新型合成水蛭肽Hirulog-s抗动脉血栓和抗弥散性血管内凝血作用的实验研究
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摘要
目的:研究新型合成水蛭肽Hirulog-s抗凝、抗动脉血栓作用及其对大鼠血液流变学的改善作用,以及抗家兔弥散性血管内凝血(DIC)作用,为其新药开发提供实验依据。
方法:通过测定凝血时间参数CT、TT、PT、APTT检测Hirulog-s对凝血系统的影响;以血流阻塞时间(OT值)为指标,研究Hirulog-s的抗动脉血栓形成作用;通过测定全血黏度和血浆黏度研究Hirulog-s对血液流变学的影响。大鼠经舌静脉给予低(0.5 mg·kg-1)、中(1.0 mg·kg-1)和高(2.0 mg·kg-1)剂量的Hirulog-s后取血检测上述指标,并与NS对照组进行比较,研究中分别设相应阳性对照药(比伐卢定、肝素、赖氨匹林和己酮可可碱)。采用凝血酶(100 U·kg-1×1 h)和氨基已酸(50 mg·kg-1×1 h)静脉滴注造成家兔急性DIC模型,观察Hirulog-s对凝血酶原时间(PT)、血小板计数(PLT)、纤维蛋白原(FIB)含量和血浆鱼精蛋白副凝固(3P)试验以及对MDA、SOD和血浆TXA2/ PGI2比值的影响,研究中设阳性对照药(比伐卢定、肝素)。
结果:Hirulog-s呈剂量依赖性延长大鼠血凝时间TT、PT、APTT值,且TT的延长远超过对PT和APTT的延长;Hirulog-s各给药组显著延长OT值,并呈剂量依赖性,作用可持续至药后8 h;i.v. Hirulog-s可明显降低大鼠全血比黏度和血浆比黏度,且降低全血比黏度作用较其降低血浆比黏度作用更为明显。静脉注射高、中、低剂量(125.00、62.50、31.25μg·kg-1)的Hirulog-s后DIC的抑制率:用PT表示分别为69.72 %、42.48 %和24.48 %;用PLT表示分别为62.13 %、47.93 %和31.52 %;用FIB表示分别为66.73 %、48.90 %和28.19 %;MAD含量显著下降,下降百分率分别为25.00 %、14.47 %和6.58 %, SOD活性显著上升(p<0.01),上升百分率分别为198.52 %、150.08 %和42.05 %;TXB2/6-keto-PGF1α的比值显著下降(p<0.01)。
结论:大鼠静注Hirulog-s具有强大的抗凝、抗动脉血栓及改善血液流变学作用。Hirulog-s具有明显的抗凝血酶诱发的家兔急性DIC作用。
Objective: To investigate the effects of Hirulog-s, a novel hirudin-derived peptide, on anti-coagulation, anti-artery thrombosis and improving hemorrheology in rats, on anti-disseminated intravascular coagulation (DIC) in rabbits in order to provide preclinical pharmacological basis for its development as a new drug.
Methods: CT, TT, PT and APTT were determined to examine the effect of Hirulog-s on anti-coagulantion. Occlusion Time ( OT ) and blood viscosity, plasma viscosity were measured to investigate its effects on anti-thrombosis and hemorrheology. The above blood parameters were measured after iv administration of Hirulog-s at low (0.5), middle (1.0) and high (2.0 mg/kg) doses to rats in comparation with positive drug Bivalirudin, Heparin, LAS and Pentoxifylline. Rabbit acute DIC was induced by iv infusion of thrombin and PT, PLT, FIB, 3P test and MDA, SOD as well as plasma TXA2/PGI2 ratio were measured to examine the effect of Hirulog-s on DIC in comparation with positive drug Bivalirudin and Heparin.
Results: Hirulog-s prolonged TT, PT and APTT, dose-dependently. After iv dosing, OT was significantly and dose-dependently prolonged, with the action duration of 8 h. Hirulog-s decreased blood viscosity(high shear rate and low shear rate), plasma viscosity markedly. iv administration of Hirulog-s at high (125.00), middle (62.50) and low (32.25μg/kg) doses to rabbits resulted in a dose-dependent inhibition against DIC with inhibitory rate being 69.72, 42.48 and 24.48 % (PT), 62.13, 47.93 and 31.52 % (PLT), and 66.73, 48.90 and 28.19 % (FIB). After iv dosing, MDA was significantly reduced, SOD was markedly elevated, TXB2/6-keto-PGF1αratio was substantially descended.
