普罗布考在动脉粥样硬化心血管疾病防治中的再认识
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摘要
动脉粥样硬化性心血管疾病(ASCVD)是危害人类健康的首要疾病,血脂异常是ASCVD发生和发展的核心致病性危险因素。目前,国内外指南均推荐以低密度脂蛋白-胆固醇(LDL-C)作为ASCVD防控的首要干预靶点,首选他汀类药物。但众多临床研究显示,即使强化他汀治疗,患者仍存在较高的ASCVD剩余风险,且他汀类药物本身亦有其局限性。普罗布考作为唯一的抗氧化类降脂药,既往主要用于家族性高胆固醇血症的治疗。近年研究发现,普罗布考具有抗动脉粥样硬化作用,并受到国内外指南的推荐。本文系统阐述普罗布考的药理学特点及其在基础领域和临床研究的最新进展,为临床医生在治疗ASCVD过程中再认识普罗布考提供新的信息。
Atherosclerotic cardiovascular disease( ASCVD) is one of major threatening diseases to human health, and dyslipidemia has been demonstrated as the core risk factor to initiate and accelerate ASCVD. Low density lipoprotein-cholesterol( LDL-C) has been recommended as the primary target to prevent and treat ASCVD in the worldwide guidelines; meanwhile, statins have been served as the first choice. However,a lot of clinical studies have shown that patients with ASCVD still have high residual risk after aggressive statins treatment; moreover, statins also have their own limitations. Probucol, the only antioxidant lipid-lowering drug,has been previously used for the treatment of familial hypercholesterolemia. Recent studies have shown that probucol exerts strong antioxidant and anti-inflammation effects,which can benefit anti-atherogenic effects. All these new evidences on probucol have been acknowledged by national and international Guidelines. The article systematically reviews the pharmacological characteristics of probucol,and its advanced progresses in basic and clinical research, eventually providing new information for clinicians to further recognize probucol in the treatment of ASCVD.
Atherosclerotic cardiovascular disease( ASCVD) is one of major threatening diseases to human health, and dyslipidemia has been demonstrated as the core risk factor to initiate and accelerate ASCVD. Low density lipoprotein-cholesterol( LDL-C) has been recommended as the primary target to prevent and treat ASCVD in the worldwide guidelines; meanwhile, statins have been served as the first choice. However,a lot of clinical studies have shown that patients with ASCVD still have high residual risk after aggressive statins treatment; moreover, statins also have their own limitations. Probucol, the only antioxidant lipid-lowering drug,has been previously used for the treatment of familial hypercholesterolemia. Recent studies have shown that probucol exerts strong antioxidant and anti-inflammation effects,which can benefit anti-atherogenic effects. All these new evidences on probucol have been acknowledged by national and international Guidelines. The article systematically reviews the pharmacological characteristics of probucol,and its advanced progresses in basic and clinical research, eventually providing new information for clinicians to further recognize probucol in the treatment of ASCVD.
引文
[1]Stone NJ,Robinson JG,Lichtenstein AH,et al.2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults:a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines[J].J Am Coll Cardiol,2014,63(25 Pt B):2889-2934.
[2]Ference BA,Ginsberg HN,Graham I,et al.Low-density lipoproteins cause atherosclerotic cardiovascular disease.1.Evidence from genetic,epidemiologic,and clinical studies.A consensus statement from the European Atherosclerosis Society Consensus Panel[J].Eur Heart J,2017,38(32):2459-2472.
[3]Graham IM,Catapano AL.Management of dyslipidemias in Europe and the USA:same evidence,different conclusions?Can we find common ground[J].Curr Cardiol Rep,2017,19(6):49.
[4]中国成人血脂异常防治指南修订联合委员会.中国成人血脂异常防治指南(2016年修订版)[J].中国循环杂志,2016,31(10):937-950.
[5]胡露,郭凯,赵金珍,等.降脂药物联合应用防治心血管剩留风险新进展[J].实用医学杂志,2017,33(8):1220-1222.
