CN1163571A - 用于治疗irds和ards的含有至少一种糖皮质激素并混以一种肺表面活性剂的组合物 - Google Patents

用于治疗irds和ards的含有至少一种糖皮质激素并混以一种肺表面活性剂的组合物 Download PDF

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CN1163571A
CN1163571A CN95196265A CN95196265A CN1163571A CN 1163571 A CN1163571 A CN 1163571A CN 95196265 A CN95196265 A CN 95196265A CN 95196265 A CN95196265 A CN 95196265A CN 1163571 A CN1163571 A CN 1163571A
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P·G·杰曼
K·艾斯提特
U·基利恩
D·哈夫纳
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Abstract

本发明公开了一类新的治疗IRDS和ARDS的组合物，其中含有至少一种糖皮质激素和一种肺表面活性剂。其治疗的疗程和与这些症候群相关的死亡率均随此新组合物使用显著降低。

Description

用于治疗IRDS和ARDS的含有至少一种糖皮质激素 并混以一种肺表面活性剂的组合物
新组合物
技术范围
本发明是关于用以治疗IRDS和ARDS的新组合物的。
技术现状
人们知道，用糖肾上腺皮质激素甾醇(G＜S)治疗有早产倾向的母亲，对新生儿可以产生减轻婴儿呼吸窘迫综合症(IRDS)的结果(例如H.R.Gamsu，B.M.Mulliger，P.Donai和C.M.Dash：倍他米松(Betamefhasone)产前服用预防产前婴儿的呼吸窘迫综合症：一项英国的多中心试验报告，BrifJ.Obsf.Gyn.，1989，96：410-10；评论：A.N.Papaqeorgiou和L.Sfern，J.Perinat.Med.，1986，14：75-86)。出于此种原因用GCS维持母亲，试图延迟分娩至少24小时，以利于经GCS作用的肺成熟形成。同样地，多年来通过气管内或支气管内滴注肺表面活性剂(LSF)治疗新生儿以预防和/或治疗IRDS(A.Jobe，M.Ikeqami：表面活性剂治疗呼吸窘迫综合症Am，Rev.Respir.Dis，1987，136：1256-75；M.S.Reynolds and K.A.Wallander：表面活性剂在预防和治疗新生儿呼吸窘迫综合症中的应用，Clin.Pharm.，1989，8：559-76)。近来越来越多的中心研究成功地将LSF用于其它原因的成人呼吸窘迫综合症(ARDS)的疗法(概述如，B，Lachmann，D.Gommers and E.P.Eijking：成人的外源表面活性剂疗法，Atemw.Lunqenkrkn.，1993，19：581-91；T.J.Gregory等：对成人呼吸窘迫综合症患者(ARDS)的补充，Am.J.Respir.Crit.Care Med.，1994，149：A567)。肾上腺皮质甾醇同于ARDS只有很少效用(G.R.Bernard等，高剂量皮质甾醇对成人呼吸窘迫综合症病人应用，N.Engl.J.Med.，1987，371：1565-70)。
本发明的说明
现已令人惊异地发现，通过施用糖皮质甾醇和肺表面活性剂组合物能在IRDS和ARDS治疗中达到一种协同作用。
因此本发明的目的就是一种治疗IRDS和ARDS的含至少一种糖皮质激素甾醇和一肺表面活性剂的组合物。
本发明的其它实施方案在权利要求中给出。
作为糖皮质激素甾醇，可以考虑那些适用于肺的，可例举倍他米松，布地缩松(Budesonide)，甲基氢化泼尼松，地塞米松和西乐松尼(Ciclesonide)。
根据本发明，肺表面活性剂被理解为具有天然的肺表面活性剂功能的大量的已知组合物。在此也涉及特别是磷脂的成分，在另外一些中还可能含肺表面活性蛋白。可提及的商购产品有Carosarfoe，(Serono Pharma GmbH，85716 Unterschleiβheim)，是由匀浆的猪肺高度提纯的天然表面活性剂；Survantaoe(Abbott GmbH，Wiesbaden)和Alveofactoe(Dr.Karl Thomae GmbH Biberach)，是由牛肺的两种提取物；以及Exosurfoe(Deufsche Wellcome GmbH，Burwedel)，一种带助剂的合成磷脂。肺表面活性蛋白不仅可考虑由天然来源，即如肺灌洗液或羊水提取物，而且也可考虑由基团工程制造的蛋白。根据本发明，最感兴趣的就是以SP-B和SP-C标记的肺表面活性蛋白及其相关的修饰衍生物。这些肺表面活性蛋白的氨基酸序列，其之分离和基团工程制备都是已知的(WO-86/03408，EP-A-025 1448，WO-89/04326，WO-87/06943，WO-88/03170，EP-A-0368823和EP-A-0348967)。在EP-B-0100910，EP-A-0110498，EP-B-0119058，EP-B-0145005和EP-B-0286011中带有或没有肺表面活性蛋白的磷脂组合物曾被述及，它们可以被考虑，例如，作为根据本发明的组合物的成分。
本发明的组合物或以粉剂吸入给药或以流体形式向气管内或支气管内给药。液态的肺表面活性剂配制物在糖皮质激素甾醇加入之前或加入以后冻干并接着微粉化，就得到粉剂。本发明的组合物含1到30重量百分比的糖皮质激素甾醇(根据GCS的效力，糖皮质激素甾醇的相对效力表见于Goodman/Gillman，治疗学的药理基础，Perqamon出版社，1447页，第8版)，和15至95重量百分比的干重的肺表面活性剂(例如倍他米松7％和LSF 92％或甲基氢化泼尼松37％和LSF 63％)。
本发明的制剂给药2至4日，每天给药3到4次。例如含有4mg倍他米松和50mg磷脂的制剂以每6小时的间隔吸入给药或气管内、支气管内给药6次。
药理
成熟的(成年)Spragne Dawley大鼠用纯氧和一个正的末端呼气压(＝PEEP，保证大鼠在氧气氛中)人工呼吸并时常灌洗，至其特有的LSF被洗掉(B.lachmann，B.Roberfson和J.Voqel：体内肺灌洗作为呼吸窘迫综合症的实验模型，Acta Anesth.Scand.，1980，24：231-6；D.hfner，U.Kilian和R.Beume，在成人呼吸窘迫综合症的动物模型中四种肺表面活性剂制备的比较，Am.Rev.Respir.Dis.，1993，147：A719；D.Hfner，P.-G.Germann，D.Hauschke，肺的药理学(1994)7，319-332.)。这可由动物的动脉氧分压(PaO2)由500-550mmHg的起始值(在纯氧呼吸和PEEP状态)降低到50-110mmHg表现出来。不用LSF处理的对照组动物，则在观察时间内保持其低的氧分压(PaO2)。氧分压降低至此数值五分钟之后，LSF或LSF和一种糖皮质甾醇一起作支气管滴注。在滴注之后，5，30，60，90和120分钟测定血中气体。然后PEEP由8cm降低到6cm水柱(第一次PEEP降低)。接着15分钟后PEEP再减至3cm水柱(第二次PEEP降低)。血中气体总是在两次PEEP降低后5分钟测定。
下面的表1中A栏中是在进行气管内滴注后5到120分钟时间内(8cm水柱恒定PEEP)氧分压PaO2平均值(±标准偏差)。B栏中表示在气管内滴注后第一次PEEP降低后的氧分压PaO2平均值(±标准偏差)。由C行得知在滴注之后第二次PEEP降低时氧分压PaO2平均值(±标准偏差)。由表明显看出，糖皮质激素甾醇的剂量(这里是布地松尼Budesonide)对氧分压PaO2并无影响。这是通过与不处理的对照组比较得出的。给药LSF(25或100mg/μg)导致氧分压PaO2升高。相对于给定的LSF剂量向此剂量中附加600μg布地松尼则明显地改善氧分压PaO2值。由此就生产了糖皮质激素甾醇和LSF联合用药以具有意外的协同作用。因此这就可能节约一部分贵重的LSF，但得到各单一成分增强的作用。表1：
 对照 布地缩松600μg/kg  LSF25mg/kg   LSF25mg/kg+布地缩松600μg/kg  LSF100mg/kg    LSF100mg/kg+布地缩松600μg/kg
 A  82±30 61±17 396±49   453±50 496±35 525±16
 B  77±23   96 316±91   437±71 491±72 533±25
 C  50±8   58 103±63   251±156 170±127 341±103
在实验结束时，对动物的肺进行组织病理学检查，显示了作为急性呼吸综合症的发生的症状：大量形成所谓的透明蛋白膜和强烈的炎性细胞浸润。
由含有地塞米松(Dexamefhason)或西乐松尼(Ciclesonide)和一种含或不含表面活性蛋白的磷脂混合物的本发明的制剂对这些模型的研究发现，与单独施用LSF或GCS相比，其含氧和组织学上的变化(制止HM形成和制止PMNL的涌入)被协同改善了。由此得出结论：通过这种未曾预料的协同效应缩短了IRDA和ARDS的治疗，并降低这些综合症伴随的高死亡率。

