西洛他唑与氯吡格雷对冠心病不稳定型心绞痛患者的抗血小板疗效比较
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摘要
目的
冠状动脉粥样硬化是涉及脂质、斑块形成与破裂、血小板的激活与聚集以及血栓形成的多因素疾病。内皮细胞损伤、斑块的溃疡、破裂，引起血小板的黏附，并激活血小板导致其功能异常，引起一系列活化反应，最终致血栓形成。有效的抑制血小板聚集将减少动脉粥样硬化性疾病的急性及慢性缺血性并发症。本实验就抗血小板这一环节，采用α-颗粒膜蛋白140(GMP-140)，这一最具有特异性的血小板活化指标，对两种较新的抗血小板药物西洛他唑和氯吡格雷进行临床疗效比较。
方法
1．病例选择：2003年3月至2003年11月间中国医科大学附属第一医院心内科的冠心病不稳定型心绞痛患者，均符合1979年WHO制定的CHD诊断标准，冠脉造影示管腔狭窄小于70％，病程大于1个月者。
排除标准：①年龄＜13岁或＞80岁；②1个月内出现急性心肌梗死或脑中风者；③重度高血压、慢性肺病、慢性肾功能不全者；④原有出血性疾病，有脑出血、消化道或其它脏器出血病史；⑤在继续服用阿司匹林、潘生丁或其它有抗血小板药效的药物者；⑥粒细胞或血小板减少者。
2．实验药品：西洛他唑片，每片含西洛他唑50mg；氯吡格雷片，每片含氯吡格雷25mg；
实验试剂：血浆GMP-140含量测定ELISA试剂盒；
实验器材：Elx800酶标仪、离心机、水浴箱。
3．病例分组：
所有入选患者按随机表分为两组，西洛他唑(CS)组给予CS片100mg日两次口服；氯吡格雷(CPG)组给予CPG片75mg日一次口服。两组皆联合使用阿司匹林100mg日一次口服，观察期为8天，观察期间患者用于治疗心血管疾病的基础药物维持其剂量与用法不变，但禁用抗凝药物。
4．检测指标：
采用酶联免疫双抗体夹心法原理检测血浆GMP一140水平，所有患者
于入选时、用药第3天、第8天空腹采取前臂静脉外周血严格按照试剂盒说
明书检测。
5.一般化验指标:包括血Rt、凝血酶原时间、肝功能、肾功能，于人选时
检测，于用药第8天复查血Rt及凝血酶原时间。
6.临床观察:包括性别、年龄、基础疾病、血压、心绞痛症状在治疗前后
的变化、冠造结果，同时记录不良反应。
7.统计方法:
采用SPSS10.o统计软件包，计量资料，以均数士标准差表示，符合正态
分布的资料经过齐性检验后，两两比较采用方差分析，q检验;两组间计量
资料比较采用两样本均数的t检验;计数资料，用校正的x“检验，所有显著
检验均采用双侧检验，以p<0.05为差异有显著性。
结果
1.病例基础情况:
依据冠造结果排除心肌桥及冠脉无异常者，共入选患者76例，CS组36
例，平均年龄(63 .6士9.5)岁，CPG组40例，平均年龄(65.6士8.5)岁。两
组在治疗前在性别、基础疾病、血压、血象、肝肾功能、凝血酶原时间及冠脉
病变方面均具有可比性。
2.用药前后血浆GMP一140浓度的变化:
两组用药前血浆GMP一140浓度明显增高，组间无显著差异性。CS组
GMP一1 40浓度在用药 3d下降(34.43*1 1 .48)%，用药sd下降(52.37士
8.87)%;CPG组GMP一140浓度在用药3d下降(勿.64士10.74)%，用药
8d下降(52.83士9.94)%，各组内各时段间的比较显示，用药前和用药3d、
8d的GMP一140浓度差异均有显著意义，用药后3d和8d间的差别也有显
著性，提示使用CS与CPG皆可明显降低血浆GMP一140浓度。
两组间相比，用药3d CPG组的GMP一140浓度较CS组低，p<0.05，有
显著性差异，提示CPG起效较快较强，而用药8d两组GMP一140浓度无差
异性，提示CS组与CPG组在用药sd后疗效相同。
两组间及组内按性别分组，GMP一140浓度下降的差别无显著性，提示
CS组与CPG组的疗效在性别上无差异性。
3.用药前后凝血酶原时间的变化
两组病例于服药后，凝血酶原时间均有不同程度的延长，CS组的凝血
酶原时间由用药前的(14.0士2.2)秒延长至(14.3土2.0)秒;CPG组的凝血
酶原时间由用药前的(13.8士1.9)秒延长至(14.2土2.0)秒，两组内凝血酶
原时间差别无显著性，两组间同时段的凝血酶原时间相比也无显著性差异
(p>0 .05)。
4.用药前后血象的变化
两组患者用药前的血象均在正常范围，CS组用药后WBC计数和PLT
计数分别为(6.9土1.4)*109/L和(165.4士37.3)*109/L，ePe组用药后
WBC计数和PLT计数分别为(6 .5土1 .3)*109/L和(171 .4*33.7)*rog/
L，也均在正常范围内。
5.不良反应
因观察时间短暂，未见明显不良反应，仅CPG组出现1例皮肤斑点，停
药后可自行消失。
讨论
西洛他哇与氯毗格雷同属口服较新型抗凝药物，但二者的抗血小板作
用机制不同。
西洛他哇是一种磷酸二醋酶(PDElll)抑制剂，抑制血小板及平滑肌上
磷酸二醋酶的活性，阻碍cAMP降解(和转化)，导致cAMP在血小板和血管
内上升，降低血小板的敏感性，抑制了血小板聚集，并使血管扩张，在体外实
验中可强力地抑制存在于体内的几乎所有的血小板聚集诱导物引起的聚
集。
氯毗格雷是唾吩并毗咤类药物，主要是通过选择性地阻断血小板膜表
面的ADP受体，抑制与此受体相偶联的血小板糖蛋白即nb一la受体的