[6]HPS2-THRIVE randomized placebo-controlled trial in 25 673high-risk patients of ER niacin/laropiprant:trial design,prespecified muscle and liver outcomes,and reasons for stopping study treatment[J].Eur Heart J,2013,34(17):1279-1291.
[7]Fulcher J,O'Connell R,Voysey M,et al.Efficacy and safety of LDL-lowering therapy among men and women:meta-analysis of individual data from 174,000 participants in 27 randomised trials[J].Lancet,2015,385(9976):1397-1405.
[8]Yamashita S,Matsuzawa Y.Where are we with probucol:a new life for an old drug[J].Atherosclerosis,2009,207(1):16-23.
[9]曾彦.动脉粥样硬化性心血管疾病抗氧化应激治疗的新启示[J].中国卒中杂志,2017,27(1):85-88.
[10]Tawara K,Tomikawa M,Abiko Y.Mode of action of probucol in reducing serum cholesterol in mice[J].Jpn J Pharmacol,1986,40(1):123-133.
[11]Lau AK,Leichtweis SB,Hume P,et al.Probucol promotes functional reendothelialization in balloon-injured rabbit aortas[J].Circulation,2003,107(15):2031-2036.
[12]Buckley MM,Goa KL,Price AH,et al.Probucol:a reappraisal of its pharmacological properties and therapeutic use in hypercholesterolaemia[J].Drugs,1989,37(6):761-800.
[13]Sakuma N,Yoshikawa M,Hibino T,et al.HDL3 exerts a more powerful antiperoxidative and protective effect against peroxidative modification of LDL than HDL2 does[J].J Nutr Sci Vitaminol(Tokyo),2002,48(4):278-282.
[14]Hazen S.HDL structure,f unction,therapeutics,and imaging[J].Arterioscler Thromb Vasc Biol,2010,30(2):138.
[15]Cuchel M,Rader DJ.Macrophage reverse cholesterol transport:key to the regression of atherosclerosis[J].Circulation,2006,113(21):2548-2555.
[16]倪占玲,王丽霞,赵水平.普罗布考对体内巨噬细胞胆固醇逆转运的作用[J].中国动脉硬化杂志,2013,21(8):695-699.
[17]Zannis VI,Chroni A,Krieger M.Role of apoA-I,ABCA1,LCAT,and SR-BI in the biogenesis of HDL[J].J Mol Med(Berl),2006,84(4):276-294.
[18]Timmins JM,Lee JY,Boudyguina E,et al.Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I[J].J Clin Invest,2005,115(5):1333-1342.
[19]Zhong JK,Guo ZG,Li C,et al.Probucol alleviates atherosclerosis and improves high density lipoprotein function[J].Lipids Health Dis,2011,10:210.
[20]Adlouni A,El MM,Sa6le R,et al.Probucol promotes reverse cholesterol transport in heterozygous familial hypercholesterolemia.Effects on apolipoprotein AI-containing lipoprotein particles[J].Atherosclerosis,2000,152(2):433-440.
[21]刘朋.普罗布考抗动脉粥样硬化作用机制及研究进展[J].天津药学,2009,21(3):74-76.
[22]Radomska-Les'niewska DM,Hevelke A,Skopiński P,et al.Reactive oxygen species and synthetic antioxidants as angiogenesis modulators:clinical implications[J].Pharmacol Rep,2016,68(2):462-471.
[23]Umeji K,Umemoto S,Itoh S,et al.Comparative effects of pitavastatin and probucol on oxidative stress,Cu/Zn superoxide dismutase,PPAR-gamma,and aortic stiffness in hypercholesterolemia[J].Am J Physiol Heart Circ Physiol,2006,291(5):H2522-H2532.
[24]Zhang Q,Chen L,Si Z,et al.Probucol protects endothelial progenitor cells against oxidized low-density lipoprotein via suppression of reactive oxygen species formation in vivo[J].Cell Physiol Biochem,2016,39(1):89-101.
