多廿烷醇的基础与临床-胡大一

Haga clic para cambiar el estilo de ttulo,Haga clic para modificar el estilo de texto del patrn,Segundo nivel,Tercer nivel,Cuarto nivel,Quinto nivel,*,北京大学人民医院心脏中心,胡大一,多廿烷醇的根底与临床,多廿烷醇,的作用机制,胆固醇,的生化合成,乙酰 CoA,HMGCoA,甲羟戊酸,mevalonic pyrophosphate,不饱和焦磷酸酯,香叶草醇 焦磷酸酯,菌绿烯醇焦磷酸酯,角鲨烯,胆固醇,dolicholes,ubiquinones,角鲨烯合成酶,HMGCoA 合成,HMGCoA 复原,多廿烷醇,调节酶的活性,他汀,完全阻断,Singh et al, 2006 (Universidad de Kentucky, US),最新成果说明.,在肝癌细胞培养中多廿烷醇 不改变细胞存活率。,这些成果确定多廿烷醇:,在甲羟戊酸合成前, 醋酸利用之后的步骤，调节 HMG-CoA 复原酶,如何调节?,通过激活AMP激酶的活性, 促进HMGCoA 复原酶失活,增加,LDL,肝脏受体的数量,.,所以,肝代谢过程增加,LDL C,分解代谢升高,致使,LDL-C,血清水平下降,Liver,LDL,receptor,LDL,receptor,+ LDL-C,多廿烷醇,LDL,receptor,LDL,receptor,LDL,receptor,多廿烷醇,降脂作用,对多廿烷醇进行临床实验的古巴及海外的医院和健康中心,.,Hospital,Salvador Allende,Hospital Manuel Fajardo,Hospital Enrique Cabrera.,Hospital Naval Luis Daz Soto.,Hospital Militar Carlos J. Finlay,Hospital CIMEQ.,National Institute of Neurology.,National Institute of Nefrology.,National Institute of Angiology,Hospital Julio Trigo,Hospital Miguel Enrquez,Medical Services MININT,Policlnico Plaza,Policlnico Gonzlez Coro,Policlnico 26 de Julio .,Policlnico docente de Playa,Policlnico Elpidio Berovides.,Policlnico Artemisa,Policlnico Jaimanitas.,Policlnico Santa FE,Veterans Houses.,国外医院,墨西哥,: 2,委内瑞拉,: 6,智利,: 2,斯洛伐克,: 1,俄罗斯,: 4,阿根廷,: 6,中国,: 4,合计,: 25,多廿烷醇,的单一用药效果,*,*,*,多廿烷醇降脂效果的剂量效用,*p 0.05; *p 0.01 Comparison with 抚慰剂 (Mann Whitney U test).,Castao G, Nodarse , Illnait J et al CENIC Cien Biol 1996,*,*,*,*,*,多廿烷醇 (mg/d),%,变化,患者总数,: 46,Patients/dose,7,7,6,7,5,7,多廿烷醇 (20 & 40 mg/d),6,个月降脂作用观察,+p 0.05, +p 0.01, +p 0.001Comparison with 抚慰剂 (Mann Whitney U test).,Castao G, Mas R, Fernndez L et al. Int J Clin Pharmacol Res 2001, XXI 43 - 58.,+,+,+,+,+,+,+,+,% change,患者总数: 89,多廿烷醇 20: 29,多廿烷醇 40: 30,抚慰剂: 30,+p0.05, +p0.001 Comparison with 抚慰剂 (Mann Whitney U test).,Crespo N, Alvarez R. et al: Curr Ther Res 1997, 58 : 44 - 51, 多廿烷醇, 抚慰剂,多廿烷醇 (10 mg/d),对非胰岛素依赖性糖尿病患者,3,个月的降脂作用,+,+,+,% de change,患者总数:19,多廿烷醇: 10,抚慰剂: 9,+p0.01 +p0.0001; Comparison with 抚慰剂 (Mann Whitney U test).,Castao G, Mas R, Fernndez L et al: Gynecol Endocrinol 2000, 13: 1 - 9,+,多廿烷醇 (5 & 10 mg/d),对绝经后女性,24,周的效用,+ +,+ +,+ +,多廿烷醇,安慰剂,+ +,+ +,5 mg/d x 12 周,10 mg/d x 12 周,+,% de change,Total patients: 244,多廿烷醇: 122,抚慰剂: 122,多廿烷醇 5 & 10 mg/d,对高龄患者的效用,%,change,5 mg/d,+,+,+,+,+,+,+,+,多廿烷醇,安慰剂,10 mg/d,+ p0.001; +p 0.00001 Comparison with 抚慰剂 (Mann Whitney U test).,Castao G, Mas R, Fernndez JC: J Gerontol Med Sci 2001,患者总数: 179,多廿烷醇: 90,抚慰剂: 89,+,+ p0.001 Comparison with 抚慰剂. (t test for