CXT的抗脑缺血作用研究
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摘要
本文研究了CXT对实验性脑缺血的作用，并对其作用机制进行了初步探讨。
实验结果表明：CXT可显著延长断头小鼠喘气时间(10、20、40、60mg／kg)，延长双侧颈总动脉及迷走神经结扎小鼠和常压缺氧小鼠(15、30、60mg／kg)的存活时间，说明CXT对脑缺血缺氧具有保护作用。CXT(10、20、40mg／kg)能够降低急性脑缺血大鼠脑指数和脑含水量。预防给药和治疗给药后，CXT(10、20、40mg／kg)能够改善大脑中动脉阻断(occlusion of the middle cerebral artery，MCAO)大鼠神经功能障碍，减少脑梗塞范围。CXT(10、20、40mg／kg)治疗给药后可以降低MCAO大鼠脑组织和血浆中丙二醛(MDA)的含量，同时升高超氧化歧化酶(SOD)的含量，升高血浆中NO的含量，降低脑组织中NO的含量。以上结果表明CXT可以改善脑水肿，保护受损神经元，改善缺血性脑损伤。CXT能够降低肺血栓小鼠(15、30、60mg／kg)的死亡率，减轻大鼠(10、20、40mg／kg)体内血栓重量，以及ADP、胶原诱导的体外血小板聚集(50、100、200、400、800mg／L)，表明CXT具有抑制血小板聚集的作用。CXT能够延长家兔(0.1、1、10mg／ml)血浆复钙时间，减轻小鼠(15、30、60mg／kg)全血凝块重量，缩短小鼠(15、30、
沈阳药科人学硕士学位论文 摘要
60mg儿g）优球蛋白溶解时间，提示CXT通过减少血浆中凝血因于，
增加纤溶酶原激活物活性，抑制血栓形成。此外，CXT门、20、
40mg儿g）还可以降低MCAO大鼠的全血比粘度（高、中、低切粘
度），降低红细胞压积，降低红细胞聚集指数，从而改善血液流变
性。
另外，本文还对CXT的一般药理学和急性毒性进行了研究。
一般药理学研究结果表明：CXT（4、8、16mg儿g）对麻醉猫心电
图的 P波、T波、QRS波群、P－R间期、Q丁 fd期、P波高度、T
波高度、S1段高度的变化均无明显影响，CXT能够降低麻醉猫的
心率、平均动脉压和呼吸频率。急性毒性试验结果为：CXT小鼠静
脉给药的LD。。为488．3mg／kg，95％置信限为：435．7～540．gmg／kg。
初步药效学实验研究表明，CXT有防治脑缺血作用，其作用机
制可能与降低脑耗能，抑制血小板聚集，改善血液流变学，并通过
升高SOD活力、降低MDA含量减少氧自由基，改善缺血性脑损伤
等作用有关。
本研究为CXT的临床应用提供了基础实验依据，但其抗脑缺
血的作用机制还有待进一步探讨。
The effects of CXT on cerebral ischemia and the mechanism of action were studied preliminarily in this paper.
The results indicated that the gasping time of mice(l0, 20 , 40 , 60mg/kg) which were cut heads were obviously prolonged and the survival time of hypoxic mice and mice which were ligated bilateral caratid artery were also prolonged after intravenous injection of CXT(15, 30, 60mg/kg). The index and water content of brain were decreased in rats which were pretreated with CXT(10, 20 , 40mg/kg). The neurological deficits were improved and the range of infarction were after MCAO in rats which were pretreated and treated with CXT(10, 20 , 40mg/kg). The contents of MDA of plasma and brain were decreased and SOD of plasma and brain were increased, and NO of plasma were increased and NO of brain were decreased after MCAO in rats which were treated with CXT(10, 20, 40mg/kg). The results indicated that CXT could improve brain
ABSTRACT
edema and ischemic brain injury. The rates of death of encephalic thrombus in mice(15, 30,60mg/kg) and the thrombus weight in vivo in rats(l0, 20 , 40mg/kg) were decreased. The platelet aggregation induced by ADP and collagen in vitro in rabbits(50, 100, 200, 400 , 800mg/L) was inhibited. The result indicated that CXT has the inhibition effects on platelet aggregation. The plasma recalcification time (PRT) in rabbits(0.1 , 1 , 10mg/ml) was prolonged, and the bleed clot wet weight was lighted and euglobulin lysis time (ELT) was shorted in mice(15, 30, 60mg/kg). The results showed that CXT can inhibit thrombosis by reducing coagulation factor of plasma and increasing activity of plasminogen activator. Besides, CXT also improved blood rheology in rats after MCAO.
