【药品名称】
【通用名】普罗布考片
【别名】丙丁酚
【商品名】之乐
【英文名】Probucol Tablets
【化学名称】4，4'-[（1-甲基亚乙基）二双]2，6-二（1，1-二甲基乙基）苯酚
【化学结构】
【分子式】：C13H48O2S2
【分子量】：516.85
【性状】
本品为白色或类白色片。
【构效关系】
普罗布考在脂蛋白颗粒中的分布多位于磷脂(PL)及游离胆固醇(FC)所组成脂蛋白的单层表面 。
普罗布考的两个酚羟基结构决定其作为断链抗氧化剂和氧离子捕捉剂的性能，酚羟基是本身就很易被氧化的化学基团，与氧离子结合后形成稳定的酚氧基 。
【药理机制】
本品为抗氧化血脂调节药并具有抗动脉粥样硬化作用。本品有显著的抗氧化作用，能抑制泡沫细胞的形成，延缓动脉粥样硬化斑块的形成，消退已形成的动脉粥样硬化斑块。其降脂作用是通过降低胆固醇合成与促进胆固醇分解使血胆固醇和低密度脂蛋白降低，还改变高密度脂蛋白亚型的性质和功能，使血高密度脂蛋白胆固醇减低。本品对血甘油三酯的影响小。
1．抗氧化
抑制50% Cu++引起的脂质和LDL过氧化作用（IC50）的硫代巴比妥酸反应物量（TBARS），普罗布考的抗氧化作用是维生素E的5~6倍 。
普罗布考的抗氧化能力分别是尼莫地平、维拉帕米、卡托普利的16倍、95.5倍、104倍 。
服普罗布考4周后，血浆ox-LDL水平和血清丙二醛（MDA）的水平比服药前分别下降38%和14%，SOD/MDA的比值明显增高 。治疗24周后，测量硫代巴比妥酸反应物量（TBARS），高胆固醇血症患者的血浆过氧化物降低40%，LDL过氧化物降低44% 。
HDL亦易于发生氧化修饰，普罗布考可明显抑制由Cu++介导的HDL体外氧化 。
2．影响细胞基因表达
血管细胞粘连分子-1（VCAM-1）、细胞间粘附分子-1（ICAM-1）、巨噬细胞集落刺激因子（M-CSF）、单核细胞趋化性蛋白（MCP-1）是动脉粥样硬化形成过程中的单核-巨噬细胞系统粘附-趋化-增殖-退化最重要的细胞因子，普罗布考明显降低VCAM-1、M-CSF、ICAM-1、MCP-1在内皮细胞（EC）上的基因表达到基线（正常表达水平）以下，且剂量越大，作用越强 。
粘连分子P-选择素（P-selectin）、E-选择素（E-selectin）可介导单核细胞向血管内皮的粘附-旋转，普罗布考可明显降低粘连分子P-选择素（P-selectin）、E-选择素（E-selectin）在内皮细胞（EC）上的基因表达 。
氧化敏感调控的基因--核转录因子-κB（NF-κB）的转录翻译增加是动脉粥样硬化启动的关键环节，普罗布考显著性抑制NF-κB基因表达 。
组织因子（TF）是动脉粥样硬化血栓形成的初始激活因子，普罗布考显著抑制单核细胞和内皮细胞的TF基因表达 。
白介素-1（IL-1）是动脉粥样硬化形成过程中重要的炎症趋化因子，普罗布考可明显降低IL-1的基因表达 。
肿瘤坏死因子-α(TNF-α) 是动脉粥样硬化形成过程中重要的炎症因子，普罗布考可明显降低IL-1的基因表达 。
血小板衍生生长因子（PDGF）是血管内皮损伤氧化应激产生的重要因子，对血栓形成及血管重塑起关键作用，普罗布考显著抑制内皮细胞和平滑肌细胞的PDGF基因表达 。
3．影响生物酶活性
一氧化氮(NO)可保护内皮细胞免受氧化损伤而抗动脉粥样硬化，普罗布考可通过增加一氧化氮合酶(NOS)，促进一氧化氮（NO）生成，预防NO失活并减少血管氧化损伤 。
基质金属蛋白酶(MMP)是影响冠脉不稳定粥样斑块破裂的重要生物酶，普罗布考显著抑制MMP活性，稳定粥样斑块 。
15-脂加氧酶（15-LO）可促进LDL的氧化修饰，加速动脉粥样硬化的形成，普罗布考可抑制15-LO 生物活性，降低ox-LDL浓度 。
4．调节受体功能
普罗布考可加强肝内和动脉壁的高密度脂蛋白(HDL)与B类I型清道夫受体（SR-BI）的相互结合作用，使HDL的胆固醇酯（CE）部分吸收入肝清除或吸收入肾上腺合成激素增加2倍以上 。
5．降血脂、促进胆固醇逆转运
普罗布考显著降低血浆胆固醇（TC）、低密度脂蛋白-胆固醇（LDL-C） 。
普罗布考可改变高密度脂蛋白(HDL)亚型分布，可使HDL2 亚型降低8%左右，又使HDL3 亚型增高8%左右 。
胆固醇酯转移蛋白（CETP）、卵磷脂胆固醇酰基移换酶（LCAT）是胆固醇逆转运过程中最重要的蛋白和生物酶，普罗布考在血中胆固醇浓度增高时，可使脂肪组织中CETP的mRNA基因表达增加，升高CETP血浓度和活性29~64% ，又能增加LCAT的活性4.5倍 ，从而促进胆固醇逆转运和HDL代谢循环。
普罗布考增加载脂蛋白Ｅ（Apo-E）的mRNA表达，使Apo-E水平升高2～4倍，从而促进从外周转运胆固醇通过肝HDL受体和Apo-E受体进入肝分解代谢及清除 。
6．其他
ox-LDL在人心脏大血管内皮细胞内的浓度越高，纤溶酶原激活剂抑制因子-1（PAI-1）活性越高，普罗布考的强抗氧化活性能完全阻断这种促凝血活性 。
前列腺环素(PGI2)是机体内重要的抗氧化物质，普罗布考通过抑制ox-LDL而促进PGI2的生物合成 。
低密度脂蛋白-胆固醇（LDL-C）中溶血磷脂胆碱（LPC）是致动脉粥样硬化的重要物质，普罗布考可明显降低LPC水平且抑制LDL的致粥性 。
血管成形术后，有丝分裂激活蛋白（MAP）激酶和蛋白激酶C（PKC）促进VSMC增殖，普罗布考灭活MAP激酶和PKC，预防VSMC增殖，抑制新内膜形成 。
【药代动力学】
本品经胃肠道吸收有限且不规则，如与食物同服可使其吸收达最大。一次口服本品后18小时达血药浓度峰值，T1/2为52-60小时。每天服本品，血药浓度逐渐增高，3-4个月达稳态水平。本品在体内产生代谢产物。口服剂量的84%从粪便排出，1%-2%从尿中排出，粪便中以原形为主，尿中以代谢产物为主。
【适应症】
1. 动脉粥样硬化及其引发的心脑血管疾病病
2. 血管介入治疗（PTCA、神经介入）术后再狭窄
3. 高脂蛋白血症
4. 脂肪瘤
【用法用量】
成人常用量 每次0.5g，每日2次，早、晚餐时服用。
【不良反应】
1. 本品最常见的不良反应为胃肠道不适，腹泻的发生率大约为10%，还有胀气、腹痛、恶心和呕吐。