Conclusion: Hirulog-s has significant effects on anti-coagulantion, anti-artery thrombosis and improving hemorrheology in rats,on anti-acute-DIC induced by thrombin in rabbits.
方法:通过测定凝血时间参数CT、TT、PT、APTT检测Hirulog-s对凝血系统的影响;以血流阻塞时间(OT值)为指标,研究Hirulog-s的抗动脉血栓形成作用;通过测定全血黏度和血浆黏度研究Hirulog-s对血液流变学的影响。大鼠经舌静脉给予低(0.5 mg·kg-1)、中(1.0 mg·kg-1)和高(2.0 mg·kg-1)剂量的Hirulog-s后取血检测上述指标,并与NS对照组进行比较,研究中分别设相应阳性对照药(比伐卢定、肝素、赖氨匹林和己酮可可碱)。采用凝血酶(100 U·kg-1×1 h)和氨基已酸(50 mg·kg-1×1 h)静脉滴注造成家兔急性DIC模型,观察Hirulog-s对凝血酶原时间(PT)、血小板计数(PLT)、纤维蛋白原(FIB)含量和血浆鱼精蛋白副凝固(3P)试验以及对MDA、SOD和血浆TXA2/ PGI2比值的影响,研究中设阳性对照药(比伐卢定、肝素)。
结果:Hirulog-s呈剂量依赖性延长大鼠血凝时间TT、PT、APTT值,且TT的延长远超过对PT和APTT的延长;Hirulog-s各给药组显著延长OT值,并呈剂量依赖性,作用可持续至药后8 h;i.v. Hirulog-s可明显降低大鼠全血比黏度和血浆比黏度,且降低全血比黏度作用较其降低血浆比黏度作用更为明显。静脉注射高、中、低剂量(125.00、62.50、31.25μg·kg-1)的Hirulog-s后DIC的抑制率:用PT表示分别为69.72 %、42.48 %和24.48 %;用PLT表示分别为62.13 %、47.93 %和31.52 %;用FIB表示分别为66.73 %、48.90 %和28.19 %;MAD含量显著下降,下降百分率分别为25.00 %、14.47 %和6.58 %, SOD活性显著上升(p<0.01),上升百分率分别为198.52 %、150.08 %和42.05 %;TXB2/6-keto-PGF1α的比值显著下降(p<0.01)。
结论:大鼠静注Hirulog-s具有强大的抗凝、抗动脉血栓及改善血液流变学作用。Hirulog-s具有明显的抗凝血酶诱发的家兔急性DIC作用。
Objective: To investigate the effects of Hirulog-s, a novel hirudin-derived peptide, on anti-coagulation, anti-artery thrombosis and improving hemorrheology in rats, on anti-disseminated intravascular coagulation (DIC) in rabbits in order to provide preclinical pharmacological basis for its development as a new drug.
Methods: CT, TT, PT and APTT were determined to examine the effect of Hirulog-s on anti-coagulantion. Occlusion Time ( OT ) and blood viscosity, plasma viscosity were measured to investigate its effects on anti-thrombosis and hemorrheology. The above blood parameters were measured after iv administration of Hirulog-s at low (0.5), middle (1.0) and high (2.0 mg/kg) doses to rats in comparation with positive drug Bivalirudin, Heparin, LAS and Pentoxifylline. Rabbit acute DIC was induced by iv infusion of thrombin and PT, PLT, FIB, 3P test and MDA, SOD as well as plasma TXA2/PGI2 ratio were measured to examine the effect of Hirulog-s on DIC in comparation with positive drug Bivalirudin and Heparin.
Results: Hirulog-s prolonged TT, PT and APTT, dose-dependently. After iv dosing, OT was significantly and dose-dependently prolonged, with the action duration of 8 h. Hirulog-s decreased blood viscosity(high shear rate and low shear rate), plasma viscosity markedly. iv administration of Hirulog-s at high (125.00), middle (62.50) and low (32.25μg/kg) doses to rabbits resulted in a dose-dependent inhibition against DIC with inhibitory rate being 69.72, 42.48 and 24.48 % (PT), 62.13, 47.93 and 31.52 % (PLT), and 66.73, 48.90 and 28.19 % (FIB). After iv dosing, MDA was significantly reduced, SOD was markedly elevated, TXB2/6-keto-PGF1αratio was substantially descended.
Conclusion: Hirulog-s has significant effects on anti-coagulantion, anti-artery thrombosis and improving hemorrheology in rats,on anti-acute-DIC induced by thrombin in rabbits.