[25]杨鑫,石家振,李新征,等.普罗布考联合二甲双胍对2型糖尿病伴血脂异常患者的疗效评价[J].中国药师,2017,20(3):485-488.
[26]Zhu H,Jin X,Zhao J,et al.Probucol protects against atherosclerosis through lipid-lowering and suppressing immune maturation of CD11c+dendritic cells in STZ-induced diabetic LDLR-/-mice[J].J Cardiovasc Pharmacol,2015,65(6):620-627.
[27]Zhang M,Hou Y,Shen Y,et al.Probucol reverses homocysteine induced inflammatory monocytes differentiation and oxidative stress[J].Eur J Pharmacol,2018,818:67-73.
[28]朱洪.普罗布考及其衍生物防治动脉粥样硬化和血管成形术后再狭窄的研究现状及进展[J].中国动脉硬化杂志,2014,22(10):1062-1066.
[29]Zucoloto AZ,Manchope MF,Staurengo-Ferrari L,et al.Probucol attenuates lipopolysaccharide-induced leukocyte recruitment and inflammatory hyperalgesia:effect on NF-кB activation and cytokine production[J].Eur J Pharmacol,2017,809:52-63.
[30]Niimi M,Keyamura Y,Nozako M,et al.Probucol inhibits the initiation of atherosclerosis in cholesterol-fed rabbits[J].Lipids Health Dis,2013,12:166.
[31]Zhang D,Jiang X,Fang P,et al.Hyperhomocysteinemia promotes inflammatory monocyte generation and accelerates atherosclerosis in transgenic cystathionine beta-synthase-deficient mice[J].Circulation,2009,120(19):1893-1902.
[32]Choy K,Beck K,Png FY,et al.Processes involved in the sitespecific effect of probucol on atherosclerosis in apolipoprotein E gene knockout mice[J].Arterioscler Thromb Vasc Biol,2005,25(8):1684-1690.
[33]Chen Z,Li S,Zhao W,et al.Protective effect of co-administration of rosuvastatin and probucol on atherosclerosis in rats[J].Can J Physiol Pharmacol,2014,92(10):797-803.
[34]Braun A,Zhang S,Miettinen HE,et al.Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse[J].Proc Natl Acad Sci U S A,2003,100(12):7283-7288.
[35]Sawayama Y,Maeda S,Ohnishi H,et al.Effect of probucol on elderly hypercholesterolemic patients in the FAST study[J].Fukuoka Igaku Zasshi,2006,97(1):15-24.
[36]Sawayama Y,Shimizu C,Maeda N,et al.Effects of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia.Fukuoka Atherosclerosis Trial(FAST)[J].J Am Coll Cardiol,2002,39(4):610-616.
[37]Yamashita S,Hbujo H,Arai H,et al.Long-term probucol treatment prevents secondary cardiovascular events:a cohort study of patients with heterozygous familial hypercholesterolemia in Japan[J].J Atheroscler Thromb,2008,15(6):292-303.
[38]Walldius G,Erikson U,Olsson AG,et al.The effect of probucol on femoral atherosclerosis:the Probucol Quantitative Regression Swedish Trial(PQRST)[J].Am J Cardiol,1994,74(9):875-883.
[39]李巍.PCI术后再狭窄的病理生理及其危险因素[J].中国动脉硬化杂志,2013,21(4):375-380.
[40]Auer J,Leitner A,Berent R,et al.Long-term outcomes following coronary drug-eluting-and bare-metal-stent implantation[J].Atherosclerosis,2010,210(2):503-509.
[41]Tardif JC,C8téG,Lespérance J,et al.Impact of residual plaque burden after balloon angioplasty in the MultiVitamins and Probucol(MVP)trial[J].Can J Cardiol,2001,17(1):49-55.
[42]Wakeyama T,Ogawa H,Iida H,et al.Effects of candesartan and probucol on restenosis after coronary stenting:results of insight of stent intimal hyperplasia inhibition by new angiotensin II receptor antagonist(ISHIN)trial[J].Circ J,2003,67(6):519-524.