Coronary atherosclerosis is a kind of disease that is involved with lipid, plaque formation rupture, platelet activation and aggregation, thrombosis, and et al. Platelet adhesion, activation and dysfunction due to endothelial cell injury and plaque ulcer, rupture, cause a series of active acting and result to thrombosis at last. So effective inhibition in platelet aggregation will decrease acute and chronic complications impossibilities of CAD. The following test is designed to compare the clinical effect of the two new anti - platelet drugs ( cilostazol and clopidogrel) with GMP - 140, which is a index characteristic of platelet activation.
Methods
1. Case selection: All patients are selected in the circulation unit in the first affiliated hospital of CMU from March to December in 2003. They are diagnosed as unstable angina pectoris by two senior doctors according to the CHD diagnosis standards made by WHO in 1979. , all of them with history over one month.
Exclusion standards: (1) age less than 13 or older than 80; (2) acute my-ocardial infarction or stroke in a month; (3) severe hypertension, chronic pulmonary disease, chronic renal failure; (4) with a history of bleeding diseases such as gastrointestinal hemorrhage, brain hemorrhage or other organ hemorrhage ; (5) taking drugs with the effect of anti - platelet at the same time such as aspirin, dipyridamole or other drugs; (6) granulocytopenia or thrombocyto-penia.
2. Drugs; cilostazol, including 50 mg cilostazol per tablet; clopidogrel, including 25 mg clopidogrel per tablet.
3. Group division; All patients were randomized into 2 groups: one group took CS tablets ( 100mg ) twice a day; the other group took CPG tablets (75mg) once a day; and the two group both took aspirin ( 100mg ) once a day at the same time. The observation period is 8 days, and during the period, other drugs used as basic heart and vessel disease therapy were permit, but anti - coagulation drugs were prohibited.
4. Index: The plasma level of GMP - 140 was assayed using ELISA.
5. General index: including blood routine examination, plasma prothrombin time, liver function, kidney function were examined before treatment and after eight days therapy, blood routine examination and plasma prothrombin time were examined again.
