CN102210695A - 磷酸肌酸钠用于制备抗休克药物中的应用 - Google Patents
磷酸肌酸钠用于制备抗休克药物中的应用 Download PDFInfo
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Abstract
本发明公开了磷酸肌酸钠用于制备抗休克药物中的应用,尤其是磷酸肌酸钠用于制备治疗因矿难、电击、溺水、外伤失血引起的休克的药物中的应用。通过研究发现,磷酸肌酸钠可以有效改善失血性休克症状,抑制缺氧状态下无氧呼吸乳酸产生,具有很好的肝肾保护功能,明显延长休克动物的存活时间。
Description
技术领域
本发明涉及磷酸肌酸钠用于制备抗休克药物中的应用,尤其涉及磷酸肌酸钠用于制备治疗多种原因引起的休克的药物中的应用。
背景技术
休克是指由于心排量不足或周围血流分布异常引起周围组织的灌注量不足,不能维持生命需要的一种状态,通常都有低血压和少尿。
休克可由低血容量、血管扩张、心源性或这些因素综合引起。休克的基础损害是低血压所致的各器官、组织灌注减少,于是由于O2的传送或摄取不足,组织细胞不能维持有氧代谢的需要,而转为无氧代谢,致使乳酸的产生和积聚增加。随着休克的持续,脏器功能出现障碍,随之以不可逆的细胞损害和死亡。
近年来,随着对休克发病机制的新认识,休克治疗措施也得以相应发展,出现了许多新的抗休克药物,它们大体可分为3种类型:第一类是在较老抗休克药物基础上向增强疗效、减少不良反应或向定向作用点上发展的抗休克药物,如新型肾上腺素能激动剂、阿片受体拮抗剂、钙通道阻滞剂、花生四烯酸代谢产物抑制剂或拮抗剂;第二类是发现新用途的抗休克药物如磷酸二脂酶抑制剂;第三类就是近年来出现的新型抗休克药物,如休克细胞因子拮抗药物以及内毒素拮抗药物等。抗休克的药物种类虽然较多,但大多数药物的抗休克机理在于:对于休克时由于组织缺血缺氧状态下无氧代谢反应及由此产生的代谢产物的生成都是比较单一的被动拮抗、阻断或抑制,从而减少因休克对生命的影响。显然,这些抗休克药物不能真正减少有氧呼吸的发生,减少因缺血缺氧对组织的影响,不能起到主动保护作用,同时药物安全性存在一定风险。
磷酸肌酸是肌体如心肌、骨骼肌、脑、肾、视网膜等高耗能组织细胞内一种重要成分。它于1927年首先在肌肉中被发现,至上世纪七十年代清楚了它的主要生理作用:第一,它是细胞内能量代谢的缓冲物质。由于它的作用,上述组织或细胞内的ATP含量才能基本保持恒定,不至于因消耗能量的增加而有大的变化。第二,它是能量的载体。磷酸肌酸分子中的高能磷酸键来自线粒体产生的ATP分子,磷酸肌酸分子携带着来自ATP分子的高能磷酸键在胞浆内被酶促转运至耗能部位(如肌纤维,肌浆网,细胞膜等),使那里不断产生的ADP得以重新被磷酸化。
1974年,英国人发现了磷酸肌酸有保护细胞膜的作用,从此开始了对它的药理作用系统性研究。经过多年的努力,它作为药物(针剂)于九十年代中期国外开始在临床上使用,在心内科被用于心肌梗死的治疗,纠正心肌梗死发展前期的心室心律不齐;在心外科它被添加至停搏液中,使手术后病人心脏的功能快速恢复正常。
磷酸肌酸钠自上市以来,主要作为缺血缺氧状态下的心肌保护功能使用,开发和使用,实际上,由于其具有:(1)由于参与能量代谢。磷酸肌酸分子中的高能磷酸键来自线粒体产生的ATP分子,磷酸肌酸分子携带着来自ATP分子的高能磷酸键在胞浆内被酶促转运至耗能部位(如肌纤维,肌浆网,细胞膜等),使那里不断产生的ADP得以重新被磷酸化,去除ADP,抑制血小板聚集,具有改善微循环的作用;同时由于外源性的磷酸肌酸参加,可以为细胞组织提供必要的能量,而减少代偿性的无氧呼吸的发生,减少了乳酸的产生和积聚,减少细胞损害和死亡。(2)过抑制肌纤膜上的5′核苷酸酶反应,使心肌细胞内的腺苷酸流失量减少。