[43]Stettler C,Wandel S,Allemann S,et al.Outcomes associated with drug-eluting and bare-metal stents:a collaborative network meta-analysis[J].Lancet,2007,370(9591):937-948.
[44]Massberg S,Byrne RA,Kastrati A,et al.Polymer-free sirolimusand probucol-eluting versus new generation zotarolimuseluting stents in coronary artery disease:the Intracoronary Stenting and Angiographic Results:Test Efficacy of Sirolimusand Probucol-Eluting versus Zotarolimus-eluting Stents(ISAR-TEST 5)trial[J].Circulation,2011,124(5):624-632.
[45]Watts GF,Gidding S,Wierzbicki AS,et al.Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation[J].J Clin Lipidol,2014,8(2):148-172.
[46]成西霞,王金.抗氧化剂普罗布考的临床应用[J].临床合理用药杂志,2009,2(13):125-126.
[47]中国医师协会心血管内科医师分会女医师工作委员会,中华医学会心血管病学分会女性心脏健康学组.中国女性心血管疾病预防专家共识[J].中华内科杂志,2017,56(6):472-476.
[48]李莉,龚淼,王慧娟,等.普罗布考减轻氧糖剥夺/复氧小鼠睾丸支持细胞损伤[J].实用医学杂志,2017,33(16):2642-2645.
[49]王瑜.普罗布考联合瑞舒伐他汀对急性脑梗死患者脂质代谢的影响[J].中国医药,2016,11(5):679-682.
[2]Ference BA,Ginsberg HN,Graham I,et al.Low-density lipoproteins cause atherosclerotic cardiovascular disease.1.Evidence from genetic,epidemiologic,and clinical studies.A consensus statement from the European Atherosclerosis Society Consensus Panel[J].Eur Heart J,2017,38(32):2459-2472.
[3]Graham IM,Catapano AL.Management of dyslipidemias in Europe and the USA:same evidence,different conclusions?Can we find common ground[J].Curr Cardiol Rep,2017,19(6):49.
[4]中国成人血脂异常防治指南修订联合委员会.中国成人血脂异常防治指南(2016年修订版)[J].中国循环杂志,2016,31(10):937-950.
[5]胡露,郭凯,赵金珍,等.降脂药物联合应用防治心血管剩留风险新进展[J].实用医学杂志,2017,33(8):1220-1222.
[6]HPS2-THRIVE randomized placebo-controlled trial in 25 673high-risk patients of ER niacin/laropiprant:trial design,prespecified muscle and liver outcomes,and reasons for stopping study treatment[J].Eur Heart J,2013,34(17):1279-1291.
[7]Fulcher J,O'Connell R,Voysey M,et al.Efficacy and safety of LDL-lowering therapy among men and women:meta-analysis of individual data from 174,000 participants in 27 randomised trials[J].Lancet,2015,385(9976):1397-1405.
[8]Yamashita S,Matsuzawa Y.Where are we with probucol:a new life for an old drug[J].Atherosclerosis,2009,207(1):16-23.
[9]曾彦.动脉粥样硬化性心血管疾病抗氧化应激治疗的新启示[J].中国卒中杂志,2017,27(1):85-88.
[10]Tawara K,Tomikawa M,Abiko Y.Mode of action of probucol in reducing serum cholesterol in mice[J].Jpn J Pharmacol,1986,40(1):123-133.
[11]Lau AK,Leichtweis SB,Hume P,et al.Probucol promotes functional reendothelialization in balloon-injured rabbit aortas[J].Circulation,2003,107(15):2031-2036.
[12]Buckley MM,Goa KL,Price AH,et al.Probucol:a reappraisal of its pharmacological properties and therapeutic use in hypercholesterolaemia[J].Drugs,1989,37(6):761-800.
[13]Sakuma N,Yoshikawa M,Hibino T,et al.HDL3 exerts a more powerful antiperoxidative and protective effect against peroxidative modification of LDL than HDL2 does[J].J Nutr Sci Vitaminol(Tokyo),2002,48(4):278-282.