6. Clinical observation; Sex, age, basic disease, blood pressure, symptoms of angina pectoris result of coronary arteriography, adverse events.
7. Statistical analysis; All statistical analysis was performed with Windows SPSS 10. 0. Continuous date are presented as mean + SD if normally distributed, q and t test were used. Statistical significance was defined as P <0.05.
Result
1. The conditions of the two groups:
According to the result of coronary arteriograpphy myocardial bridge and normal were excluded. 76 cases were selected, including 36 cases in CS group with mean age (63. 6 +9. 5) years and 40 cases in CPG group with mean age (65. 6 +8.5 ) years. The two groups are comparable before the therapy in sex, primary diseases, blood pressure, liver and kidney function, PTT and coronary diseases.
2. The change of the plasma level of GMP - 140 before and after treatment;
The plasma level of GMP - 140 of the two groups was high obviously, and there was no statistical significance difference. In CS group, on 3rd day and 8th
day, the reduction of the plasma level of GMP - 140 was (34. 43 + 11. 48)% and (52. 37 +8. 87)% ; in CPG group, on 3rd day and 8th day, the reduction of the plasma level of GMP - 140 was ( 39. 64 + 10. 74 ) % and ( 52. 83 + 9. 94) %. In either of the two groups, the concentration of GMP -140 had statistical significance before and after treatment, so did it in 3rd day and in 8th day after treatment, which indicated that CS and CPG could decrease the plasma level of GMP -140.
The concentration of GMP -140 of GPG group was lower than CS group (p <0. 05) in the 3rd day after treatment, that is significantly different, which indicated that CPG has faster and stronger effect than CS. However, the conc
冠状动脉粥样硬化是涉及脂质、斑块形成与破裂、血小板的激活与聚集以及血栓形成的多因素疾病。内皮细胞损伤、斑块的溃疡、破裂，引起血小板的黏附，并激活血小板导致其功能异常，引起一系列活化反应，最终致血栓形成。有效的抑制血小板聚集将减少动脉粥样硬化性疾病的急性及慢性缺血性并发症。本实验就抗血小板这一环节，采用α-颗粒膜蛋白140(GMP-140)，这一最具有特异性的血小板活化指标，对两种较新的抗血小板药物西洛他唑和氯吡格雷进行临床疗效比较。
方法
1．病例选择：2003年3月至2003年11月间中国医科大学附属第一医院心内科的冠心病不稳定型心绞痛患者，均符合1979年WHO制定的CHD诊断标准，冠脉造影示管腔狭窄小于70％，病程大于1个月者。
排除标准：①年龄＜13岁或＞80岁；②1个月内出现急性心肌梗死或脑中风者；③重度高血压、慢性肺病、慢性肾功能不全者；④原有出血性疾病，有脑出血、消化道或其它脏器出血病史；⑤在继续服用阿司匹林、潘生丁或其它有抗血小板药效的药物者；⑥粒细胞或血小板减少者。
2．实验药品：西洛他唑片，每片含西洛他唑50mg；氯吡格雷片，每片含氯吡格雷25mg；
实验试剂：血浆GMP-140含量测定ELISA试剂盒；
实验器材：Elx800酶标仪、离心机、水浴箱。
3．病例分组：