The general pharmacology and acute toxicity of CXT were also investigated. The results of general pharmacology indicated that CXT(4, 8, 16mg/kg) has no significant effects on T, P and QRS wave duration, T ,S-T and P wave height, P-R and Q-T wave interphase duration, however heart rate, mean arterial pressure and respiratory frequency of anesthetized cats were decreased. The results of acute toxicity showed median lethal dose (LD50) of CXT is 488.3mg/kg.
All experimental results above showed that the anti-cerebral ischemia effects of CXT. The mechanism maybe involved in decreasing brain energy exhaust, inhibiting platelet aggregation ,
ABSTRACT
reducing oxygen free radicals (OFR) by increasing the action of SOD and decreasing contents of MDA, improving ischemic brain injury and improving blood rheology.
This study provided the experimental basis to the clinical application of CXT. However, the mechanisms accouted for the effects of CXT' s anti-cerebral ischemia deserve further study.
实验结果表明：CXT可显著延长断头小鼠喘气时间(10、20、40、60mg／kg)，延长双侧颈总动脉及迷走神经结扎小鼠和常压缺氧小鼠(15、30、60mg／kg)的存活时间，说明CXT对脑缺血缺氧具有保护作用。CXT(10、20、40mg／kg)能够降低急性脑缺血大鼠脑指数和脑含水量。预防给药和治疗给药后，CXT(10、20、40mg／kg)能够改善大脑中动脉阻断(occlusion of the middle cerebral artery，MCAO)大鼠神经功能障碍，减少脑梗塞范围。CXT(10、20、40mg／kg)治疗给药后可以降低MCAO大鼠脑组织和血浆中丙二醛(MDA)的含量，同时升高超氧化歧化酶(SOD)的含量，升高血浆中NO的含量，降低脑组织中NO的含量。以上结果表明CXT可以改善脑水肿，保护受损神经元，改善缺血性脑损伤。CXT能够降低肺血栓小鼠(15、30、60mg／kg)的死亡率，减轻大鼠(10、20、40mg／kg)体内血栓重量，以及ADP、胶原诱导的体外血小板聚集(50、100、200、400、800mg／L)，表明CXT具有抑制血小板聚集的作用。CXT能够延长家兔(0.1、1、10mg／ml)血浆复钙时间，减轻小鼠(15、30、60mg／kg)全血凝块重量，缩短小鼠(15、30、
沈阳药科人学硕士学位论文 摘要
60mg儿g）优球蛋白溶解时间，提示CXT通过减少血浆中凝血因于，
增加纤溶酶原激活物活性，抑制血栓形成。此外，CXT门、20、
40mg儿g）还可以降低MCAO大鼠的全血比粘度（高、中、低切粘
度），降低红细胞压积，降低红细胞聚集指数，从而改善血液流变
性。
另外，本文还对CXT的一般药理学和急性毒性进行了研究。
一般药理学研究结果表明：CXT（4、8、16mg儿g）对麻醉猫心电
图的 P波、T波、QRS波群、P－R间期、Q丁 fd期、P波高度、T
波高度、S1段高度的变化均无明显影响，CXT能够降低麻醉猫的
心率、平均动脉压和呼吸频率。急性毒性试验结果为：CXT小鼠静
脉给药的LD。。为488．3mg／kg，95％置信限为：435．7～540．gmg／kg。
初步药效学实验研究表明，CXT有防治脑缺血作用，其作用机
制可能与降低脑耗能，抑制血小板聚集，改善血液流变学，并通过
升高SOD活力、降低MDA含量减少氧自由基，改善缺血性脑损伤
等作用有关。
本研究为CXT的临床应用提供了基础实验依据，但其抗脑缺
血的作用机制还有待进一步探讨。
The effects of CXT on cerebral ischemia and the mechanism of action were studied preliminarily in this paper.