[14]Hazen S.HDL structure,f unction,therapeutics,and imaging[J].Arterioscler Thromb Vasc Biol,2010,30(2):138.
[15]Cuchel M,Rader DJ.Macrophage reverse cholesterol transport:key to the regression of atherosclerosis[J].Circulation,2006,113(21):2548-2555.
[16]倪占玲,王丽霞,赵水平.普罗布考对体内巨噬细胞胆固醇逆转运的作用[J].中国动脉硬化杂志,2013,21(8):695-699.
[17]Zannis VI,Chroni A,Krieger M.Role of apoA-I,ABCA1,LCAT,and SR-BI in the biogenesis of HDL[J].J Mol Med(Berl),2006,84(4):276-294.
[18]Timmins JM,Lee JY,Boudyguina E,et al.Targeted inactivation of hepatic Abca1 causes profound hypoalphalipoproteinemia and kidney hypercatabolism of apoA-I[J].J Clin Invest,2005,115(5):1333-1342.
[19]Zhong JK,Guo ZG,Li C,et al.Probucol alleviates atherosclerosis and improves high density lipoprotein function[J].Lipids Health Dis,2011,10:210.
[20]Adlouni A,El MM,Sa6le R,et al.Probucol promotes reverse cholesterol transport in heterozygous familial hypercholesterolemia.Effects on apolipoprotein AI-containing lipoprotein particles[J].Atherosclerosis,2000,152(2):433-440.
[21]刘朋.普罗布考抗动脉粥样硬化作用机制及研究进展[J].天津药学,2009,21(3):74-76.
[22]Radomska-Les'niewska DM,Hevelke A,Skopiński P,et al.Reactive oxygen species and synthetic antioxidants as angiogenesis modulators:clinical implications[J].Pharmacol Rep,2016,68(2):462-471.
[23]Umeji K,Umemoto S,Itoh S,et al.Comparative effects of pitavastatin and probucol on oxidative stress,Cu/Zn superoxide dismutase,PPAR-gamma,and aortic stiffness in hypercholesterolemia[J].Am J Physiol Heart Circ Physiol,2006,291(5):H2522-H2532.
[24]Zhang Q,Chen L,Si Z,et al.Probucol protects endothelial progenitor cells against oxidized low-density lipoprotein via suppression of reactive oxygen species formation in vivo[J].Cell Physiol Biochem,2016,39(1):89-101.
[25]杨鑫,石家振,李新征,等.普罗布考联合二甲双胍对2型糖尿病伴血脂异常患者的疗效评价[J].中国药师,2017,20(3):485-488.
[26]Zhu H,Jin X,Zhao J,et al.Probucol protects against atherosclerosis through lipid-lowering and suppressing immune maturation of CD11c+dendritic cells in STZ-induced diabetic LDLR-/-mice[J].J Cardiovasc Pharmacol,2015,65(6):620-627.
[27]Zhang M,Hou Y,Shen Y,et al.Probucol reverses homocysteine induced inflammatory monocytes differentiation and oxidative stress[J].Eur J Pharmacol,2018,818:67-73.
[28]朱洪.普罗布考及其衍生物防治动脉粥样硬化和血管成形术后再狭窄的研究现状及进展[J].中国动脉硬化杂志,2014,22(10):1062-1066.
[29]Zucoloto AZ,Manchope MF,Staurengo-Ferrari L,et al.Probucol attenuates lipopolysaccharide-induced leukocyte recruitment and inflammatory hyperalgesia:effect on NF-кB activation and cytokine production[J].Eur J Pharmacol,2017,809:52-63.
[30]Niimi M,Keyamura Y,Nozako M,et al.Probucol inhibits the initiation of atherosclerosis in cholesterol-fed rabbits[J].Lipids Health Dis,2013,12:166.
[31]Zhang D,Jiang X,Fang P,et al.Hyperhomocysteinemia promotes inflammatory monocyte generation and accelerates atherosclerosis in transgenic cystathionine beta-synthase-deficient mice[J].Circulation,2009,120(19):1893-1902.