所有入选患者按随机表分为两组，西洛他唑(CS)组给予CS片100mg日两次口服；氯吡格雷(CPG)组给予CPG片75mg日一次口服。两组皆联合使用阿司匹林100mg日一次口服，观察期为8天，观察期间患者用于治疗心血管疾病的基础药物维持其剂量与用法不变，但禁用抗凝药物。
4．检测指标：
采用酶联免疫双抗体夹心法原理检测血浆GMP一140水平，所有患者
于入选时、用药第3天、第8天空腹采取前臂静脉外周血严格按照试剂盒说
明书检测。
5.一般化验指标:包括血Rt、凝血酶原时间、肝功能、肾功能，于人选时
检测，于用药第8天复查血Rt及凝血酶原时间。
6.临床观察:包括性别、年龄、基础疾病、血压、心绞痛症状在治疗前后
的变化、冠造结果，同时记录不良反应。
7.统计方法:
采用SPSS10.o统计软件包，计量资料，以均数士标准差表示，符合正态
分布的资料经过齐性检验后，两两比较采用方差分析，q检验;两组间计量
资料比较采用两样本均数的t检验;计数资料，用校正的x“检验，所有显著
检验均采用双侧检验，以p<0.05为差异有显著性。
结果
1.病例基础情况:
依据冠造结果排除心肌桥及冠脉无异常者，共入选患者76例，CS组36
例，平均年龄(63 .6士9.5)岁，CPG组40例，平均年龄(65.6士8.5)岁。两
组在治疗前在性别、基础疾病、血压、血象、肝肾功能、凝血酶原时间及冠脉
病变方面均具有可比性。
2.用药前后血浆GMP一140浓度的变化:
两组用药前血浆GMP一140浓度明显增高，组间无显著差异性。CS组
GMP一1 40浓度在用药 3d下降(34.43*1 1 .48)%，用药sd下降(52.37士
8.87)%;CPG组GMP一140浓度在用药3d下降(勿.64士10.74)%，用药
8d下降(52.83士9.94)%，各组内各时段间的比较显示，用药前和用药3d、
8d的GMP一140浓度差异均有显著意义，用药后3d和8d间的差别也有显
著性，提示使用CS与CPG皆可明显降低血浆GMP一140浓度。
两组间相比，用药3d CPG组的GMP一140浓度较CS组低，p<0.05，有
显著性差异，提示CPG起效较快较强，而用药8d两组GMP一140浓度无差
异性，提示CS组与CPG组在用药sd后疗效相同。
两组间及组内按性别分组，GMP一140浓度下降的差别无显著性，提示
CS组与CPG组的疗效在性别上无差异性。
3.用药前后凝血酶原时间的变化
两组病例于服药后，凝血酶原时间均有不同程度的延长，CS组的凝血
酶原时间由用药前的(14.0士2.2)秒延长至(14.3土2.0)秒;CPG组的凝血
酶原时间由用药前的(13.8士1.9)秒延长至(14.2土2.0)秒，两组内凝血酶
原时间差别无显著性，两组间同时段的凝血酶原时间相比也无显著性差异
(p>0 .05)。
4.用药前后血象的变化
两组患者用药前的血象均在正常范围，CS组用药后WBC计数和PLT
计数分别为(6.9土1.4)*109/L和(165.4士37.3)*109/L，ePe组用药后
WBC计数和PLT计数分别为(6 .5土1 .3)*109/L和(171 .4*33.7)*rog/
L，也均在正常范围内。
5.不良反应
因观察时间短暂，未见明显不良反应，仅CPG组出现1例皮肤斑点，停
药后可自行消失。
讨论
西洛他哇与氯毗格雷同属口服较新型抗凝药物，但二者的抗血小板作
用机制不同。
西洛他哇是一种磷酸二醋酶(PDElll)抑制剂，抑制血小板及平滑肌上
磷酸二醋酶的活性，阻碍cAMP降解(和转化)，导致cAMP在血小板和血管
内上升，降低血小板的敏感性，抑制了血小板聚集，并使血管扩张，在体外实
验中可强力地抑制存在于体内的几乎所有的血小板聚集诱导物引起的聚
集。
氯毗格雷是唾吩并毗咤类药物，主要是通过选择性地阻断血小板膜表
面的ADP受体，抑制与此受体相偶联的血小板糖蛋白即nb一la受体的
Coronary atherosclerosis is a kind of disease that is involved with lipid, plaque formation rupture, platelet activation and aggregation, thrombosis, and et al. Platelet adhesion, activation and dysfunction due to endothelial cell injury and plaque ulcer, rupture, cause a series of active acting and result to thrombosis at last. So effective inhibition in platelet aggregation will decrease acute and chronic complications impossibilities of CAD. The following test is designed to compare the clinical effect of the two new anti - platelet drugs ( cilostazol and clopidogrel) with GMP - 140, which is a index characteristic of platelet activation.