在缺血缺氧情况下,由于心肌细胞内磷酸肌酸、肌酸、肌酸激酶等多种能量代谢必须物质的流失,多种耗能酶反应所生成的ADP只能通过胞浆内的腺苷酸激酶来使其重新磷酸化。但是,腺苷酸激酶每进行一次反应,就要有一半的腺苷酸变成AMP,而AMP被细胞膜上的5′核苷酸酶催化生成容易透过膜而流失的核苷一腺苷和肌苷,使细胞内的腺苷酸库存量减少。大量试验已表明,外源性磷酸肌酸是5′核苷酸酶的抑制剂,通过对该酶活力的抑制可使AMP保留在肌细胞内,它可再通过腺苷酸激酶反应重新生成参与能量代谢的ADP和ATP。(3)安全性好,因为磷酸肌酸钠,作为心肌保护剂药品已经在国内外上市应用多年,由于其本身即为机体细胞内源性物质,经临床应用表现出良好的安全性。
目前国内外还没有文献报道磷酸肌酸钠具有抗休克的医药活性。
发明内容
本发明人意外的发现,磷酸肌酸钠具有抗休克的医药活性,随后通过大量动物试验进一步验证了磷酸肌酸钠的抗休克医药活性。因此,本发明的目的在于提供磷酸肌酸钠用于制备抗休克药物中的应用,尤其提供磷酸肌酸钠用于制备治疗多种原因引起的休克的药物中的应用。
为了实现上述目的,本发明提供了如下技术方案:磷酸肌酸钠用于制备抗休克药物中的新用途。
具体来说,所述的休克是因矿难、电击、溺水、外伤失血引起的休克。
优选地,所述的药物为磷酸肌酸钠注射剂。
进一步优选地,所述的磷酸肌酸钠注射剂为无菌分装粉针剂或注射用冻干粉针剂。
磷酸肌酸钠制剂的制备方法可以为以下任何一种:(1)磷酸肌酸钠原料经无菌制剂分装,制备成无菌制剂。(2)磷酸肌酸钠原料经注射用水溶解后,活性炭吸附并脱碳,除菌过滤,然后超滤除热源,乙醇沉淀,减压干燥,无菌分装后制备成注射用粉针剂。(3)按照中国专利申请CN101288649A公开的方法制备成磷酸肌酸钠粉针剂。
磷酸肌酸钠无菌分装制剂的用法为:用时采用注射溶媒溶解,静脉滴注或推注。
本发明涉及的磷酸肌酸钠用于抗休克具有如下优点和显著的进步:(1)药效显著。根据实施例1的磷酸肌酸钠对大鼠休克模型的影响试验可以看出,大鼠累计失血量达总血量的40%后造成失血模型,经磷酸肌酸钠注射治疗,与模型对照组比较,给药组可以有效改善失血性休克症状(P<0.01),抑制缺氧状态下无氧呼吸乳酸产生,具有很好的肝肾保护功能,明显延长大鼠存活时间。(2)安全性好。由于磷酸肌酸钠作为心肌保护剂药品已经在国内外上市应用多年,由于其本身即为机体细胞内源性物质,经临床应用表现出良好的安全性。
具体实施方式
实施例1磷酸肌酸钠对大鼠休克模型的影响
1、试验材料
(1)受试品:磷酸肌酸钠
(2)试验动物:SD雄性大鼠
(3)仪器:BL-420E生物机能试验系统
2、模型建立
取健康雄性大鼠40只,体重300~330g,大鼠试验前禁食12小时,期间自由饮水。随机分成4组:假术组、模型组(模型对照组)、模型给药低剂量组(磷酸肌酸钠低剂量组)、模型给药高剂量组(磷酸肌酸钠高剂量组)。每组10只。
试验时戊巴比妥钠35mg/kg腹腔注射麻醉后,将动物仰卧固定于手术台上。手术部位剪去毛后用75%乙醇消毒,分离右颈动脉、左股动静脉。右颈动脉插管通过压力传感器连接于BL-420E生物机能试验系统监测血压,通过引导电极检测II导联心电图记录心率。左股动脉插管用于放血和采集血样,左股静脉插管用于回输液。试验过程中经肛门置入测温探头检测体温,必要时应用白炽灯照射,使大鼠体温维持在35~37℃。试验前各导管均用肝素溶液(2.5U/ml)冲洗以抗凝,不给予全身肝素抗凝。操作完毕后动物稳定30分钟,测各检测指标基础值。(血压、心率、血乳酸、谷丙转氨酶(ALT)、肌苷(Cr)含量、死亡率)