[32]Choy K,Beck K,Png FY,et al.Processes involved in the sitespecific effect of probucol on atherosclerosis in apolipoprotein E gene knockout mice[J].Arterioscler Thromb Vasc Biol,2005,25(8):1684-1690.
[33]Chen Z,Li S,Zhao W,et al.Protective effect of co-administration of rosuvastatin and probucol on atherosclerosis in rats[J].Can J Physiol Pharmacol,2014,92(10):797-803.
[34]Braun A,Zhang S,Miettinen HE,et al.Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse[J].Proc Natl Acad Sci U S A,2003,100(12):7283-7288.
[35]Sawayama Y,Maeda S,Ohnishi H,et al.Effect of probucol on elderly hypercholesterolemic patients in the FAST study[J].Fukuoka Igaku Zasshi,2006,97(1):15-24.
[36]Sawayama Y,Shimizu C,Maeda N,et al.Effects of probucol and pravastatin on common carotid atherosclerosis in patients with asymptomatic hypercholesterolemia.Fukuoka Atherosclerosis Trial(FAST)[J].J Am Coll Cardiol,2002,39(4):610-616.
[37]Yamashita S,Hbujo H,Arai H,et al.Long-term probucol treatment prevents secondary cardiovascular events:a cohort study of patients with heterozygous familial hypercholesterolemia in Japan[J].J Atheroscler Thromb,2008,15(6):292-303.
[38]Walldius G,Erikson U,Olsson AG,et al.The effect of probucol on femoral atherosclerosis:the Probucol Quantitative Regression Swedish Trial(PQRST)[J].Am J Cardiol,1994,74(9):875-883.
[39]李巍.PCI术后再狭窄的病理生理及其危险因素[J].中国动脉硬化杂志,2013,21(4):375-380.
[40]Auer J,Leitner A,Berent R,et al.Long-term outcomes following coronary drug-eluting-and bare-metal-stent implantation[J].Atherosclerosis,2010,210(2):503-509.
[41]Tardif JC,C8téG,Lespérance J,et al.Impact of residual plaque burden after balloon angioplasty in the MultiVitamins and Probucol(MVP)trial[J].Can J Cardiol,2001,17(1):49-55.
[42]Wakeyama T,Ogawa H,Iida H,et al.Effects of candesartan and probucol on restenosis after coronary stenting:results of insight of stent intimal hyperplasia inhibition by new angiotensin II receptor antagonist(ISHIN)trial[J].Circ J,2003,67(6):519-524.
[43]Stettler C,Wandel S,Allemann S,et al.Outcomes associated with drug-eluting and bare-metal stents:a collaborative network meta-analysis[J].Lancet,2007,370(9591):937-948.
[44]Massberg S,Byrne RA,Kastrati A,et al.Polymer-free sirolimusand probucol-eluting versus new generation zotarolimuseluting stents in coronary artery disease:the Intracoronary Stenting and Angiographic Results:Test Efficacy of Sirolimusand Probucol-Eluting versus Zotarolimus-eluting Stents(ISAR-TEST 5)trial[J].Circulation,2011,124(5):624-632.
[45]Watts GF,Gidding S,Wierzbicki AS,et al.Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation[J].J Clin Lipidol,2014,8(2):148-172.
[46]成西霞,王金.抗氧化剂普罗布考的临床应用[J].临床合理用药杂志,2009,2(13):125-126.
[47]中国医师协会心血管内科医师分会女医师工作委员会,中华医学会心血管病学分会女性心脏健康学组.中国女性心血管疾病预防专家共识[J].中华内科杂志,2017,56(6):472-476.
[48]李莉,龚淼,王慧娟,等.普罗布考减轻氧糖剥夺/复氧小鼠睾丸支持细胞损伤[J].实用医学杂志,2017,33(16):2642-2645.
[49]王瑜.普罗布考联合瑞舒伐他汀对急性脑梗死患者脂质代谢的影响[J].中国医药,2016,11(5):679-682.