引文
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2. Yavin YY, Wolozinsky M , Cohen AT. New antithrombotics in the prevention of thromboembolic disease[J]. Eur J Intern Med, 2005;16( 4) : 257~266.
3. Wei Mo,Yan-Ling Zhang,Hong-Shan Chen,Long-Sheng Wang,Hou-Yan Song. A novel hirudin derivative characterized with anti-platelet aggregations and thrombin inhibition[J]. J Thromb Thrombolysis,2009;28:230~237
4.张传领,于爱平,靳继德,等.水蛭素融合蛋白研究进展[J].中国实验血液学杂志,2007;15(1):215-218
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6. Warkentin TE. Bivalent direct thrombin inhibitors: hirudin and bivalirudin[J]. Best Pract Res Clin Haematol, 2004;17 (1):105~125
7.潘春梅,向定成.抗凝药比伐卢定国外临床应用进展[J].中国新药杂志,2008;17(9):725~727、732
8.陈伟宏,向定成,邱健,等.比较国产比伐卢定与肝素对大鼠颈总动脉血栓模型凝血系统的影响[J].岭南心血管病杂志,2009;15(2):136~139
9.朱春燕,郭瑞臣,郭新庆.抗凝药比伐卢定的研究进展[J].菏泽医学专科学校学报,2010;22(2):74~76
10.吕莉,李欣燕,韩国柱.重组水蛭素体内抗凝活性的研究[J].中草药,2002;33(6): 520~523
11. Sirrdge MS, et al. Laboratory Evaluation of Hemostasis & Thrombosis[M]. 3rd ed, Philadelphia: Led & Febiger, 1983: 124, 161
12.陈奇.中药药理研究方法学[M].北京:人民卫生出版社,1993: 572
13.李麟仙,李树清,张晓霏,赵文杰,张宏基,肖昌华.去纤酶对大鼠实验性血栓形成的预防效应[J].中华医学杂志,1982;62(2): 328-329
14. Hladovec J. Experimental arterial thrombosis in rats with continuous registration[J]. Thromb Death Heamorrh,1971;26(2): 407-410
15.金春花,姜秀莲,王英军,张金亭,张淑芳.灵芝多糖活血化淤作用实验研究[J] .中草药,1998;29(7):470~472
16.杨静娴,戴淑芳,韩国柱,等.乌苏里藜芦碱对家兔和大鼠血液流变学及小鼠出血时间的影响[J].中药药理与临床,1998;14(6):22~24
17.吕莉,王艳春,韩国柱.重组水蛭素抗栓及抗弥漫性血管内凝血作用的实验研究[J].中国药学杂志,2002;37(9):707~709
18.叶应妩,李建斋,王玉琛.临床实验诊断学(上)[M].北京:北京卫生出版社,1989:381-2、976、1112、1131、1164
19.李美珍,孙必强,曾姣飞,等.左归丸对老年性痴呆模型大鼠SOD活性和MDA含量的影响[J].中华中医药学刊,2010;28(12):2583~2585
20.李世军,李小鹰.二氢睾酮和其受体对雄性大鼠血小板激活、TXA2/PGI2平衡与细胞内钙离子浓度的调节[J].血栓与止血学,2007;13(5):197~202
21.曹洪,张颖,张功礼.丹参注射液预防深静脉血栓形成的实验研究[J].时珍国医国药,2008;19(5):1146~1147
22.陈冬梅,陈凯,汪海.吗啉环和哌嗪类衍生物的抗栓作用及其分子机制[J].药学学报,2003;38(9):641~645
23.吴会生,郭培培,尚游,等.氟比洛芬酯预处理对大鼠全脑缺血/再灌注时脑组织TXA2/PGI2的影响[J].中国药理学通报,2009;25(9):1176~1180
24.唐映红,梁燕,杨静,等. FeCl3诱导的大鼠颈总动脉血栓模型血浆TXA2、PGI2、抗凝和纤溶活性的变化[J].中国药理学通报,2006;22(11):1353~1356
1. MURRAY CJ, LOPEZ AD. Mortallty by cause for eight regious of the world: global burden of disease study[J]. Luncet, 1997;349(9061): 1269-1276
2. Sinnaeve PR. Simes J, Yusuf S, et al. Direct thrombin inhibitors in acute coronary syndromes: effect in petients undergoing early percutaneous coronary intervention[J]. Eur heart, 2005;26(22): 2396-2403
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2. Yavin YY, Wolozinsky M , Cohen AT. New antithrombotics in the prevention of thromboembolic disease[J]. Eur J Intern Med, 2005;16( 4) : 257~266.