Claims (7)

1.含有至少一种糖皮质激素甾醇和一种肺表面活性剂的治疗IRDS和ARDS的组合物。
2.权利要求1之组合物，其特征在于含有倍他米松、布地缩松、甲基泼尼松、地塞米松和/或西乐松尼作为糖皮质激素甾醇。
3.权利要求1之组合物，其特征在于含有磷脂混合物作为肺表面活性剂。
4.权利要求3之组合物，其特征在于含有以天然的肺表面活性剂存在的磷脂。
5.权利要求3之组合物，其特征在于含有附加的肺表面活性蛋白。
6.权利要求5之组合物，其特征在于含有SP-B和/或SP-C和/或其修饰的衍生物。
7.权利要求4之组合物，其特征在于含有经肺灌洗所得之肺表面活性剂。
CN95196265A 1994-09-28 1995-09-27 用于治疗irds和ards的含有至少一种糖皮质激素并混以一种肺表面活性剂的组合物 Expired - Fee Related CN1100542C (zh)

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DE4434629A DE4434629C1 (de) 1994-09-28 1994-09-28 Zusammensetzungen zur Behandlung von IRDS und ARDS
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UA43378C2 (uk) 2001-12-17
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CN1100542C (zh) 2003-02-05
DE4434629C1 (de) 1996-06-27
NO971403L (no) 1997-04-17
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