CN101778635A - 妊娠高血压病变或胎儿生长迟缓的治疗或预防 - Google Patents
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Abstract
Description
技术领域
本发明涉及妊娠高血压病变(HPD)或胎儿生长迟缓的治疗或预防。
背景技术
妊娠高血压病变和胎儿生长迟缓的共同之处在于它们都与经由子宫动脉的血液供给不足有关。这些病变的另一共同之处在于目前它们很难治疗。
妊娠高血压病变的实例包括选自先兆子痫、子痫、HELLP综合征以及妊娠高血压或妊娠诱发的高血压的高血压病变。所有这些高血压病变被认为与经由子宫动脉的血液供给不足有关。
WO 95/02408教导在先兆子痫和早产的治疗中联合使用孕激素和一氧化氮合成酶底物。从该国际专利申请中注意到先兆子痫、毒血症以及妊娠子痫可能是妊娠期间严重的健康问题,而且它们是胎儿生长迟缓、胎儿死亡率和发病率、早产和产妇死亡率的主要原因。
胎儿生长迟缓(或宫内发育迟缓(IUGR))意味着胎儿生长不充分且胎儿没有达到其生长势(growth potential)。因此,IUGR胎儿或新生儿的特征为对于孕龄来说过低的体重(小于胎龄儿)。胎儿生长迟缓与经由子宫动脉的血液供给低于最适值相关。
发明内容
发明人意外地发现诸如雌四醇的类固醇能够大幅地提高经由子宫动脉的血流量,特别是在经由该动脉的血流量因血管收缩而受到限制的情况下。
控制动脉(control arteries)区别于诸如主动脉和肺动脉的输送动脉(transport arteries)。不同于输送动脉,控制动脉调节对器官的血液供给。如果控制动脉过度收缩,对器官的血液供给可能受阻碍到引起不良影响的程度。例如,对于子宫动脉,孕妇内的血管收缩可能引起妊娠高血压病变和/或胎儿生长迟缓。
Tulchinsky等(J Clin Endocrinol Metab.1975Apr;40(4):560-567)报道雌四醇被认为是胎肝的特有产物并且其被建议作为胎儿健康的良好指标。在该文章中,作者得出结论:血浆雌四醇看来是患有妊娠高血压病变的患者内胎儿健康的良好指标。
本发明的发明人已经认识到本发明的类固醇可以有利地被用于预防或降低妊娠高血压病变(HPD)情况下的高血压。此外,这些同样的类固醇可以适当地被用于预防或治疗胎儿生长迟缓。如本文之前所说明的,发明人认为该类固醇在HPD和胎儿生长迟缓治疗中的有效性与这些类固醇能够大幅提高经由子宫动脉以及诸如肾动脉、肝动脉以及肠系膜动脉的可能的其它控制动脉的血流量相关。
下式表示本发明所使用的类固醇:
其中,式R1、R2、R3、R4独立地为氢原子、羟基或含有1-5个碳原子的烷氧基;R5、R6、R7各自为羟基;且R1、R2、R3、R4中至多3个为氢原子。
发明详述
因此,本发明涉及类固醇在生产用于妊娠高血压病变(HPD)或胎儿生长迟缓的治疗或预防性治疗中的药物组合物中的用途,所述治疗包括对雌性哺乳动物给药选自下组的类固醇:
下式表示的物质
其中,式R1、R2、R3、R4独立地为氢原子、羟基或含有1-5个碳原子的烷氧基;R5、R6、R7各自为羟基;且R1、R2、R3、R4中至多3个为氢原子;
在本治疗中使用时,能够释放前述式物质的前体,该前体为前述类固醇的衍生物,其中至少一个羟基的氢原子被1-25个碳原子的烃羧酸、磺酸或氨基磺酸的酰基基团、四氢呋喃基、四氢吡喃基(tetrahydropyranal)、或每个残基含有1-20个糖苷单元的直链或支链的糖苷残基取代;以及
