多廿烷醇的基礎(chǔ)與臨床-胡大一

北京大學(xué)人民醫(yī)院心臟中心胡大一多廿烷醇的根底與臨床多廿烷醇的作用機(jī)制膽固醇的生化合成乙酰CoAHMGCoA甲羥戊酸mevalonicpyrophosphate不飽和焦磷酸酯香葉草醇焦磷酸酯菌綠烯醇焦磷酸酯角鯊烯膽固醇dolicholesubiquinones角鯊烯合成酶HMGCoA合成HMGCoA復(fù)原多廿烷醇調(diào)節(jié)酶的活性他汀完全阻斷Singhetal,2006(UniversidaddeKentucky,US)最新成果說(shuō)明...在肝癌細(xì)胞培養(yǎng)中多廿烷醇不改變細(xì)胞存活率。這些成果確定多廿烷醇:在甲羥戊酸合成前,醋酸利用之后的步驟，調(diào)節(jié)HMG-CoA復(fù)原酶如何調(diào)節(jié)?通過(guò)激活A(yù)MP激酶的活性,促進(jìn)HMGCoA復(fù)原酶失活

…增加LDL肝臟受體的數(shù)量.所以,肝代謝過(guò)程增加…LDL–C分解代謝升高致使LDL-C血清水平下降LiverLDLreceptorLDLreceptor+LDL-C多廿烷醇LDLreceptorLDLreceptorLDLreceptor多廿烷醇降脂作用對(duì)多廿烷醇進(jìn)行臨床實(shí)驗(yàn)的古巴及海外的醫(yī)院和健康中心.

HospitalSalvadorAllendeHospitalManuelFajardoHospitalEnriqueCabrera.HospitalNavalLuisDíazSoto.HospitalMilitarCarlosJ.FinlayHospitalCIMEQ.NationalInstituteofNeurology.NationalInstituteofNefrology.NationalInstituteofAngiologyHospitalJulioTrigoHospitalMiguelEnríquezMedicalServicesMININTPoliclínicoPlazaPoliclínicoGonzálezCoroPoliclínico26deJulio.PoliclínicodocentedePlayaPoliclínicoElpidioBerovides.PoliclínicoArtemisaPoliclínicoJaimanitas.PoliclínicoSantaFEVeteran’sHouses.國(guó)外醫(yī)院墨西哥:2委內(nèi)瑞拉:6智利:2斯洛伐克:1俄羅斯:4阿根廷:6中國(guó):4合計(jì):25

多廿烷醇的單一用藥效果

*****多廿烷醇降脂效果的劑量效用*p<0.05;**p<0.01Comparisonwith撫慰劑(MannWhitneyUtest).Casta?oG,Nodarse,IllnaitJetalCENICCienBiol1996**********多廿烷醇(mg/d)%變化

患者總數(shù):46¤Patients/dose7¤76757多廿烷醇(20&40mg/d)6個(gè)月降脂作用觀(guān)察+p<0.05,++p<0.01,+++p<0.001Comparisonwith撫慰劑(MannWhitneyUtest).Casta?oG,MasR,FernándezLetal.IntJClinPharmacolRes2001,XXI43-58.++++++++++++++++%change患者總數(shù):89多廿烷醇20:29多廿烷醇40:30撫慰劑:30+p<0.05,++p<0.001Comparisonwith撫慰劑(MannWhitneyUtest).CrespoN,AlvarezR.etal:CurrTherRes1997,58:44-51多廿烷醇撫慰劑多廿烷醇(10mg/d)對(duì)非胰島素依賴(lài)性糖尿病患者3個(gè)月的降脂作用+++++%dechange患者總數(shù):19多廿烷醇:10撫慰劑:9+p<0.01++p<0.0001;Comparisonwith撫慰劑(MannWhitneyUtest).Casta?oG,MasR,FernándezLetal:GynecolEndocrinol2000,13:1-9+多廿烷醇(5&10mg/d)對(duì)絕經(jīng)后女性24周的效用++++++

多廿烷醇

安慰劑++++5mg/dx12周10mg/dx12周+%dechangeTotalpatients:244多廿烷醇:122撫慰劑:122多廿烷醇5&10mg/d對(duì)高齡患者的效用%change5mg/d+++++++++++++++++++++