Methods
1. Case selection: All patients are selected in the circulation unit in the first affiliated hospital of CMU from March to December in 2003. They are diagnosed as unstable angina pectoris by two senior doctors according to the CHD diagnosis standards made by WHO in 1979. , all of them with history over one month.
Exclusion standards: (1) age less than 13 or older than 80; (2) acute my-ocardial infarction or stroke in a month; (3) severe hypertension, chronic pulmonary disease, chronic renal failure; (4) with a history of bleeding diseases such as gastrointestinal hemorrhage, brain hemorrhage or other organ hemorrhage ; (5) taking drugs with the effect of anti - platelet at the same time such as aspirin, dipyridamole or other drugs; (6) granulocytopenia or thrombocyto-penia.
2. Drugs; cilostazol, including 50 mg cilostazol per tablet; clopidogrel, including 25 mg clopidogrel per tablet.
3. Group division; All patients were randomized into 2 groups: one group took CS tablets ( 100mg ) twice a day; the other group took CPG tablets (75mg) once a day; and the two group both took aspirin ( 100mg ) once a day at the same time. The observation period is 8 days, and during the period, other drugs used as basic heart and vessel disease therapy were permit, but anti - coagulation drugs were prohibited.
4. Index: The plasma level of GMP - 140 was assayed using ELISA.
5. General index: including blood routine examination, plasma prothrombin time, liver function, kidney function were examined before treatment and after eight days therapy, blood routine examination and plasma prothrombin time were examined again.
6. Clinical observation; Sex, age, basic disease, blood pressure, symptoms of angina pectoris result of coronary arteriography, adverse events.
7. Statistical analysis; All statistical analysis was performed with Windows SPSS 10. 0. Continuous date are presented as mean + SD if normally distributed, q and t test were used. Statistical significance was defined as P <0.05.
Result
1. The conditions of the two groups:
According to the result of coronary arteriograpphy myocardial bridge and normal were excluded. 76 cases were selected, including 36 cases in CS group with mean age (63. 6 +9. 5) years and 40 cases in CPG group with mean age (65. 6 +8.5 ) years. The two groups are comparable before the therapy in sex, primary diseases, blood pressure, liver and kidney function, PTT and coronary diseases.
2. The change of the plasma level of GMP - 140 before and after treatment;
The plasma level of GMP - 140 of the two groups was high obviously, and there was no statistical significance difference. In CS group, on 3rd day and 8th
day, the reduction of the plasma level of GMP - 140 was (34. 43 + 11. 48)% and (52. 37 +8. 87)% ; in CPG group, on 3rd day and 8th day, the reduction of the plasma level of GMP - 140 was ( 39. 64 + 10. 74 ) % and ( 52. 83 + 9. 94) %. In either of the two groups, the concentration of GMP -140 had statistical significance before and after treatment, so did it in 3rd day and in 8th day after treatment, which indicated that CS and CPG could decrease the plasma level of GMP -140.
The concentration of GMP -140 of GPG group was lower than CS group (p <0. 05) in the 3rd day after treatment, that is significantly different, which indicated that CPG has faster and stronger effect than CS. However, the conc
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．第二版，上海：上海科学技术出版社，1996．
2. Schror K. the pharmacology of cilostazol. Diabetes, obesity & metabolism,2002, 4 (2): P. S14-19.
3．西洛他唑片．中国新药杂志，1998，7(4)：288-289．
4. Kimura Y, Tani T, Kanbe T, et al. Effect of cilostazol on platelet aggregation and experimental thrombosis. Forsch/Drug Res, 1985, 35 : 1144.
5. Boneu B, Destelle G. Platelet anti-aggregating activity and tolerance of clopidogrel in atherosclerotic patients[J]. Thrombosis and Haemostasis, 1996, 76 (6): 939-943.
6. Steinhubl SR, Tan WA, Foody JM, et al. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting[J]. JAMA, 1999, 281 (9) : 806 -810.