一种或多种前述物质和/或前体的混合物。
在本发明的优选实施方案中,所述类固醇含有4个羟基。并且,在前述式中,R1优选地表示氢原子。在所述式中,优选基团R1、R2、R3和R4中的至少2个表示氢原子,更优选至少3个表示氢原子。
由于带有羟基取代基R5、R6和R7的碳原子具有手性活性,所以所述式的类固醇包括多种对映异构体。在一个优选实施方案中,该类固醇为15α-羟基取代的。在另一个优选实施方案中,该物质为16α-羟基取代的。在又一个优选的实施方案中,该物质为17β-羟基取代的。最优选所述类固醇为15α,16α,17β-三羟基取代的。
在本发明的优选实施方案中,R3表示羟基或烷氧基。在另一个优选实施方案中,基团R1、R2和R4表示氢原子,在这种情况下,如果R3、R5、R6和R7为羟基,则该物质为1,3,5(10)-雌甾三烯-3,15,16,17-四醇。后一物质的优选异构体为1,3,5(10)-雌甾三烯-3,15α,16α,17β-四醇(雌四醇)。
优选地,作为本组合物中活性成分被施用的类固醇是所谓的生物源***(即在人体内天然存在的***)、生物源***的前体或其混合物。由于生物源***天然存在于胎儿体内和女性体内,预期不发生副作用,如果外源给药这类***所导致的血清水平没有大幅地超过天然存在的浓度,则尤其预期不发生副作用。天然存在的类固醇典型地表现为具有8β,9α,13β,14α构型的类固醇骨架。
根据本发明,能够适当地被使用的前体的典型实例为能够通过使***物质的羟基与含有一个或多个羧基(M+-OOC-)的物质发生反应而得到的酯,其中M+表示氢或(碱)金属阳离子。因此,在特别优选的实施方案中,所述前体为***物质的衍生物,其中所述式中的至少一个羟基的氢原子已被-CO-R取代,其中R为包含1-25个碳原子的烃基。优选R为氢或包含1-20个碳原子的烷基、烯基或芳基。
本治疗可以适当地被用于治疗人、牛、绵羊、猪、山羊、马以及诸如狗和猫的宠物。最优选本治疗被用于治疗人。
本治疗可以适当地使用肠内或肠胃外给药所述类固醇。本文所用的术语“肠胃外给药”包括经皮给药、静脉内给药、鼻内给药、***内给药、肺部给药、含服给药、皮下给药、肌内给药或子宫内给药。术语“肠内给药”包括口服给药以及直肠给药。
优选给药方式选自静脉内给药、***内给药、直肠给药、皮下给药、肌内给药、子宫内给药或口服给药。更优选给药方式选自***内给药、皮下给药、肌内给药或口服给药。在特别优选的实施方案中,本治疗使用口服给药或***内给药。最优选本治疗使用口服给药。
根据本治疗,所述类固醇通常以每kg体重每天小于2mg的量给药,优选以每kg体重每天小于1mg的量给药。为了从所述类固醇的给药中获得显著的作用,建议以每kg体重每天至少2.5μg的量给药。更优选给药剂量为每kg体重每天至少5μg。
本治疗包括对需要这种治疗的哺乳动物给药有效量的所述类固醇。所需的有效量在个体之间会有所不同,并且取决于诸如体重、给药途径和所使用的具体类固醇的功效的因素。
在本治疗中,尤其当被用于人体时,所述类固醇通常以每天0.1-100mg的平均剂量进行给药,优选每天0.5-50mg。
根据本发明,可以被治疗的妊娠高血压病变的实例包括先兆子痫、子痫、HELLP综合征和妊娠高血压。本治疗特别适合用于治疗或预防先兆子痫。
子痫是妊娠的严重并发症,且以惊厥为特征。通常子痫发生于先兆子痫发作之后,但有时无法识别先兆子痫的症状。惊厥可能出现于分娩之前、分娩期间或分娩之后,但已有妊娠期刚20周后的子痫病例记录。子痫对母亲和胎儿都是致命的,尽管有最佳的医疗处理,仍有仅低于五十分之一的患病女性和十四分之一患病女性的胎儿死亡。