independent samples),Mas R, Castao G, Illnait J et al: Clin Pharmacol Ther 1999, 65: 439 - 447,(5mg/d),(10mg/d), 多廿烷醇, 抚慰剂,+,多廿烷醇,对,II,型,HC,且危险因子, 2,患者,6,个月的效用,% change,+,+,+,+,+,Total patients: 437,多廿烷醇: 219,抚慰剂: 218,对不耐受他汀患者疗效观察,多廿烷醇,(20 mg/d) (,6,个月,),对他汀类非敏感者或弱耐受性患者的疗效,+p 0.05, +p 0.001 Comparison with baseline,Wright W, Whayne T, et al Int J Angiol 2004,+,+,% change,+,Total patients: 21,与他汀类药物比照研究,多廿烷醇,Simvastatin,%,change,老年患者多廿烷醇,(5mg/d),与辛伐他汀,(5mg/d),对照研究,Ortensi G, Tesone P, Goldstein H Curr Ther Res 1997,患者总数: 53,多廿烷醇: 28,Simvastatina : 25,+ p0.05, + p0.01 Comparison between groups ( Mann Whitney U test),Castao, G., Ms, R., Arruzazabala, M.L. et al, 1999. Int. J. Clin. Phar. Res, XIX (4) 105-116,.,老年患者,多廿烷醇,同普伐他汀,(10 mg/d),的疗效对照,(2,个月,),+,+,+ +,多廿烷醇,普伐他汀,% change,患者总数: 68,多廿烷醇: 33,Pravastatin : 35,+,多廿烷醇,Atorvastatin,老年患者多廿烷醇,vs,阿托伐他汀,(10 mg /d) (8,周,),的对照研究,+p 0.05,Comparison between groups ( Mann Whitney U test),Castao G, Mas R, Fernndez L: Drugs & Aging 2003,患者总数: 75,多廿烷醇: 38,阿托伐他汀,: 37,+ p0.05 Comaparison between groups (Mann Whitney U test),Prats H, Roman O, Pino E: Rev Med Chil 1999, 127: 286 - 294.,多廿烷醇,(10 mg/d),与洛伐他汀,(20 mg/d),对照研究,% change,+,多廿烷醇,洛伐他汀,辛伐他汀,患者总数,: 106,多廿烷醇: 55,洛伐他汀,: 26,辛伐他汀,: 25,*,+,*,+,*,p 0.001 Comparison with Beseline ( Wilcoxon test ), + p 0.01 Comparison with lovastaton (U d Mann Whitney test),t (sem),Basal,20,Basal,20,m,多廿烷醇,与普伐他汀对照研究,普伐他汀,多廿烷醇,AC,D,IC,D,多廿烷醇,与普伐他汀对,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,改善了几个生活指标,同贝特类药物联合应用,+,+ p0.05,Comparison between groups ( Mann Whitney U test),Soltero I et al Arch Venezol Farmacol Terap 1993,多廿烷醇,(10 mg/d),与 苯扎贝特,(400 mg/d),合用在俄罗斯研究,(,8,周,),多廿烷醇,苯扎贝特,% change,+,+,患者总数: 38,多廿烷醇: 18,苯扎贝特,: 20,多廿烷醇,同苯扎贝特联合用药在阿根廷的试验,% change,多廿烷醇,+,苯扎贝特,安慰剂,+,苯扎贝特,+,+,+,+ p0.05, + p0.01 Comparacin con 抚慰剂. (U de Mann Whitney).,Marcello S, Gladstein J, Tesone P, Curr Ther Res 2000, 61: 346 - 357.,患者总数: 29,多廿烷醇 +Bezafibrato: 14,抚慰剂 + Bezafibrato: 15,平安性和耐受性,药物研究中所发生的严重不良反响SAE,抚慰剂 多廿烷醇 Total,SAE (n=218) (n=219) (n=437),n % n % n %,致死性的,心血管的 2 0.900 2 0.5,非致死性的,心血管的 52.30 0 5 1.1,脑血管的10.50 0 1 0.2,代谢10.50 0 1 0.2,外科 20,900 2 0,5,* p0.001 Comparison with 抚慰剂. (Fisher Exact probability test),Mas R, Castao G, Illnait J et al: Clin Pharmacol Ther 1999, 65: 439 - 447.,AE,合计,11 5.1 0 0,*,11 2.5,w/AE,病例合计,10 4.6 0 0,*,10 2.3,+ +,+,+,p0.05, + p 30 000 的患者证实了先前的结论,多廿烷醇比临床上现有的治疗药物，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 (10M,g,/,d,),与普伐他汀,(,10M,g,/,d,),对内皮细胞的影响,* +,*,* p0.0001; * p0.00001, Comparison with baseline .