CN1116872C - 制剂产品 - Google Patents
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- CN1116872C CN1116872C CN97192641A CN97192641A CN1116872C CN 1116872 C CN1116872 C CN 1116872C CN 97192641 A CN97192641 A CN 97192641A CN 97192641 A CN97192641 A CN 97192641A CN 1116872 C CN1116872 C CN 1116872C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
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- Animal Behavior & Ethology (AREA)
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- Pregnancy & Childbirth (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
本发明的主题是一分子,其特征是通式I,其中X的意义:从治疗的观点上看是适当的1或2价金属离子,n的值:1或2,或其代谢物用于治疗或预防胚胎发育迟缓或不一致性的用途。
Description
技术领域
本发明的目的是一分子,其特征为通式I,其中,
X的意义:从治疗的观点上看是适当的1或2价金属离子,
n的值:1或2,
或其代谢物,它用于治疗或预防胚胎发育迟缓或不一致性。
背景技术
已知从70年代起,在人体治疗中在几个适应症范围使用了含有氢醌磺酸钙作为有效成分的制剂产品。
这种有效成分被用于几种剂型中,其中最重要的产品是口服产品(片剂、胶囊)而且它们以由例如OB实验室(瑞士)生产的广泛注册为Doxium(氢醌磺酸钙)的名称广为人知。
在US 3509207和ES 335945专利中讨论了氢醌磺酸钙(2,5-二羟基苯磺酸的钙盐)的生产。
主要的适应症范围和经验综述如下:
由Pietrek,G.(Z.Allg.Med.56./1980/1217-1222)对120名患静脉扩张(初发性和长期性静脉曲张)的病人在3个月长期口服Doxium治疗后进行了检查。根据他的经验,病人的病情减轻了(皮着色异常,浮肿,过重感)。
由Haachen,H.J.和Lorenz,P.(脉管学(Angiology)1982.7月
33(7)480-488)报道了经双盲试验对患慢性静脉机能不全病人的治疗。作为Doxium治疗的结果,病人病情显著减轻而且根据体积扫描分析他们的健康也改善了。
由Balmer,A(Schweiz.Rundschau fur Med.Praxis,67(39)1978,1440-1443)对患上述疾病的病人在外用Doxivenil凝胶治疗之前和之后进行了检查。此产品含2%氢醌磺酸钙和2%类肝素(氢化葡聚糖硫酸钾)。病人很好地接受了治疗,而且他们80-87%的健康状况好转。
Barras,J.P.和Graf,C.(VASA/1980/9(2)161-164)发表了对诊断为视网膜病变糖尿病的患者用口服Doxium三个月长期治疗的情况。根据三种不同的分析方法,在其实验的最后血浆和全血的粘度都降低了。相对粘度和血细胞比容值保持不变。
由Sevin,R和Cuendet,J.F.(眼科学(Ophtalmologica)162:33-40/1971/33-40)检查了糖尿病病人的毛细血管的通透性。视网膜病变患者被分成如下四组:
-仅有微动脉瘤,
-少量的视网膜出血,
-明显的视网膜出血,
-视网膜外出血。
根据荧光素血管造影分析的结果,口服施用Doxium对毛细血管的病理通透性和毛细血管的阻力值具有有益的效果。
由Berson,I.(Schweizerische Rundschau fur Med.Praxis(1975.03.11./64(10)299-301)发表了用Doxiproct栓剂(含250mg氢醌磺酸钙和40mg利多卡因有效成分)治疗痔出血的报道。两周中每天服药两次,结果87%的病例检查有改善。