7．柏瑾，李志善，戚文航，等．国产硫酸氯吡格雷片降低血小板聚集率的临床观察．中国临床药学杂志，2001，10(2)：67-69．
8. Tenberg PE, Meever RP, Shuman MA, et al. A platelet alpha - granule membrane protein ( GMP-140) is expressed on the plasma membrane after activation. J cell Biol, 1985, 101:880-885.
9. Sternbeny PE, Mc Ever RP, Shuman MA, et al. A platelet apha granule membrane(GMP-140)is expressed on the plasma after activation. J Cell Biology, 1985, 101: 880.
10．阮健，赵相印，等．血小板α颗粒膜蛋白140在治疗急性心肌梗塞的动态检测．中华内科杂志，1995，34(4)：253．
11．宋玉强，邹宏丽，韩仲学．脑血管病患者血小板α颗粒膜蛋白140的变化及临床意义．中风与神经疾病杂志，1997，14(3)：149．
12. Warzok F, Steiner M, Blann AD, et al. Immediate and late effects of coronary angiography on soluble endothelia cell markers and P- selectin in patients with and without coronary artery disease. Blood Coagul Fibrinolysis, 1999, 10:381-387.
13. Schror K. The basic pharmacology of ticlopidine and clopidogrel [J]. Platelet, 1993,4 (2): 252-261.
14．曾红，柳林，杨平，等．尿激酶及阿司匹林对血浆α颗粒膜蛋白140的影响意义[J]．中国循环杂志，1999，14(2)：84-85．
15. Verheugt FW. Aspirin, the poor man' s station? Lancet, 1998, 315 : 227 -228.
2. Schror K. the pharmacology of cilostazol. Diabetes, obesity & metabolism,2002, 4 (2): P. S14-19.
3．西洛他唑片．中国新药杂志，1998，7(4)：288-289．
4. Kimura Y, Tani T, Kanbe T, et al. Effect of cilostazol on platelet aggregation and experimental thrombosis. Forsch/Drug Res, 1985, 35 : 1144.
5. Boneu B, Destelle G. Platelet anti-aggregating activity and tolerance of clopidogrel in atherosclerotic patients[J]. Thrombosis and Haemostasis, 1996, 76 (6): 939-943.
6. Steinhubl SR, Tan WA, Foody JM, et al. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting[J]. JAMA, 1999, 281 (9) : 806 -810.
7．柏瑾，李志善，戚文航，等．国产硫酸氯吡格雷片降低血小板聚集率的临床观察．中国临床药学杂志，2001，10(2)：67-69．
8. Tenberg PE, Meever RP, Shuman MA, et al. A platelet alpha - granule membrane protein ( GMP-140) is expressed on the plasma membrane after activation. J cell Biol, 1985, 101:880-885.
9. Sternbeny PE, Mc Ever RP, Shuman MA, et al. A platelet apha granule membrane(GMP-140)is expressed on the plasma after activation. J Cell Biology, 1985, 101: 880.
10．阮健，赵相印，等．血小板α颗粒膜蛋白140在治疗急性心肌梗塞的动态检测．中华内科杂志，1995，34(4)：253．
11．宋玉强，邹宏丽，韩仲学．脑血管病患者血小板α颗粒膜蛋白140的变化及临床意义．中风与神经疾病杂志，1997，14(3)：149．
12. Warzok F, Steiner M, Blann AD, et al. Immediate and late effects of coronary angiography on soluble endothelia cell markers and P- selectin in patients with and without coronary artery disease. Blood Coagul Fibrinolysis, 1999, 10:381-387.
13. Schror K. The basic pharmacology of ticlopidine and clopidogrel [J]. Platelet, 1993,4 (2): 252-261.
14．曾红，柳林，杨平，等．尿激酶及阿司匹林对血浆α颗粒膜蛋白140的影响意义[J]．中国循环杂志，1999，14(2)：84-85．
15. Verheugt FW. Aspirin, the poor man' s station? Lancet, 1998, 315 : 227 -228.