(Wilcoxon test),+ p0.001; Comparison between groups .( U Mann Whitney test),Castao, G., Ms, R., Arruzazabala, M.L. et al, 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, +p0.00001Comparison between groups ( Mann Whitney U test),Castano G et al Clin Drug Inest 2003,多廿烷醇(10 mg /d)与阿托伐他汀(10 mg/d) 抗血小板聚集的作用比较,+,+,% change,+,患者总数:,多廿烷醇:,阿托伐他汀,:,AA 3mM,多廿烷醇 (10MG/D) 与普伐他汀 (10MG/D) 抗血小板聚集效用比较,+p 0.01, Comparison between groups (Mann Whitney U test ),Castao, G., Ms, R., Arruzazabala, M.L. et al, 1999. Int. J. Clin. Phar. Res, XIX (4) 105-116, 1999,% change,ADP 2,M,胶原,1,/ml,+,+ +,+ +,+ +,多廿烷醇,普伐他汀,多廿烷醇与氟伐他汀对老年妇女,LDL-C,脂质过氧化敏感性的影响,*,多廿烷醇,氟伐他汀,*,Castao G, Ms R, Fernndez L, Fernndez JC, Illnait J,. Clin Drug Invest 2001 21(2): 103-113.,患者总数: 70,多廿烷醇: 35,Fluvastatin: 35,多廿烷醇,的临床效果,* p 0,05 Comparison with baseline (Wilcoxon), + p0,05), Comparison with 抚慰剂 (Mann Whitney U test).,a Number of metabolic equivalents (X),Castao G, Mas R, Fernndez JC: J Gerontol Med Sci 2001,+, 抚慰剂, 多廿烷醇,Basal 3 6,Basal 3 6,months,*,*,METE,a,多廿烷醇,对心脏运动耐量的影响,多廿烷醇,对初次或绝对跛行距离的效用,*p 0.01; *p 0.001 Comparison with Baseline values .(Wilcoxon test).,+ p 0.05, + p 0.01 Comparison with 抚慰剂 (Mann Whitney U test),TOTAL SAE 722,60 0,*,7 11,3,SAE Severe adverse events , *p 0.01 Comparison with 抚慰剂 .(Fisher Exact Probability test ),Castao G, Mas R, Illnait J et al: Angiology 1998, 50: 123 - 130,多廿烷醇 对IC患者临床病症的效用, 抚慰剂 多廿烷醇,冷,疼痛,感觉异常,.,+ +,a frequency of cases (%) refering improvement of symptons,L.L. Lower limbs,+ + p 0.0001 Compariosn with 抚慰剂 (Fisher Exact Probability test ).,Castao G, Mas R, Illnait J et al: Angiology 2001, 52: 115 - 125,%,+ +,+ +,抑制脂质过氧化,无药物毒性,.,优秀的耐受性指标,抑制平滑肌细胞,(SMC),增生,降低血清中,LDL-C,和,TC,抑制血小板聚集, TxB2 PgI,对内皮细胞有益的作用,对预防动脉粥样硬化有益的作用,有助于提高 中老人的生活质量,多廿烷醇,升高,HDL-C,水平,多廿烷醇,作为降脂药已经在,30,多个国家注册,多廿烷醇 的提取和成效已经在40多个国家取得专利，包括澳大利亚、西欧、加拿大、美国、日本等。,1996,年荣获世界知识产权组织金奖,所授予专利,4,4,8,8,18,18,Producto:,-,EPO:,Austria, Alemania, Belgica, Dinamarca, Espaa, Francia, Grecia, Gran Bretaa, Holanda, Italia, Liechtenstein, Suiza Suecia/ Japn/,Mxico/,Cuba.,Procedimiento:,Argentina, Colombia,China, Espaa, India, Per,Venezuela,Cuba,Producto y Procedimiento:,Australia (2) , Canad, China, Estados Unidos (2), Egipto, Corea del Sur, India (2), Israel, , Japn, Lbano, Taiwn, Rusia,Austria, Alemania, Belgica, Dinamarca, Espaa, Francia, Grecia, Gran Bretaa, Holanda, Hungra,Italia, Irlanda, Liechtenstein, Luxemburgo, Monaco, Portugal, Suiza, Suecia/,Cuba,学术论文,178,合计,136,国际,42,国内,学术论文分布,按大洲划分,Subject:,谢谢！,