3. Wei Mo,Yan-Ling Zhang,Hong-Shan Chen,Long-Sheng Wang,Hou-Yan Song. A novel hirudin derivative characterized with anti-platelet aggregations and thrombin inhibition[J]. J Thromb Thrombolysis,2009;28:230~237
4.张传领,于爱平,靳继德,等.水蛭素融合蛋白研究进展[J].中国实验血液学杂志,2007;15(1):215-218
5.李珊,盖鲁粤.国产水蛭肽对兔抗凝疗效观察[J].中国康复理论与实践,2007;13(5):421~422
6. Warkentin TE. Bivalent direct thrombin inhibitors: hirudin and bivalirudin[J]. Best Pract Res Clin Haematol, 2004;17 (1):105~125
7.潘春梅,向定成.抗凝药比伐卢定国外临床应用进展[J].中国新药杂志,2008;17(9):725~727、732
8.陈伟宏,向定成,邱健,等.比较国产比伐卢定与肝素对大鼠颈总动脉血栓模型凝血系统的影响[J].岭南心血管病杂志,2009;15(2):136~139
9.朱春燕,郭瑞臣,郭新庆.抗凝药比伐卢定的研究进展[J].菏泽医学专科学校学报,2010;22(2):74~76
10.吕莉,李欣燕,韩国柱.重组水蛭素体内抗凝活性的研究[J].中草药,2002;33(6): 520~523
11. Sirrdge MS, et al. Laboratory Evaluation of Hemostasis & Thrombosis[M]. 3rd ed, Philadelphia: Led & Febiger, 1983: 124, 161
12.陈奇.中药药理研究方法学[M].北京:人民卫生出版社,1993: 572
13.李麟仙,李树清,张晓霏,赵文杰,张宏基,肖昌华.去纤酶对大鼠实验性血栓形成的预防效应[J].中华医学杂志,1982;62(2): 328-329
14. Hladovec J. Experimental arterial thrombosis in rats with continuous registration[J]. Thromb Death Heamorrh,1971;26(2): 407-410
15.金春花,姜秀莲,王英军,张金亭,张淑芳.灵芝多糖活血化淤作用实验研究[J] .中草药,1998;29(7):470~472
16.杨静娴,戴淑芳,韩国柱,等.乌苏里藜芦碱对家兔和大鼠血液流变学及小鼠出血时间的影响[J].中药药理与临床,1998;14(6):22~24
17.吕莉,王艳春,韩国柱.重组水蛭素抗栓及抗弥漫性血管内凝血作用的实验研究[J].中国药学杂志,2002;37(9):707~709
18.叶应妩,李建斋,王玉琛.临床实验诊断学(上)[M].北京:北京卫生出版社,1989:381-2、976、1112、1131、1164
19.李美珍,孙必强,曾姣飞,等.左归丸对老年性痴呆模型大鼠SOD活性和MDA含量的影响[J].中华中医药学刊,2010;28(12):2583~2585
20.李世军,李小鹰.二氢睾酮和其受体对雄性大鼠血小板激活、TXA2/PGI2平衡与细胞内钙离子浓度的调节[J].血栓与止血学,2007;13(5):197~202
21.曹洪,张颖,张功礼.丹参注射液预防深静脉血栓形成的实验研究[J].时珍国医国药,2008;19(5):1146~1147
22.陈冬梅,陈凯,汪海.吗啉环和哌嗪类衍生物的抗栓作用及其分子机制[J].药学学报,2003;38(9):641~645
23.吴会生,郭培培,尚游,等.氟比洛芬酯预处理对大鼠全脑缺血/再灌注时脑组织TXA2/PGI2的影响[J].中国药理学通报,2009;25(9):1176~1180
24.唐映红,梁燕,杨静,等. FeCl3诱导的大鼠颈总动脉血栓模型血浆TXA2、PGI2、抗凝和纤溶活性的变化[J].中国药理学通报,2006;22(11):1353~1356
1. MURRAY CJ, LOPEZ AD. Mortallty by cause for eight regious of the world: global burden of disease study[J]. Luncet, 1997;349(9061): 1269-1276
2. Sinnaeve PR. Simes J, Yusuf S, et al. Direct thrombin inhibitors in acute coronary syndromes: effect in petients undergoing early percutaneous coronary intervention[J]. Eur heart, 2005;26(22): 2396-2403
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