2. 其它少见的反应有：头痛、头晕、感觉异常、失眠、耳鸣、皮疹、皮肤瘙痒等。
3. 有报道发生过血管神经性水肿的过敏反应。
4. 罕见的严重的不良反应有：心电图Q-T间期延长、室性心动过速、血小板减少等。
【禁忌症】
1. 对普罗布考过敏者禁用。
2. 用于本品可引起心电图Q-T间期延长和严重室性心律失常，故在下列情况忌用：
近期心肌损害，如新近心肌梗死者；
严重室性心律失常，如心动过缓者；
有心源性晕厥或有不明原因晕厥者；
有Q-T间期延长者；
正在反应延长Q-T间期的药物；
血钾或血镁过低者。
【注意事项】
1. 服用本品对诊断有干扰：可使血氨基转移酶、胆红素、肌酸磷酸激酶、尿酸、尿素氮短暂升高。
2. 服用本品期间应定期检查心电图Q-T间期。
3. 服用三环类抗抑郁药、Ⅰ类及Ⅲ类抗心律失常药和吩噻嗪类药物的患者服用本品发生心律失常的危险性大。
【孕妇及哺乳期妇女用药】
本品在妊娠期的安全性未知，是否排泌进入乳汁尚不清楚，故不推荐用于孕妇及哺乳期妇女。
【儿童用药】
本品在儿童的安全性未知，故不宜应用。
【老年患者用药】
肾功能减退时本品剂量应减少。本品用于65岁以上老年人，其降胆固醇和低密度脂蛋白胆固醇的效果较年轻患者更为显著。
【药物相互作用】
1. 本品与可导致心律失常的药物，如三环类抗抑郁药、Ⅰ类及Ⅲ类抗心律失常药和吩噻嗪类药物合用时，应注意不良反应发生的危险性增加。
2. 本品能加强香豆素类药物的抗凝血作用。
3. 本品能加强降糖药的作用。
4. 本品与环孢素合用时，与单独服用环孢素相比，可明降低后者的血药浓度。
【规格】0.125g×32片/盒
【贮藏】遮光密闭,干燥处保存。
【生产企业】山东齐鲁制药厂
【参考文献】
1. Bard JM,et al. Location of probucol in lipoproteins inferred from compositional analysis of lipoprotein particles. An in-vitro study. J Pharm Pharmacol 1994 Oct;46(10):797-800
2. O'Leary VJ,et al. The resistance of low density lipoprotein to oxidation promoted by copper and its use as an index of antioxidant therapy. Atherosclerosis 1996 Jan 26;119(2):169-79
3. Barnhart RL, et al. Concentration-dependent antioxidant activity of probucol in low density lipoproteins in vitro: probucol degradation precedes lipoprotein oxidation. J Lipid Res 1989 Nov;30(11):1703-10
4. Baumstark MW, et al. Probucol, incorporated into LDL particles in vivo, inhibits generation of lipid peroxides more effectively than endogenous antioxidants alone. Clin Biochem 1992 Oct;25(5):395-7
5. 南京铁道医学院心血管研究室；尼莫地平、维拉帕米、卡托普利及普罗布考的体外抑制脂质过氧化作用；南京铁道医学院学报，1996；15(2): 70-73
6. 纪求尚，等；普罗布考对冠心病合并高胆固醇血症患者血脂及心绞痛发作的影响；中国新药杂志 1999.08.15; 8(8): 553-555
7. Masana L, et al. Effectiveness of probucol in reducing plasma low-density lipoprotein cholesterol oxidation in hypercholesterolemia. Am J Cardiol 1991 Oct 1;68(9):863-7
8. 胡厚源，等；HDL的体外氧化及丙丁酚的抗氧化作用；重庆医科大学学报 2000.09.05; 25(3): 253-255
9. Liu GX, et al. Probucol inhibits oxidized-low density lipoprotein-induced adhesion of monocytes to endothelial cells in vitro. Acta Pharmacol Sin 2002 Jun;23(6):516-522
10. Oh GT, et al. Dietary hematein ameliorates fatty streak lesions in the rabbit by the possible mechanism of reducing VCAM-1 and MCP-1 expression. Atherosclerosis 2001 Nov;159(1):17-26
11. Zapolska-Downar D, et al. Selective inhibition by probucol of vascular cell adhesion molecule-1 (VCAM-1) expression in human vascular endothelial cells. Atherosclerosis 2001 Mar;155(1):123-30
12. Fruebis J, et al. Inhibition of VCAM-1 expression in the arterial wall is shared by structurally different antioxidants that reduce early atherosclerosis in NZW rabbits. J Lipid Res 1999 Nov;40(11):1958-66
