8ShamSADBRS(ms/mmHg)0100200ShamSADDBP(mmHg)0100200ShamSADheartperiod(ms).*0204060ShamSADInfarctvolume(%ofhemisphere)■偶联皂草素的P物质(SP-SAP)SP-SAPSP-SAPonthehemodynamicandcerebralischemia*0204060ControlSP-SAPInfarctvolume(%ofhemisphere)*0100200ControlSP-SAPSBP(mmHg)*050100ControlSP-SAPDBP(mmHg)0100200ControlSP-SAPHeartperiod(ms)**00.61.2ControlSP-SAPBRS(ms/mmHg)hemodynamicandcerebralischemiainratswithlowerBRS050100150BRS-lowBRS-highSBP(mmHg)**00.511.5BRS-lowBRS-highBRS(ms/mmHg)050100150BRS-lowBRS-highDBP(mmHg)0100200BRS-lowBRS-highheartperiod(ms).050100150BRS-lowBRS-highSBP(mmHg)**00.511.5BRS-lowBRS-highBRS(ms/mmHg)050100150BRS-lowBRS-highDBP(mmHg)0100200BRS-lowBRS-highheartperiod(ms).*0204060BRS-lowBRS-highInfarctvolume(%ofhemisphere)二、ABR介导热量限制的保护作用热量限制延长寿命热门话题CNS低等生物SHR-SP寿命与脑卒中3月龄正常食料的60%EffectsofCRonSurvivaltimeinSHR-SP787.5050100ALCRSurvivalrate(%)43W71W****050100ALCRWeeksAtageof12monthsMeansofsurvivaltime(weeks)EffectsofCRonBP&BRS*00.20.40.6ALCRms/mmHgBRS100150200250ALCRmmHgSBP050100150200ALCRDBP050100150200250ALCRmsHeartperiodEffectsofCRonapoptosisofneuralandmyocardialcellsALCRMyocardialcellsNeuralcellsSir2-likeproteins(sirtuins)areafamilyofNAD+-depandentdeacetylases.ItisacceptedthattheeffectsofCRonlifespanismediatedbytheactivationofsirtuins.SirtuinsEffectsofCRonsirtuin***0123BrainHeartKidneyFoldsALCRALCRALCRALCRNature2004;430:686-689Sirtuinactivators：resveratrol,isoliquiritigenin,chalcones,etc.Redwine,peanut,etc.EffectsofCRonBP&BRSSADattenuatedtheprotectionofCRonstroke三、ABR功能影响脑卒中的机制EffectsofSADandCRontheexpressionofVAChT•Apoptosis•Inflammation•Oxidativestress•VasogenesisACha7nAChRStrokeABRStroke?EffectsofCRonapoptosisofneuralandmyocardialcellsALCRMyocardialcellsNeuronsTheprotectionofAChonneuronsrequiredα7nAChR.Hydrogenperoxide-inducedneuronapoptosismethyllycaconitineTheprotectionofAChonneuronsrequiredα7nAChR.Hydrogenperoxide-inducedneuronapoptosisa7nAChRmediatedtheexpressionofSirt1stimulatedbyACha7nAChR+/+-/-AChMLAACh(uM)Sirt1GAPDHALCRSirt1actinSirt1actinSirt1GAPDHShamSAD-+-+-+--++--01003001000TheeffectofSirt1onthecerebralischemicinjuryinducedbyMCAOTheanti-apoptosiseffectofAChinneuronsdependsonSirt1InflammationEffectsofSADandCRoninflammation050100150IL-1β(ng/g)012IL-6(μg/g)050100150TNFalpha(ng/g).050100150IL-1β(ng/g)012IL-6(μg/g)050100150TNFalpha(ng/g).**********BAShamSADShamSADShamSADALCRALCRALCRTheanti-inflammatoryeffectsofAChrequireda7nAChRandSirt1LPS-inducedinflammationingliocytesResveratrolandsirtinoaretheactivatorandinhibitorofSirt1050100150IL-6(pg/ml).0100200300400IL-1β(pg/ml).020406080100TNFalpha(pg/ml).-+++--++---+LPS-+++ACh--++MLA---+-+++--++---+******************0100200T