The results indicated that the gasping time of mice(l0, 20 , 40 , 60mg/kg) which were cut heads were obviously prolonged and the survival time of hypoxic mice and mice which were ligated bilateral caratid artery were also prolonged after intravenous injection of CXT(15, 30, 60mg/kg). The index and water content of brain were decreased in rats which were pretreated with CXT(10, 20 , 40mg/kg). The neurological deficits were improved and the range of infarction were after MCAO in rats which were pretreated and treated with CXT(10, 20 , 40mg/kg). The contents of MDA of plasma and brain were decreased and SOD of plasma and brain were increased, and NO of plasma were increased and NO of brain were decreased after MCAO in rats which were treated with CXT(10, 20, 40mg/kg). The results indicated that CXT could improve brain
ABSTRACT
edema and ischemic brain injury. The rates of death of encephalic thrombus in mice(15, 30,60mg/kg) and the thrombus weight in vivo in rats(l0, 20 , 40mg/kg) were decreased. The platelet aggregation induced by ADP and collagen in vitro in rabbits(50, 100, 200, 400 , 800mg/L) was inhibited. The result indicated that CXT has the inhibition effects on platelet aggregation. The plasma recalcification time (PRT) in rabbits(0.1 , 1 , 10mg/ml) was prolonged, and the bleed clot wet weight was lighted and euglobulin lysis time (ELT) was shorted in mice(15, 30, 60mg/kg). The results showed that CXT can inhibit thrombosis by reducing coagulation factor of plasma and increasing activity of plasminogen activator. Besides, CXT also improved blood rheology in rats after MCAO.
The general pharmacology and acute toxicity of CXT were also investigated. The results of general pharmacology indicated that CXT(4, 8, 16mg/kg) has no significant effects on T, P and QRS wave duration, T ,S-T and P wave height, P-R and Q-T wave interphase duration, however heart rate, mean arterial pressure and respiratory frequency of anesthetized cats were decreased. The results of acute toxicity showed median lethal dose (LD50) of CXT is 488.3mg/kg.
All experimental results above showed that the anti-cerebral ischemia effects of CXT. The mechanism maybe involved in decreasing brain energy exhaust, inhibiting platelet aggregation ,
ABSTRACT
reducing oxygen free radicals (OFR) by increasing the action of SOD and decreasing contents of MDA, improving ischemic brain injury and improving blood rheology.
This study provided the experimental basis to the clinical application of CXT. However, the mechanisms accouted for the effects of CXT' s anti-cerebral ischemia deserve further study.