13. Fruebis J, et al. Effect of probucol treatment on gene expression of VCAM-1, MCP-1, and M-CSF in the aortic wall of LDL receptor-deficient rabbits during early atherogenesis. Arterioscler Thromb Vasc Biol 1997 Jul;17(7):1289-302
14. Cominacini L, et al. Antioxidants inhibit the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 induced by oxidized LDL on human umbilical vein endothelial cells. Free Radic Biol Med 1997;22(1-2):117-27
15. Takahara N et al. Oxidized lipoproteins found in patients with NIDDM stimulate radical-induced monocyte chemoattractant protein-1 mRNA expression in cultured human endothelial cells. Diabetologia 1997 Jun;40(6):662-70
16. Li LX et al, Probucol inhibits oxidized-low density lipoprotein-induced adhesion of monocytes to endothelial cells by reducing P-selectin synthesis in vitro. Endothelium 1998;6(1):1-8
17. Kaneko M et al. Probucol downregulates E-selectin expression on cultured human vascular endothelial cells. Arterioscler Thromb Vasc Biol 1996 Aug;16(8):1047-51
18. Aoki M,et al. Endothelial apoptosis induced by oxidative stress through activation of NF-kappaB: antiapoptotic effect of antioxidant agents on endothelial cells. Hypertension 2001 Jul;38(1):48-55
19. Dichtl W, et al. Very low-density lipoprotein activates nuclear factor-kappaB in endothelial cells. Blood 1998 Nov 15;92(10):3924-35
20. Nishio Y,et al. Altered activities of transcription factors and their related gene expression in cardiac tissues of diabetic rats. Diabetes 1998 Aug;47(8):1318-25
21. Aoki M,et al. Endothelial apoptosis induced by oxidative stress through activation of NF-kappaB: antiapoptotic effect of antioxidant agents on endothelial cells. Hypertension 2001 Jul;38(1):48-55
22. Dichtl W,et al. Very low-density lipoprotein activates nuclear factor-kappaB in endothelial cells. Circ Res 1999 May 14;84(9):1085-94
23. Ichikawa K,et al. Advanced glycosylation end products induced tissue factor expression in human monocyte-like U937 cells and increased tissue factor expression in monocytes from diabetic patients. Atherosclerosis 1998 Feb;136(2):281-7
24. Crutchley DJ,et al. Copper-induced tissue factor expression in human monocytic THP-1 cells and its inhibition by antioxidants. Circulation 1995 Jul 15;92(2):238-43
25. Weis JR,et al. Oxidized low-density lipoprotein increases cultured human endothelial cell tissue factor activity and reduces protein C activation. FASEB J 1991 Jul;5(10):2459-65
26. Lin SJ,et al. Effects of Ginkgo biloba extract on the proliferation of vascular smooth muscle cells in vitro and on intimal thickening and interleukin-1beta expression after balloon injury in cholesterol-fed rabbits in vivo. J Cell Biochem 2002;85(3):572-82
