CN100391535C - 蝮蛇血凝酶在制备抗水蛭素类药物出血的药物中的用途 - Google Patents
蝮蛇血凝酶在制备抗水蛭素类药物出血的药物中的用途 Download PDFInfo
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Abstract
本发明涉及一种酶性止血剂的用途，具体而言是该酶性止血剂能够拮抗水蛭素类药物引起的出血倾向，从而扩大了水蛭素类抗凝药的临床应用前景。
Description
所属技术领域
本发明涉及一种抗出血的凝血药物，尤其是能拮抗水蛭素类引起的副作用，即出血倾向。
背景技术
血管栓塞性疾病是常见病，也是重要的致残、致死性疾病。凝血酶在血栓形成中起重要的核心作用。因此，凝血酶抑制剂成为近些年来抗凝药研究的主要内容，并取得了迅速的进展。肝素是依赖抗凝血酶III(ATIII)的凝血酶抑制剂，在临床沿用已50多年，为常用抗凝药，其出血副作用可用鱼精蛋白中和。但肝素在应用中存在一定的局限性，例如应用肝素可导致血小板减少，导致过敏反应。其后发展的水蛭素类为不依赖ATIII的凝血酶直接抑制剂，可以通过与凝血酶及纤维蛋白复合物的结合，而起到特异的抗凝作用，其已成为有作用特点的新一代抗凝血药，但在某些情况下存在出血的副作用，并且至今为止还未发现拮抗水蛭素类的解救药物，因此很影响它的推广应用。虽然凝血酶可以中和水蛭素，但注射后又可引发血管内弥漫性凝血(DIC)，故无实际应用价值。为此提供人体切实可用的对抗水蛭素类引起的出血副作用的药物极为重要。
发明内容
本发明的发明人经研究发现，从巴西腹蛇蛇毒中提取出的酶性止血制剂能够拮抗水蛭素类药物的副作用，即出血倾向，因此降低水蛭素类抗凝药的出血倾向。其中的水蛭素类药物是水蛭素、水蛭素的缓释制剂、水蛭素的长效制剂或者水蛭素的融合蛋白。
本发明所称的酶性止血制剂含有两种酶：一种具有凝血酶样作用，称为“类凝血酶”。类凝血酶在出血部位的作用与人体凝血酶相似，能促进出血部位的血小板聚集，形成白色栓子，产生止血效应，从而对抗水蛭素的出血副反应。类凝血酶在血管内只产生纤维蛋白A单体，同时只促进出血部位血小板聚集，而对正常血管系统内无血小板聚集作用，不会引起DIC，故可以在人体中注射应用。
另一种具有凝血激酶样作用，称为“类凝血激酶”。该酶性止血剂包括Reptilase、Batroxobin及其类似物，主要组成成分是蝮蛇血凝酶，是从巴西蝮蛇蛇毒中分离、纯化而成。
出血部位的血小板聚集，释放血小板第3因子并积聚，从而激发了此酶性止血剂中的“类凝血激酶”和凝血激酶的活性，使出血部位的凝血酶形成，从而中和水蛭素，降低水蛭素引起的出血倾向。下面以巴曲亭为例附图说明该酶性止血剂在拮抗水蛭素出血方面的作用。
图1为犬滴注水蛭素不同时间，活化部分凝血活酶时间(APTT)的变化百分数。
图2为犬滴注水蛭素不同时间，凝血活酶时间(TT)的变化百分数。(注：各点的值均为平均百分数，各时间点的百分数是与30min的凝血指标值相比较。)
本发明的有益效果是，拮抗水蛭素类药物引起的不良反应，防治水蛭素用药引起的出血倾向，扩大水蛭素类药物临床应用范围。
下面将以巴曲亭为例详细说明本发明
一、体外实验证实巴曲亭拮抗水蛭素作用
1.材料与方法
1.1材料
纤维蛋白原，批号(SignaF-8630)，凝血酶，批号(SignaT-4648)，水蛭素，批号(021129)，军事医学科学院放射医学研究所研制；巴曲亭，批号(010541)，山东北大高科华泰制药有限公司生产。
1.2方法
取一系列试管，每一试管加入不同滴度的水蛭素10μl(15mg/ml)，在加入凝血酶20μl(8u/ml)，纤维蛋白原50μl(5mg/ml)，以及不同量的巴曲亭(1u/ml)。10min后观察凝集情况。
2.结果
巴曲亭对不同滴度的水蛭素的拮抗作用
(注：“-”为不发生凝集反应，“+”为发生凝集反应，“±”为可疑)
由上表可见，在加入水蛭素的实验管内加入巴曲亭后又可发生凝集反应，从而表明了巴曲亭有拮抗水蛭素的作用。
二、在体外实验基础上我们又进行了体内实验
1.材料方法
1.1材料
1.1.1药品与动物
巴曲亭，批号(SignaF-8630)，水蛭素，批号(021129)，军事医学科学院放射医学研究所研制。
成年健康杂种犬，体重12～15kg，雌雄兼备，由军事医学科学院动物中心提供。
1.1.2仪器与试剂
凝血仪，北京世帝公司生产；凝血酶时间(TT)，批号(TT25003)，活化部分凝血活酶时间(APTT)，批号(BT009)，试剂盒由上海太阳生物技术公司提供。
1.2方法
上述健康成年杂种犬，随即分为两组：对照组，单给水蛭素；实验组，给予水蛭素和巴曲亭，每组三只。犬静脉注射10％异戊巴比妥钠麻醉(100mg/kg)，股静脉插管以备采血。水蛭素按1.5mg/kg给药量，2/3药量静脉推注，1/3药量静脉滴注1h。实验组于水蛭素滴注30min后静脉推注巴曲亭(0.05u/kg)。于水蛭素滴注前、滴注后30min、1h、2h、3h、4h、5h测定凝血功能以及测定出血时间。
2.结果
2.1犬注射巴曲亭后凝血功能改变(见说明书附图)
由上述两图可见，犬给予巴曲亭后TT、APTT降低程度明显高于单给水蛭素组，从而表明巴曲亭有拮抗水蛭素的作用。
2.2犬给予巴曲亭后出血时间改变
(注：*为P＜0.05)
由上表可知，犬给予巴曲亭后出血时间明显降低，出血时间在滴注水蛭素后1h、2h、3h明显短于对照组(P＜0.05)，说明巴曲亭有拮抗水蛭素出血倾向的作用。
Claims (2)
1.从巴西蝮蛇蛇毒中提取出来的蝮蛇血凝酶在制备抗水蛭素类药物出血的药物中的用途。
2.如权利要求1所述的用途，其中的蝮蛇血凝酶是巴曲亭。
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| CNB031251048A Expired - Fee Related CN100391535C (zh) | 2003-05-09 | 2003-05-09 | 蝮蛇血凝酶在制备抗水蛭素类药物出血的药物中的用途 |
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| Country | Link |
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| CN (1) | CN100391535C (zh) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321690A (zh) * | 2001-03-28 | 2001-11-14 | 复旦大学 | 一种新型双功能水蛭素及其制备方法和应用 |
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2003
- 2003-05-09 CN CNB031251048A patent/CN100391535C/zh not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1321690A (zh) * | 2001-03-28 | 2001-11-14 | 复旦大学 | 一种新型双功能水蛭素及其制备方法和应用 |
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| Publication number | Publication date |
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| CN1548153A (zh) | 2004-11-24 |
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