引文
[1] 王振义，李家增，阮长耿主编．血栓与止血基础理论与临床[M]．上海：上海科学技术出版社，1996，451
[2] 黄如训，苏镇培主编．脑卒中[M]．北京：人民卫生出版社．33
[3] Cadroy Y, Harker LA. Platelets, thrombosis and antithrombotic therapics. In:Antonaccio M, ed. Cardiovascular pharmacology; third ed. New York: Raven Press, 1990;515～539
[4] Gersh BJ, Opic LH. Antithrombotic agents: Platelet inhibitors, anticoagulants, and fibrinolytics. In: Opic L H, ed. Drugs for the heart; 4th ed. Philadelphia: Saunders Co, 1995;248～287
[5] Metha P, Metha JL. Anticoagulants. In: Singh B N, eds. Cardiovascular Pharmacology and Therapeutics; New York:Churchill livingstone Press, 1994;281～288
[6] Becker RC. Seminars in thrombosis, thrombolysis and vascular biology. 1. The vascular endothelium. Cardiology 1991 ;78:13
[7] 陈维洲，芮耀诚主编．脑血管疾病基础与临床研究[M]．济南：山东科技出版社，1993：68—75
[8] Witt W, Maass B, Baldus B, etal. Coronary thrombolysis with Desmodus salivary plasminogen activator in dogs. Fast and persistent recanalization by intravenous bolus administration. Circulation, 1994,90:421～426
[9] Haley EC Jr, Kassell NF, Alves WM, et al. Phase Ⅱ trial of tirilazad in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg, 1995,82:786～790
[10] Rosenbaum D M et al. Stroke, 1994,25(4):857-862
[11] 徐叔云，卞如濂，陈修主编．药理实验方法学[M]．第二版．北京：人民卫生出版社，1991，948
[12] 邓中炎，严灿，王剑．健脑片的药效学研究[J]．中药新药与临床药理，2000，11(1)：17-19
[13] 汪红仪，王喻．银杏叶提取物对实验小鼠脑缺血的防护作用[J]．中国中药杂志，1998，23(3)：169-171
[14] 陈奇主编．中药药理研究方法学[M]．北京：人民卫生出版社．第一版，1993，713-715
[15] 吴启端，方永奇，李翎等．石菖蒲醒脑开窍的有效部位筛选[J]．时珍国医国药，2002，13(5)：260-261
[16] 许国振，胡锡元．太极通天液对实验性脑缺血的保护作用[J]．中成药，1999，21(3)：141-142
[17] 董艳，韩晞，何成等．垂体腺苷酸环化酶激活肽减轻大鼠缺血性脑水肿作用的实验研究[J]．中国应用生理学杂志，2002，18(2)：121-123
[18] 孙勇，张世玲，程艳娜等．达曲班对大鼠大脑中动脉结扎所致脑梗塞的影响[J]．中国医药工业杂志，1990，30(10)：447-449
[19] 陈秋红，海平，都渝等．藏药70未珍珠丸对大鼠缺血性脑梗塞的研究[J]．辽宁中医杂志，2000，27(4)：187-188
[20] Bederson JB, Pitt LH, Tsuji M et al. Rat middle cerebral artery occlusion, evaluation of the model and development of a neurologic examination[J].Strokel, 1986,17:472
[21] Tamura A, Graham DI, McCulloch J.Focal cerebral ischemia in rat. Description of technique and darly neuropathological consequences following middle cerebral artery occlusion. J Cerebral Blood Flow Meta b,1981,1:53
[22] 石晶，陶沂，胡晋红等．姜黄素对缺血再灌大鼠脑组织 SOD，MDA和亚硝酸盐含量的影响[J]．第二军医大学学报，1999，20(6)：386-387
[23] 翟晓翔．黄芪、水蛭、地龙不同配伍治疗缺血性中风实验研究[J]．山东中医药大学学报，2000，24(1)：52-55
[24] 许荔新，李凤才，师海波等．狶莶通栓胶囊药效学研究[J]．中草药，1999，30(3)：208-210
[25] 陈奇主编．中药药理研究方法学[M]．北京：人民卫生出版社，1993，940-942