27. Sia YT,et al. Improved post-myocardial infarction survival with probucol in rats: effects on left ventricular function, morphology, cardiac oxidative stress and cytokine expression. J Am Coll Cardiol 2002 Jan 2;39(1):148-56
28. Liu GX,et al. Probucol inhibits lipid peroxidation of macrophage and affects its secretory properties. Acta Pharmacol Sin 2000 Jul;21(7):637-40
29. Sugiura T, et al. Probucol suppresses ICAM-1 expression in rat mesangial cells: possible role of IL-1. Kidney Int Suppl 1999 Jul;71:S167-70
30. Li SR,et al. RT-PCR study on the effects of minimally modified low-density lipoproteins and probucol treatment on gene expressions of interleukin-1 and platelet-derived growth factor B-chain in human peripheral blood mononuclear cells. Biol Signals 1996 Sep-Oct;5(5):263-74
31. Li SR,et al. The effects of LPS and probucol on interleukin 1 (IL-1) and platelet-derived growth factor (PDGF) gene expression in the human monocytic cell line U-937. Biochim Biophys Acta 1994 Feb 22;1225(3):271-4
32. Bolaffi JL,et al. Interrelationship of changes in islet nicotine adeninedinucleotide, insulin secretion, and cell viability induced by interleukin-1 beta. Endocrinology 1994 Feb;134(2):537-42
33. Shimizu H,et al. Probucol attenuates a reduction in serum immunoreactive insulin levels by interleukin in adrenalectomized rats. Pharmacology 1992;44(6):344-8
34. Akeson AL,et al. Inhibition of IL-1 beta expression in THP-1 cells by probucol and tocopherol. Atherosclerosis 1991 Feb;86(2-3):261-70
35. Ku G,et al. Ex vivo lipopolysaccharide-induced interleukin-1 secretion from murine peritoneal macrophages inhibited by probucol, a hypocholesterolemic agent with antioxidant properties. FASEB J 1990 Apr 1;4(6):1645-53
36. Ku G,et al. Inhibition by probucol of interleukin 1 secretion and its implication in atherosclerosis.Am J Cardiol 1988 Jul 25;62(3):77B-81B
37. Chen YH,et al. Salvianolic acid B attenuates VCAM-1 and ICAM-1 expression in TNF-alpha-treated human aortic endothelial cells. J Cell Biochem 2001;82(3):512-21
38. Niemann-Jonsson A,et al. Accumulation of LDL in rat arteries is associated with activation of tumor necrosis factor-alpha expression. Arterioscler Thromb Vasc Biol 2000 Oct;20(10):2205-11
39. Faulkner L,et al. Effects of the synthetic anti-oxidant, probucol, on the U937 monoblastoid cell line. Atherosclerosis 1993 Feb;99(1):1-13
40. Inoue K,et al. Effect of BO-653 and probucol on c-MYC and PDGF-A messenger RNA of the iliac artery after balloon denudation in cholesterol-fed rabbits. Atherosclerosis 2002 Apr;161(2):353-63