总结文献资料可得出结论:已知的口服使用氢醌磺酸钙的适应症如下:微血管病,尤其是视网膜病变糖尿病;慢性静脉机能不全;初发性静脉曲张;妊娠静脉曲张;腿部溃疡;夜间腓肠肌痉挛;踝关节水肿。根据目前已有的资料,它可以作为辅药用于下面的病例中:外周血栓性静脉炎;血栓形成后综合症;浮肿;停滞性皮肤病;痔病。
根据涉及作用方式的文献资料,氢醌磺酸钙通过调节病理性毛细血管壁的功能(增加通透性和降低阻力)起作用。它抑制胶原纤维的降解,降低血浆和血的过高粘滞性。它间接地抑制了淋巴液的流动,作为其结果,浮肿减轻。在口服给药500mg氢醌磺酸钙6小时后达到最大血浆浓度值,大约为8μg/ml。在3到10小时之间经历一平台期。在服药24小时后其血浆浓度是3μg/ml。血浆的平均半衰期是5小时。氢醌磺酸钙以其20-25%比率与血浆肽结合。它不能通过大脑和血液之间的屏障而且甚至不能通过胎盘屏障。它在母乳中可检测到少量。在最初的24小时里,口服给药量的约50%通过尿分泌,而且它通过粪便分泌的量与此值非常相似。大量的化合物没有经过任何转化就排泄了。
在治疗的任意期间,化合物可很好地被接受。其毒性非常低,用小鼠测试的LD50值是700mg/kg。根据到目前为止已知的文献资料,没有任何药物交叉作用。
发明内容
据我们的知识,还没有人提出在妊娠期间使用氢醌磺酸钙-除了治疗静脉曲张之外。其原因可能是,关于口服制剂产品(Doxium,生产商如OM实验室,瑞士)的说明书含有如下的陈述,如:“建议在妊娠的头三个月不使用”。“在怀孕的情况下应告知医疗人员”。“药物不通过胚盘屏障”。
在妊娠过程中,可形成几种临床情况,其中一种是胚胎发育迟缓。它意味着,在某一怀孕阶段将之与平均发育比值比较,子宫内的发育停滞了。根据国内和国际的统计资料,胚胎发育迟缓的发生率在10-30%之间。大的波动归因于这样的实事:检查的要求和仪器状况只是在过去的5-10年里才得以确定。目前那些出生重量为2500g的婴儿不属于发育迟缓的新生婴儿而是属于早产,尤其是如果是在第37个怀孕周前出生。在新生婴儿是在此周期后出生并且超过2500g出生重量的情况下,诊断和发育迟缓的事实只是在这样的医院确立的:在出生的过程中有新生儿学专家在场,或者新生婴儿需要强化治疗。由于这一原因,统计资料比实际的发病率可能更有意义。
另外的问题是,疾病的并发症很经常地导致子宫内坏死,而且产前死亡率和进一步损伤的发病率很高。
根据到现在为止出版的文献资料,疾病的发生可通过某些素因性的母亲的因素引起,例如吸烟,酒精中毒、营养不良、代谢和内分泌疾病、慢性肾、肝、肺疾病、妊娠毒血症、先兆子痫。胎盘也可能是一可能原因,例如子宫发育失调、胎盘植入困难、其早期老化、或不一致性双胎怀孕。然而,尚未对这些因素进行彻底的考查,因为除了先天性的子宫失调和发育迟缓的怀孕之外,也可产生正常的怀孕。
有两种典型形式的子宫内发育迟缓:
-发育迟缓是从怀孕的早期,称为“早期发育迟缓”,
-在一正常的初期发育之后,在怀孕的第二或第二阶段,胚胎的发育迟缓或停止。这是“继发性发育迟缓”。
通过现代的超声检查技术的传播,使得诊断的确立成为可能。
根据欧洲(以及匈牙利)超声联合会的建议,下面5个参数的检查是必须的而且足以对一病例中关于胚胎发育迟缓进行确定:
-胚胎颞骨的直径,
-胚胎头颅骨的周长,
-胚胎胸廓的周长,
-胚胎胸廓的直径,
-胚胎股骨长度。
通过使用彩色多普勒超声检查技术,甚至也可进行某些循环系统的测量,它们是诊断确定的基础。作为这些资料的结果,近些年日益明显的是,发育迟缓的胚胎的血细胞比容值高而碳水化合物和脂的储备被消耗了。在发育迟缓的胚胎的胎盘上经历了多病灶的血栓形成和早期坏死,它们导致胎盘的早熟。
从50年代起就致力于胚胎发育迟缓的治疗。曾尝试升高母亲的碳水化合物水平,或与此平行的施用低剂量胰岛素、氨茶碱以增加母亲的循环,使用放置于母亲腹壁上的真空罩以降低大气压,或使用含水杨酸盐的药物以降低母亲的血液粘度(或凝聚)。在后面的一些方法中,由Shen J.等人(英国临床药物学杂志(Br.J.Chin.Pharmacol.)