[26] Diminno G, Silver MJ. Mouse antethrombotic assay: a simple method for the evaluation of antithrombotic activity by ethyl alcohol. J pharmacol Exp Ther. 1983,225:57-60
[27] Molinari A, Grarneri L, Pacei F, et al. Mouse antithrombotic assay: the effect of Ca2+ channel blocker are platelet-independent. J pharmacol Exp Ther. 1987,240:623-625
[28] Cazenave JP, Packham MA, Mustard JF. Adherence of platelet to a collagen-coated surface development of a quantitative method. J Lad Clin Med. 1973,82:978-981
[29] 徐叔云，卞如濂，陈修主编．药理实验方法学[M]．第2版．北京：人民卫生出版社，1991，1124
[30] 陈领朝，连秀峰，袁秉祥等．脑络舒通胶囊对大鼠实验性脑及动静脉血栓形成的药效与研究[J]，陕西中医，2002，23(4)：376-377
[31] 马轶涛，周远鹏．氨丁苯酞对血小板聚集功能的影响[J]．中国药理学通报，2000，16(1)：72-74
[32] 唐刚华，唐晓兰，姜国辉．川芎哚及其类似物对血小板聚集和
实验性血栓形成的影响[J]．中国药理学通报，2001，17(3)：333-336
[33] 王宏涛，靳洪涛，孙建宁等．异亚丙基莽草酸抗血栓作用的实验研究[J]．药学学报，2002，37(4)：245-248
[34] 徐叔云，卞如濂，陈修主编，药理实验方法学[M]．第2版．北京：人民卫生出版社，1991，838
[35] 梅兴国，万国晖，国忠强等．火棘提取物对血液凝固的影响[J]．中药材，2001，24(12)：874-876
[36] 臧宝霞，吴伟，李蔚然等．硅胶吸附法制备红花总黄色素抗凝血作用的实验研究[J]．中国药学杂志，2002，37(2)：106-109
[37] 刘威，周重楚，师海波．脑栓通对血液系统的影响[J]．中成药，1993，15(3)：26-28
[38] 刘俭，田泽，刘振秀．止血散对凝血系统的影响[J]．中国方剂学杂志，2001，7(4)：31-33
[39] 陈奇主编．中药药理研究方法学[M]．北京：人民卫生出版社．第二版，1993，485-486
[40] 冯安吉，海春旭，梁欣．复方中药安体欣对大鼠血液流变学的影响[J]．第四军医大学学报，1999，20(8)：720-721
[41] 于丽，洪燕珠，孙建宁等．脑络通胶囊对大鼠局灶性脑缺血的影响[J]．北京中医药大学学报，2002，25(3)：27-30
[42] 姚炜，库宝善，张疆寅等．L-盐酸赖氨酸对局部脑缺血大鼠的治疗作用[J]．药学学报，1999，34(6)：401-404
[43] 郑永玲，胡常林．茅莓提取物治疗局灶性脑缺血的实验研究[J]．中医药研究，2002，18(2)；37-39
[44] 王北婴．中药新药研制与申报[M]．北京：中国中医药出版社．
1995，212
[45] 徐叔云．药理实验方法学[M]．第2版．北京：人民卫生出版社．1991，685
[46] Schurr A and Rigor BM. Cerebral Ischemia and Resuscitation. Boca Raton FL:USA CRC Press, 1990
[47] Erecinska M and Silver IA.ATP and brain function. J Cereb Blood Flow Metab,1989,9:2
[48] SaccoRL,Solic BS,Frank RS,et al. Morphometric evaluation of brain infarcts in rats and gerbils. J Pharmacol Methods,1986,16:201
[49] 刘泽霖，贺石林，李家增主编．血栓性疾病的诊断与治疗[M]．北京：人民卫生出版社．2000，53
[50] Macfarlane PG.An enzyme cascade in the blood clotting mechanesm,and its function as a biochemical amplifier. Nature, 1964,202:498-499
[51] Daves EW,Ratnoff OD.Waterfall sequence for intrinsic blood clotting. Science, 1964,145:1310-1311
[52] Robert HR,Lozier JN.New perspectives on the coagulation cascade. Hosp Pract, 1992,27:97-102
[53] Davies MJ,Thomas T. The pathological basis and microanatomy of occlusive coronary thrombus formation in human coronary arteries. Philos Trans R Soclond, 1981,294:225-229