41. Yasunari K,et al. Antioxidants improve impaired insulin-mediated glucose uptake and prevent migration and proliferation of cultured rabbit coronary smooth muscle cells induced by high glucose. Circulation 1999 Mar 16;99(10):1370-8
42. Miyauchi K,et al. Effect of probucol on smooth muscle cell proliferation and dedifferentiation after vascular injury in rabbits: possible role of PDGF. Cardiovasc Drugs Ther 1998 Jul;12(3):251-60
43. Ramasamy S,et al. Modulation of expression of endothelial nitric oxide synthase by nordihydroguaiaretic acid, a phenolic antioxidant in cultured endothelial cells. Mol Pharmacol 1999 Jul;56(1):116-23
44. Inoue N,et al. Probucol improves endothelial-dependent relaxation and decreases vascular superoxide production in cholesterol-fed rabbits. Am J Med Sci 1998 Apr;315(4):242-7
45. 刘宗汉，等；丙丁酚对氧化型低密度脂蛋白和氧自由基促血管平滑肌细胞增殖的影响；中国现代医学杂志 1996.04.15; 6(2): 1-2
46. Kajinami K,et al. Coronary ectasia in familial hypercholesterolemia: histopathologic study regarding matrix metalloproteinases. Mod Pathol 1999 Dec;12(12):1174-80
47. Nakamura R, et al. Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure: roles of oxidative stress and inflammation. Circulation 2002 Jul 16;106(3):362-7
48. Ishigami M, et al. High-density lipoproteins from probucol-treated patients have increased capacity to promote cholesterol efflux from mouse peritoneal macrophages loaded with acetylated low-density lipoproteins. Eur J Clin Invest 1997 Apr;27(4):285-92
49. Sigari F,et al. Fibroblasts that overexpress 15-lipoxygenase generate bioactive and minimally modified LDL. Arterioscler Thromb Vasc Biol 1997 Dec;17(12):3639-45
50. Upston JM,et al. Oxidation of free fatty acids in low density lipoprotein by 15-lipoxygenase stimulates nonenzymic, alpha-tocopherol-mediated peroxidation of cholesteryl esters. J Biol Chem 1997 Nov 28;272(48):30067-74
51. Ezaki M,et al. Lipoperoxides in LDL incubated with fibroblasts that overexpress 15-lipoxygenase. J Lipid Res 1995 Sep;36(9):1996-2004
52. Schnurr K,et al. 3,5-Di-t-butyl-4-hydroxytoluene (BHT) and probucol stimulate selectively the reaction of mammalian 15-lipoxygenase with biomembranes. Biochim Biophys Acta 1995 Jan 3;1254(1):66-72
53. Rinninger F,et al. Probucol enhances selective uptake of HDL-associated cholesteryl esters in vitro by a scavenger receptor B-I-dependent mechanism. Arterioscler Thromb Vasc Biol 1999 May;19(5):1325-32
54. Buckley MM,et al. Probucol. A reappraisal of its pharmacological properties and therapeutic use in hypercholesterolaemia. Drugs 1989 Jun;37(6):761-800