模型组:左股动脉插管用于放血,放血过程持续60min.采用双阶段放血方式,前40min为梯度放血期。分别按9.0ml/(kg·10min)、6.0ml/(kg·10min)、5.0ml/(kg·10min)和2.5ml/(kg·10min)的速率放血。本阶段的累计失血量达总血量的40%,平均动脉压(MAP)通常降至4.0kPa左右。后20mim为血量调节期,大鼠失血40%后5~10min收缩压可回升到8.0kPa,此时开始慢速放血,待MAP降至(4.0±1.7)kPa,即为放血终点,再维持该血压30min,完成失血性休克模型的制备。模型制备完成后进行恢复消毒缝合,然后再检测上述各项指标。
假术组:按模型组方法实施手术,但不进行放血操作。
3、复苏治疗
按上述方法制备休克模型的动物被随机分为:
模型(模型对照组):静脉滴注5%葡萄糖生理盐水50ml/kg和全部失血;
模型给药组(磷酸肌酸钠低剂量组):静脉滴注含磷酸肌酸钠0.3mg/ml的5%葡萄糖生理盐水50ml/kg和全部失血)
模型给药组(磷酸肌酸钠高剂量组):静脉滴注含磷酸肌酸钠1.5mg/ml的5%葡萄糖生理盐水50ml/kg和全部失血)
各组按上述剂量分别滴注相应的复苏液,按15分钟匀速输入。
分别于静脉滴注开始后0、15、30、60、120、180、240、360、480分钟的MAP、心率,并分别于0h、1h、4h、6h、8h取血0.3ml检测血乳酸、血清ALT、血清Cr,平均存活时间及死亡情况。
4、试验结果
大鼠累计失血量达总血量的40%,造成失血模型后,经磷酸肌酸钠注射治疗,与模型对照组比较,给药组可以有效改善失血性休克症状,抑制缺氧状态下无氧呼吸乳酸产生,具有很好的肝肾保护功能,明显延长大鼠存活时间,具体参见表1-表6。
表1大鼠MAP变化(kPa n=10X±S)
表1(续)大鼠MAP变化(kPa n=10X±S)
注:与模型对照组比较*P<0.05 **P<0.01
表2大鼠心率变化(次/分钟n=10X±S)
表2(续)大鼠心率变化(次/分钟n=10X±S)
注:与模型对照组比较*P<0.05 **P<0.01
表3不同时间大鼠血乳酸变化情况(n=10X±S)
注:与模型对照组比较*P<0.05 **P<0.01
表4不同时间大鼠血清ALT变化情况(n=10 X±S)
注:与模型对照组比较*P<0.05 **P<0.01
表5不同时间大鼠血清Cr变化情况(n=10 X±S)
注:与模型对照组比较*P<0.05 **P<0.01
表6大鼠平均存活时间及死亡情况
同样,动物试验显示:经溺水、电击等原因造成的休克大鼠模型,经给予磷酸肌酸钠后机体的各项机能较模型对照组明显恢复,存活率明显提高。
Claims (4)
1.磷酸肌酸钠用于制备抗休克药物中的应用。
2.如权利要求1所述的磷酸肌酸钠用于制备抗休克药物中的应用,其中休克是因矿难、电击、溺水或外伤失血引起的休克。
3.如权利要求1或2所述的磷酸肌酸钠用于制备抗休克药物中的应用,其中所述的药物为磷酸肌酸钠注射剂。
4.如权利要求3所述的磷酸肌酸钠用于制备抗休克药物中的应用,其中所述的磷酸肌酸钠注射剂为无菌分装粉针剂或注射用冻干粉针剂。
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CN101486730A (zh) * | 2009-02-19 | 2009-07-22 | 郑仙锋 | 一种磷酸肌酸钠化合物及其合成方法 |
CN101732263A (zh) * | 2008-11-14 | 2010-06-16 | 杨军 | 磷酸肌酸钠冻干制剂及其制备方法 |
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CN101732263A (zh) * | 2008-11-14 | 2010-06-16 | 杨军 | 磷酸肌酸钠冻干制剂及其制备方法 |
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