[54] Hirsh J, Hull RD, Raskob GE. Epidemiology and pathogenesis of venous thrombosis. J AM Coll Cardiol, 1986,8(6 suppl)104B-113B
[55] Slack SM, Cui Y, Turitto VT. The effects of flow on blood coagulation and thrombosis. Thromb Haemost, 1993,70(1): 129
[56] 王洁，张均田，脑缺血、氧自由基清除剂与脑保护[J]．中国药理
学通报，1998,14(1): 8-10
[57] Chandan KS, Lester P. Antioxidant and redoxregulation of genetranscription. FASEB J, 1996; 10:709-720
[58] Ferris DC, Kume KJ, Russo MI et al. Gender differences in cerebral ascorbate levels and ascorbate loss ischemia. Neuroreport, 1995;6(11):1485-1489
[59] Faraci FM, Brain JE. Stroke, 1994,25:692
[60] Siesjo BK, Wieloch T, ed. Advances in Neurology. Vol 71. Philadelphia: Lippinocott-Raven Pubblihers, 1996,355
[61] Zhang F, White JG, Iadecola C. Nitric oxide donors increase blood flow and reduce brain damage in focal inschemia:evidence that nitric oxide is beneficial in the early stage of cerebral ischemia. J Cereb Blood Flow Metab, 1994; 14217-226
[62] Faraci FM. Nitric oxide and the cerebral circulation. Stroke, 1994;25:692-698
[63] Kraous GE, Bucholz RD, Yoon KW,et al. Ccrebrospinal fluid endothelin-1 and endothelin-3 levels in normal and neurosurgical patients:a clinical study and liteature review. Surg Neurol, 1991 ;35:20-29
[2] 黄如训，苏镇培主编．脑卒中[M]．北京：人民卫生出版社．33
[3] Cadroy Y, Harker LA. Platelets, thrombosis and antithrombotic therapics. In:Antonaccio M, ed. Cardiovascular pharmacology; third ed. New York: Raven Press, 1990;515～539
[4] Gersh BJ, Opic LH. Antithrombotic agents: Platelet inhibitors, anticoagulants, and fibrinolytics. In: Opic L H, ed. Drugs for the heart; 4th ed. Philadelphia: Saunders Co, 1995;248～287
[5] Metha P, Metha JL. Anticoagulants. In: Singh B N, eds. Cardiovascular Pharmacology and Therapeutics; New York:Churchill livingstone Press, 1994;281～288
[6] Becker RC. Seminars in thrombosis, thrombolysis and vascular biology. 1. The vascular endothelium. Cardiology 1991 ;78:13
[7] 陈维洲，芮耀诚主编．脑血管疾病基础与临床研究[M]．济南：山东科技出版社，1993：68—75
[8] Witt W, Maass B, Baldus B, etal. Coronary thrombolysis with Desmodus salivary plasminogen activator in dogs. Fast and persistent recanalization by intravenous bolus administration. Circulation, 1994,90:421～426
[9] Haley EC Jr, Kassell NF, Alves WM, et al. Phase Ⅱ trial of tirilazad in aneurysmal subarachnoid hemorrhage. A report of the Cooperative Aneurysm Study. J Neurosurg, 1995,82:786～790
[10] Rosenbaum D M et al. Stroke, 1994,25(4):857-862