55. Tedeschi RE,et al. A long-term (9 years) clinical study of the safety and efficacy of probucol, and an analysis of morbidity and mortality rates. Nouv Presse Med 1980 Oct 30;9(40):3021-7
56. Tedeschi RE,et al. Safety and effectiveness of probucol as a cholesterol lowering agent. Artery 1982;10(1):22-34
57. Johansson J, et al. Lowering of HDL2b by probucol partly explains the failure of the drug to affect femoral atherosclerosis in subjects with hypercholesterolemia. A Probucol Quantitative Regression Swedish Trial (PQRST) Report. Arterioscler Thromb Vasc Biol 1995 Aug;15(8):1049-56
58. Quinet EM,et al. Adipose tissue cholesteryl ester transfer protein mRNA in response to probucol treatment: cholesterol and species dependence. J Lipid Res 1993 May;34(5):845-52
59. McPherson R, et al. Increase in plasma cholesteryl ester transfer protein during probucol treatment.Relation to changes in high density lipoprotein composition. Arterioscler Thromb 1991 May-Jun;11(3):476-81
60. Ou J,et al. Mechanism of action of probucol on cholesteryl ester transfer protein (CETP) mRNA in a Chinese hamster ovary cell line that had been stably transfected with a human CETP gene. Biochim Biophys Acta 1998 Jul 31;1393(1):153-60
61. Ishigami M, et al. High-density lipoproteins from probucol-treated patients have increased capacity to promote cholesterol efflux from mouse peritoneal macrophages loaded with acetylated low-density lipoproteins. Eur J Clin Invest 1997 Apr;27(4):285-92
62. Adlouni A,et al. Probucol promotes reverse cholesterol transport in heterozygous familial hypercholesterolemia. Effects on apolipoprotein AI-containing lipoprotein particles. Atherosclerosis 2000 Oct;152(2):433-40
63. Aburatani H,et al. Increased levels of messenger ribonucleic acid for apolipoprotein E in the spleen of probucol-treated rabbits. Am J Cardiol 1988 Jul 25;62(3):60B-65B
64. Brasen JH,et al.Comparison of the effects of alpha-tocopherol, ubiquinone-10 and probucol at therapeutic doses on atherosclerosis in WHHL rabbits. Atherosclerosis 2002 Aug;163(2):249-59
65. Komatsu S,et al. Effect of probucol on intracellular pH and proliferation of human vascular endothelial cells. J Pharmacol Toxicol Methods 1999 Feb;41(1):33-41
66. Yoshinari M,et al. Probucol reduces lysophosphatidylcholines in low-density lipoprotein. Eur J Clin Pharmacol 2000 Feb-Mar;55(11-12):787-92
67. Tanaka K,et al. Probucol inhibits neointimal formation in carotid arteries of normocholesterolemic rabbits and the proliferation of cultured rabbit vascular smooth muscle cells. Cardiovasc Drugs Ther 1998 Mar;12(1):19-28
|