多廿烷醇

安慰劑10mg/d++p<0.001;++++p<0.00001Comparisonwith撫慰劑(MannWhitneyUtest).Casta?oG,MasR,FernándezJC:JGerontolMedSci2001患者總數(shù):179多廿烷醇:90撫慰劑:89++++++p<0.001Comparisonwith撫慰劑.(ttestforindependentsamples)MasR,Casta?oG,IllnaitJetal:ClinPharmacolTher1999,65:439-447(5mg/d)(10mg/d)多廿烷醇撫慰劑+++多廿烷醇對(duì)II型HC且危險(xiǎn)因子2患者6個(gè)月的效用%change+++++++++++++Totalpatients:437多廿烷醇:219撫慰劑:218對(duì)不耐受他汀患者療效觀(guān)察多廿烷醇(20mg/d)(6個(gè)月)對(duì)他汀類(lèi)非敏感者或弱耐受性患者的療效+p<0.05,++p<0.001ComparisonwithbaselineWrightW,WhayneT,etalIntJAngiol2004++++%change+Totalpatients:21

與他汀類(lèi)藥物比照研究

多廿烷醇

Simvastatin%change老年患者多廿烷醇(5mg/d)與辛伐他汀(5mg/d)對(duì)照研究OrtensiG,TesoneP,GoldsteinHCurrTherRes1997患者總數(shù):53多廿烷醇:28Simvastatina:25

+p<0.05,++p<0.01Comparisonbetweengroups(MannWhitneyUtest)Casta?o,G.,Más,R.,Arruzazabala,M.L.etal,1999.Int.J.Clin.Phar.Res,XIX(4)105-116.老年患者多廿烷醇同普伐他汀(10mg/d)的療效對(duì)照(2個(gè)月)++++

多廿烷醇

普伐他汀%change患者總數(shù):68多廿烷醇:33Pravastatin:35+多廿烷醇Atorvastatin老年患者多廿烷醇

vs阿托伐他汀

(10mg/d)(8周)的對(duì)照研究++p<0.05,Comparisonbetweengroups(MannWhitneyUtest)Casta?oG,MasR,FernándezL:Drugs&Aging2003患者總數(shù):75多廿烷醇:38阿托伐他汀

:37

+p<0.05Comaparisonbetweengroups(MannWhitneyUtest)PratsH,RomanO,PinoE:RevMedChil1999,127:286-294.多廿烷醇(10mg/d)與洛伐他汀(20mg/d)對(duì)照研究%change

+

多廿烷醇,

洛伐他汀

辛伐他汀患者總數(shù):106多廿烷醇:55

洛伐他汀:26辛伐他汀:25**+***+**p<0.01,***p>0.001ComparisonwithBeseline(Wilcoxontest),+p<0.01Comparisonwithlovastaton(UdMannWhitneytest)t(sem)Basal20Basal20m多廿烷醇與普伐他汀對(duì)照研究

普伐他汀

多廿烷醇ACD

ICD多廿烷醇與普伐他汀對(duì)LDL-C,CT有相似的作用,但多廿烷醇升高HDL-C多廿烷醇,不是普伐他汀,改善了幾個(gè)生活指標(biāo)同貝特類(lèi)藥物聯(lián)合應(yīng)用

+

+p<0.05,Comparisonbetweengroups(MannWhitneyUtest)SolteroIetalArchVenezolFarmacolTerap1993

多廿烷醇(10mg/d)與苯扎貝特(400mg/d)合用在俄羅斯研究(8周)

多廿烷醇

苯扎貝特%change++患者總數(shù):38多廿烷醇:18

苯扎貝特:20多廿烷醇同苯扎貝特聯(lián)合用藥在阿根廷的試驗(yàn)%change

多廿烷醇+苯扎貝特

安慰劑+苯扎貝特+++++p<0.05,++p<0.01Comparacióncon撫慰劑.(UdeMannWhitney).MarcelloS,GladsteinJ,TesoneP,CurrTherRes2000,61:346-357.患者總數(shù):29多廿烷醇+Bezafibrato:14撫慰劑+Bezafibrato:15平安性和耐受性藥物研究中所發(fā)生的嚴(yán)重不良反響〔SAE〕 撫慰劑多廿烷醇TotalSAE (n=218)(n=219)(n=437) n%n%n%致死性的 心血管的 20.9 0 0 20.5非致死性的 心血管的 5 2.3 0 0 51.1 腦血管的 1 0.5 0 0 10.2 代謝 1 0.5 0 0 10.2 外科 2 0,9 0 0 20,5**p<0.001Comparisonwith撫慰劑.(FisherExactprobabilitytest)MasR,Casta?oG,IllnaitJetal:ClinPharmacolTher1999,65:439-447.