[11] 徐叔云，卞如濂，陈修主编．药理实验方法学[M]．第二版．北京：人民卫生出版社，1991，948
[12] 邓中炎，严灿，王剑．健脑片的药效学研究[J]．中药新药与临床药理，2000，11(1)：17-19
[13] 汪红仪，王喻．银杏叶提取物对实验小鼠脑缺血的防护作用[J]．中国中药杂志，1998，23(3)：169-171
[14] 陈奇主编．中药药理研究方法学[M]．北京：人民卫生出版社．第一版，1993，713-715
[15] 吴启端，方永奇，李翎等．石菖蒲醒脑开窍的有效部位筛选[J]．时珍国医国药，2002，13(5)：260-261
[16] 许国振，胡锡元．太极通天液对实验性脑缺血的保护作用[J]．中成药，1999，21(3)：141-142
[17] 董艳，韩晞，何成等．垂体腺苷酸环化酶激活肽减轻大鼠缺血性脑水肿作用的实验研究[J]．中国应用生理学杂志，2002，18(2)：121-123
[18] 孙勇，张世玲，程艳娜等．达曲班对大鼠大脑中动脉结扎所致脑梗塞的影响[J]．中国医药工业杂志，1990，30(10)：447-449
[19] 陈秋红，海平，都渝等．藏药70未珍珠丸对大鼠缺血性脑梗塞的研究[J]．辽宁中医杂志，2000，27(4)：187-188
[20] Bederson JB, Pitt LH, Tsuji M et al. Rat middle cerebral artery occlusion, evaluation of the model and development of a neurologic examination[J].Strokel, 1986,17:472
[21] Tamura A, Graham DI, McCulloch J.Focal cerebral ischemia in rat. Description of technique and darly neuropathological consequences following middle cerebral artery occlusion. J Cerebral Blood Flow Meta b,1981,1:53
[22] 石晶，陶沂，胡晋红等．姜黄素对缺血再灌大鼠脑组织 SOD，MDA和亚硝酸盐含量的影响[J]．第二军医大学学报，1999，20(6)：386-387
[23] 翟晓翔．黄芪、水蛭、地龙不同配伍治疗缺血性中风实验研究[J]．山东中医药大学学报，2000，24(1)：52-55
[24] 许荔新，李凤才，师海波等．狶莶通栓胶囊药效学研究[J]．中草药，1999，30(3)：208-210
[25] 陈奇主编．中药药理研究方法学[M]．北京：人民卫生出版社，1993，940-942
[26] Diminno G, Silver MJ. Mouse antethrombotic assay: a simple method for the evaluation of antithrombotic activity by ethyl alcohol. J pharmacol Exp Ther. 1983,225:57-60
[27] Molinari A, Grarneri L, Pacei F, et al. Mouse antithrombotic assay: the effect of Ca2+ channel blocker are platelet-independent. J pharmacol Exp Ther. 1987,240:623-625
[28] Cazenave JP, Packham MA, Mustard JF. Adherence of platelet to a collagen-coated surface development of a quantitative method. J Lad Clin Med. 1973,82:978-981
[29] 徐叔云，卞如濂，陈修主编．药理实验方法学[M]．第2版．北京：人民卫生出版社，1991，1124
[30] 陈领朝，连秀峰，袁秉祥等．脑络舒通胶囊对大鼠实验性脑及动静脉血栓形成的药效与研究[J]，陕西中医，2002，23(4)：376-377
[31] 马轶涛，周远鹏．氨丁苯酞对血小板聚集功能的影响[J]．中国药理学通报，2000，16(1)：72-74
[32] 唐刚华，唐晓兰，姜国辉．川芎哚及其类似物对血小板聚集和
实验性血栓形成的影响[J]．中国药理学通报，2001，17(3)：333-336
[33] 王宏涛，靳洪涛，孙建宁等．异亚丙基莽草酸抗血栓作用的实验研究[J]．药学学报，2002，37(4)：245-248
[34] 徐叔云，卞如濂，陈修主编，药理实验方法学[M]．第2版．北京：人民卫生出版社，1991，838
[35] 梅兴国，万国晖，国忠强等．火棘提取物对血液凝固的影响[J]．中药材，2001，24(12)：874-876
[36] 臧宝霞，吴伟，李蔚然等．硅胶吸附法制备红花总黄色素抗凝血作用的实验研究[J]．中国药学杂志，2002，37(2)：106-109
[37] 刘威，周重楚，师海波．脑栓通对血液系统的影响[J]．中成药，1993，15(3)：26-28
[38] 刘俭，田泽，刘振秀．止血散对凝血系统的影响[J]．中国方剂学杂志，2001，7(4)：31-33
[39] 陈奇主编．中药药理研究方法学[M]．北京：人民卫生出版社．第二版，1993，485-486
[40] 冯安吉，海春旭，梁欣．复方中药安体欣对大鼠血液流变学的影响[J]．第四军医大学学报，1999，20(8)：720-721