35.,1993.,No.6.664-67)考查并发表了施用乙酰水杨酸盐的情况,他对那些受妊娠惊厥(先兆子痫)和迟缓的胚胎发育危害的怀孕者给药。已确立,在每一个检查的病例中乙酰水杨酸盐进入了胚胎,而且母亲和胚胎的血液浓度并没有任何明显的差别。没有报道任何与胚胎发育迟缓有关的作用。由S.Campbell(第六届世界产科学与妇科学超声大会,鹿特丹,10月27-31,1996。摘要p.256,第517篇论文)对上述预测的临床模式用多普勒超声扫描方法检查了子宫动脉。在服用预防量阿斯匹林的情况下没有报道任何与胚胎发育迟缓相关的结果。这与事实是一致的-专家是熟知的-,上面所列的治疗没有一种引起发育迟缓的胚胎重量增加,因此它们中没有一种得到广泛的应用。
作为对上面的总结可得出结论,疾病的素因性因素是已知的,诊断的成立已部分解决,而治疗方法的有效性还很差。
在研究工作中致力于治疗,我们的目的是实现一种药物治疗,其适合于
-发育迟缓胚胎的治疗,
-预测的发育迟缓胚胎的预防,
-在不一致性(不同发育速度的多胎妊娠)的情况下改进发育迟缓胚胎的状况。
在实验中我们意外地认识到,氢醌磺酸钙适合于上面的治疗,尽管它不通过胚盘屏障,而且不能直接在胚胎中检测到。与前面的药物治疗相反,这是令人惊奇的,因为科学家寻找这样的产品,它能直接通过其存在影响胚胎的状态。这一认识对研究工作的其它方面也是令人惊奇的,母亲“供方”的增加被认为是实现怀孕最重要的,因而向怀孕者的机体中供给碳水化合物或葡萄糖。然而这些尝试并没有得到结果。
因此,本发明的主题是一分子,其特征是如通式I所示,其中
X的意义:从治疗的观点上看是适当的1或2价金属离子,
n的值:1或2或其代谢物的应用,适合于治疗或预防胚胎发育迟缓和治疗或预防不一致性。分子的化学结构示于第一张图中。
本发明另一目的是应用氢醌磺酸钙治疗或预防胚胎发育迟缓和治疗或预防不一致性。
因此上面的有效成分适合于在早期阶段治疗已发生的胚胎发育迟缓或预防它。以前讨论过素因性因素,因此在其较早期累积发生的情况下更可能发生疾病。如果在以前怀孕中只有一例发生发育迟缓,则不应推测发生再次发育迟缓。但是,在有两个或更多个发育迟缓的新生婴儿后,在再次怀孕的情况下非常可能将再次产生临床情况。
根据可能的机能,在有效成分的作用下,在母亲和胚胎边界的胎盘的供血增加了,因而对胚胎的氧和营养的供给增强了。在胎盘的绒毛区,充血和小血栓的形成停止了。尽管母亲和胚胎的血管并不混合,通过改善母亲的血量和血压,胚胎的血流量和血压也加强了。
根据我们的经验,在不一致性的情况下,服用有效成分对在先前发育中发育迟缓的双生儿-B或-C的发育有有益的作用。根据一可能的机制,阳性结果是由于胎盘中氧和营养的供给改善,使双生儿-B或-C得到发育。
此机制与正式的适应症的机制无关,这不能从其中推断出来。这得到了事实的支持:在对患先兆子痫(与其相伴的是:母亲的浮肿、蛋白尿和高血压)的病人检查后作者宣称,氢醌磺酸钙并不降低母亲的蛋白尿和高血压,而且血小板的转化是有利的。在上面的临床情况中(参阅大量的研究)并没叙述或考虑目前在胚胎发育迟缓方面必须的变化(Lege Artis Medicine 4月07,1994,902-910页)。
具体实施方式
为了支持在新的适应症领域的应用,对分成三组的怀孕者进行了氢醌磺酸钙试验。在属于第一组的病人的情况下,胚胎发育迟缓的诊断是通过超声分析方法,根据前述的测量如胚胎颞骨直径、胚胎头颅骨的周长、胚胎胸廓的周长、胚胎胸廓的直径、胚胎股骨的长度以及通过胚胎心血管的检查,即:
-分析脐带动脉血流的“声图下”面积并给出同一动脉的阻力指数;
-胚胎主动脉下流分支状况的测量;
-分析胚胎动脉的脑血管中层血流的“声图下”面积并给出同一动脉的阻力指数(这些分析适用于从怀孕的第28周)。
属于第二组的病人是不一致性双胞胎怀孕者,诊断是根据上述方法作出的。
在属于第3组病人的情况下,由于素因性因素的累积发生,可预期胚胎发育迟缓。在这一组中,出现了正常和双胞胎怀孕。
第1组-诊断的胚胎发育迟缓
根据上述分析后所得的诊断,144个怀孕者属于此组。病人每天接受3×1的Doxium胶囊(每个胶囊500mg氢醌磺酸钙)。
最少的治疗周期为2周,最好6-10周。
治疗在怀孕的第2-3阶段开始。除了上述胚胎分析和在进行治疗后的心血管状况的确定之外,以每周一次的频率测量羊膜液的量并且还要确定胎盘的成熟度。根据以上参数,如果胚胎发育的程度和胚胎的重量值达到了孕龄的特征值,我们便开始维持治疗。维持剂量是每天2×1 Doxium胶囊。
根据我们对胚胎身高和功能分析的结果(非应激试验,心血管参数),在那些病例中孕妇的分娩是可能的,除了发育迟缓之外,胚胎的功能状况是怀孕终止的原因。在很多病例中Doxium的作用是最明显的并导致了成熟重量或10-90%范围的新生儿重量-对到期或接近到期分娩是有益的,条件是
-治疗在第32到34个妊娠周之前开始并且
-胚胎发育迟缓与母体的疾病和/或发育中的胚胎发育迟缓和/或干产无关。
第2组-不一致性胚胎双胎怀孕
在此组中考查了23个怀孕者。诊断和对病人的控制如在第1组中所述进行。
初始剂量是每日3×2 Doxium片剂(每个胶囊250mg氢醌磺酸钙)。维持剂量是每天2×2 Doxium片剂。
我们的结果与在第一组中所写的情况一样好。在两组中新生婴儿
-没有血浓缩;
-血小板凝结的升高不是特征性的;
-血液粘度是正常的;
-氧的饱和是生理学的;
-在治疗只持续了8-10周的病例中,碳水化合物、脂和肽的代谢不需任何校正。
第3组-预测的胚胎发育迟缓
对此考查选择了93个怀孕者,在这些病例中发现有素因性因素的累积发生。对病人的控制如在第一组中所述进行。在怀孕的第14周开始服用Doxium(每天2×2 Doxium片剂,维持剂量与前面所述的相同),并且在出生两周前停止。
根据我们的经验,在考查的范围里没有发现胚胎发育迟缓。
作为我们的结果的总结:
-氢醌磺酸钙有效地适用于治疗或预防上述疾病;
-根据治疗组,没有发现疾病的禁忌证;
-在受治疗的病人的病例中没有发现任何药物交叉作用。
如果给药周期不多于两周,建议最低的每日氢醌磺酸钙剂量是500mg而最高剂量是3000mg。
对于病人此解决办法的优点:
-建议在新的适应症范围应用一有效成分,该成分在人体中的应用已经试验了20多年;
-制剂产品没有任何或只有非常有限的副作用;
-有效成分不能通过胚盘,它不加重胚胎机体的负担;
-在那些到现在为止只有很有限的成功治疗的领域中它给出了好的治疗结果;
-在怀孕的第2或第3周期开始服此药即使只是为了预防也足够了。
Claims (4)
1.氢醌磺酸钙用于生产治疗胚胎发育迟缓的药物的用途。
2.氢醌磺酸钙用于生产预防胚胎发育迟缓的药物的用途。
3.氢醌磺酸钙用于生产治疗多胚胎发育不一致性的药物的用途。
4.氢醌磺酸钙用于生产预防多胚胎发育不一致性的药物的用途。
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