AE合計(jì) 115.100**112.5

w/AE病例合計(jì)10 4.600**102.3++++p<0.05,++p<0.0001Comparisonwithcontrol(Chi2),a

ratex100000inhabitatnts+++

control

多廿烷醇CDCerebrovascularTotalPAD藥理監(jiān)測(cè)研究COHORTTRIAL(5and10mg):6611HospitalizationbecauseanycauseEvolutionofSevereVascularEventsafterfollowing.*CoronaryDiseases;**PeripheralArterialdiseaseHospitalizationinSpecialCareUnit.13%27%Age(X)Control-51多廿烷醇-52Sex(%)F-27,1M-72,9F-25,1M-74,9IV期臨床實(shí)驗(yàn):

通過(guò)25789

例患者證實(shí)出色的平安性0.31%的不良事件發(fā)生率短期和長(zhǎng)期的臨床試驗(yàn)說(shuō)明多廿烷醇沒(méi)有與藥物相關(guān)的臨床、血液學(xué)和生化學(xué)方面的不良事件開(kāi)放期研究顯示了優(yōu)秀的平安性和耐受性，與撫慰劑對(duì)照研究結(jié)果一致售后藥理學(xué)調(diào)查>30000的患者證實(shí)了先前的結(jié)論多廿烷醇比臨床上現(xiàn)有的治療藥物，具有更好平安性和耐受性。多廿烷醇作用的多效性多廿烷醇(10Mg/d)與普伐他汀(

10Mg/d)對(duì)內(nèi)皮細(xì)胞的影響***++****p<0.0001;***p<0.00001,Comparisonwithbaseline.(Wilcoxontest)++p<0.001;Comparisonbetweengroups.(UMannWhitneytest)Casta?o,G.,Más,R.,Arruzazabala,M.L.etal,1999.Int.J.Clin.Phar.Res,XIX(4)105-116.Cel/ml

多廿烷醇

阿托伐他汀++p<0.001,+++p<0.0001,+++++p<0.00001Comparisonbetweengroups(MannWhitneyUtest)CastanoGetalClinDrugInest2003多廿烷醇(10mg/d)與阿托伐他汀(10mg/d)抗血小板聚集的作用比較++++%change+患者總數(shù):多廿烷醇:阿托伐他汀:AA3mM多廿烷醇(10MG/D)與普伐他汀(10MG/D)抗血小板聚集效用比較++p<0.01,Comparisonbetweengroups(MannWhitneyUtest)Casta?o,G.,Más,R.,Arruzazabala,M.L.etal,1999.Int.J.Clin.Phar.Res,XIX(4)105-116,1999%changeADP2

M膠原1/ml

+++++++

多廿烷醇

普伐他汀多廿烷醇與氟伐他汀對(duì)老年婦女LDL-C脂質(zhì)過(guò)氧化敏感性的影響**多廿烷醇氟伐他汀*Casta?oG,MásR,FernándezL,FernándezJC,IllnaitJ,.ClinDrugInvest200121(2):103-113.患者總數(shù):70多廿烷醇:35Fluvastatin:35多廿烷醇的臨床效果**p<0,05Comparisonwithbaseline(Wilcoxon),+p<0,05),Comparisonwith撫慰劑(MannWhitneyUtest).aNumberofmetabolicequivalents(X)Casta?oG,MasR,FernándezJC:JGerontolMedSci2001+撫慰劑多廿烷醇Basal36Basal36months****METEa多廿烷醇對(duì)心臟運(yùn)動(dòng)耐量的影響多廿烷醇對(duì)初次或絕對(duì)跛行距離的效用**p<0.01;***p<0.001ComparisonwithBaselinevalues.(Wilcoxontest).+p<0.05,++p<0.01Comparisonwith撫慰劑(MannWhitneyUtest)TOTALSAE 7 22,6 0 0** 711,3SAESevereadverseevents,**p<0.01Comparisonwith撫慰劑.(FisherExactProbabilitytest)Casta?oG,MasR,IllnaitJetal:Angiology1998,50:123-130多廿烷醇對(duì)IC患者臨床病癥的效用撫慰劑多廿烷醇冷疼痛感覺(jué)異常.++afrequencyofcases(%)referingimprovementofsymptonsL.L.Lowerlimbs++p<0.0001Compariosnwith撫慰劑(FisherExactProbabilitytest).Casta?oG,MasR,IllnaitJetal:Angiology2001,52:115-12