[41] 于丽，洪燕珠，孙建宁等．脑络通胶囊对大鼠局灶性脑缺血的影响[J]．北京中医药大学学报，2002，25(3)：27-30
[42] 姚炜，库宝善，张疆寅等．L-盐酸赖氨酸对局部脑缺血大鼠的治疗作用[J]．药学学报，1999，34(6)：401-404
[43] 郑永玲，胡常林．茅莓提取物治疗局灶性脑缺血的实验研究[J]．中医药研究，2002，18(2)；37-39
[44] 王北婴．中药新药研制与申报[M]．北京：中国中医药出版社．
1995，212
[45] 徐叔云．药理实验方法学[M]．第2版．北京：人民卫生出版社．1991，685
[46] Schurr A and Rigor BM. Cerebral Ischemia and Resuscitation. Boca Raton FL:USA CRC Press, 1990
[47] Erecinska M and Silver IA.ATP and brain function. J Cereb Blood Flow Metab,1989,9:2
[48] SaccoRL,Solic BS,Frank RS,et al. Morphometric evaluation of brain infarcts in rats and gerbils. J Pharmacol Methods,1986,16:201
[49] 刘泽霖，贺石林，李家增主编．血栓性疾病的诊断与治疗[M]．北京：人民卫生出版社．2000，53
[50] Macfarlane PG.An enzyme cascade in the blood clotting mechanesm,and its function as a biochemical amplifier. Nature, 1964,202:498-499
[51] Daves EW,Ratnoff OD.Waterfall sequence for intrinsic blood clotting. Science, 1964,145:1310-1311
[52] Robert HR,Lozier JN.New perspectives on the coagulation cascade. Hosp Pract, 1992,27:97-102
[53] Davies MJ,Thomas T. The pathological basis and microanatomy of occlusive coronary thrombus formation in human coronary arteries. Philos Trans R Soclond, 1981,294:225-229
[54] Hirsh J, Hull RD, Raskob GE. Epidemiology and pathogenesis of venous thrombosis. J AM Coll Cardiol, 1986,8(6 suppl)104B-113B
[55] Slack SM, Cui Y, Turitto VT. The effects of flow on blood coagulation and thrombosis. Thromb Haemost, 1993,70(1): 129
[56] 王洁，张均田，脑缺血、氧自由基清除剂与脑保护[J]．中国药理
学通报，1998,14(1): 8-10
[57] Chandan KS, Lester P. Antioxidant and redoxregulation of genetranscription. FASEB J, 1996; 10:709-720
[58] Ferris DC, Kume KJ, Russo MI et al. Gender differences in cerebral ascorbate levels and ascorbate loss ischemia. Neuroreport, 1995;6(11):1485-1489
[59] Faraci FM, Brain JE. Stroke, 1994,25:692
[60] Siesjo BK, Wieloch T, ed. Advances in Neurology. Vol 71. Philadelphia: Lippinocott-Raven Pubblihers, 1996,355
[61] Zhang F, White JG, Iadecola C. Nitric oxide donors increase blood flow and reduce brain damage in focal inschemia:evidence that nitric oxide is beneficial in the early stage of cerebral ischemia. J Cereb Blood Flow Metab, 1994; 14217-226
[62] Faraci FM. Nitric oxide and the cerebral circulation. Stroke, 1994;25:692-698
[63] Kraous GE, Bucholz RD, Yoon KW,et al. Ccrebrospinal fluid endothelin-1 and endothelin-3 levels in normal and neurosurgical patients:a clinical study and liteature review. Surg Neurol, 1991 ;35:20-29