先兆子痫是高血压出现于妊娠期(妊娠诱发的高血压)的,与尿中大量蛋白质相关的病状。如果不加以治疗,先兆子痫常常可能迅速发展成子痫。先兆子痫可能在妊娠期内的不同的时间发生,且其在患者中的进展不同;大多数病例被诊断为早产。除了通过分娩胎儿终止妊娠(引产或流产)外,没有已知的治疗方法。先兆子痫也可能发生于产后多达六周。它是妊娠期最常见的危险的并发症,且可能对母亲和胎儿两者都造成影响。
当孕妇发生高血压(至少间隔6小时所测得的两个单独读数为140/90或更高)且在24小时尿样中含有300mg蛋白质(蛋白尿)时,诊断为先兆子痫。
一些妇女发生高血压但没有蛋白尿(尿中含有蛋白质),这称为妊娠高血压或妊娠诱发的高血压(PIH)。先兆子痫和妊娠高血压均被认为是非常严重的病状,并且需要仔细监控母亲和婴儿。
HELLP综合征是另一种威胁生命的产科并发症,其被许多人认为是先兆子痫的变体。这两种病状均发生于妊娠期的后期,或有时发生于分娩之后。HELLP是如下主要表现的缩写:
·溶血性贫血
·肝酶升高以及
·低血小板计数
通常,已对发生HELLP综合征的患者进行妊娠高血压的随访,或者怀疑其发生先兆子痫(高血压和尿蛋白)。所有病例中高达8%在分娩后出现。如果患者出现癫痫或昏迷,则病状已发展成充分发展的子痫。
本治疗有利地被用于治疗或预防至少妊娠20周,优选至少妊娠24周,且最优选妊娠28周的雌性哺乳动物中的妊娠高血压病变和/或胎儿生长迟缓。
在治疗妊娠高血压病变的情况下,如果在发现雌性哺乳动物患有高血压后24小时内,优选4小时内,且最优选60分钟内进行所述类固醇给药,则非常有利。在已诊断为高血压之后,越早开始治疗,先兆子痫、HELLP综合征或妊娠高血压会发展成子痫的风险越低。根据本发明,如果至少间隔6小时所测得的两个单独读数显示血压为140/90或更高,则诊断为高血压。
本治疗可能包括其它诸如抗高血压化合物的药物的联合给药。本治疗优选不使用孕激素、环氧合酶抑制剂、一氧化氮供体、一氧化氮底物、内皮缩血管肽拮抗剂、内皮缩血管肽合成酶抑制剂、前列环素、前列环素类似物、瓜氨酸或瓜氨酸类似物的联合给药。
最优选,本治疗不包括除本发明的类固醇以外的其它药学活性成分的联合给药。
通过如下实施例对本发明进行进一步说明。
实施例
实施例1
为了评价离体人血管***中对雌四醇的急性扩张反应(acute dilatoryresponse),已进行了如下研究。
将子宫肌层动脉和皮下动脉(直径:220μm;长度:2-3mm)从经受计划的剖腹产术的正常孕妇中解剖出来。子宫肌层动脉存在于子宫内,并且是子宫动脉的分支。
吸烟者和患有高血压、糖尿病、动脉硬化临床表现(CHD、外周动脉疾病、脑血管疾病)、静脉血管栓塞疾病、肝病变、无法解释的***出血以及个人史或家族史的乳腺癌的妇女被排除在外。没有人接受过HRT、其它类固醇激素或已知影响脂蛋白代谢或血压的任何药物。
将被解剖的动脉安置于压力肌动描记器(LSI,USA)上。用PSS(mM:NaCl 119、KCl 4.7、CaCl22.5、MgSO41.17、NaHCO325、KH2PO41.18、EDTA 0.026和葡萄糖5.5;pH 7.4、37℃、用含有5%CO2的O2通气)灌注器官浴槽(7ml/min)。
如果动脉无法维持压力,对于管腔外的去甲肾上腺素(NE,10-6M在钾替代的PSS(KPSS,64mM KCl在PSS中)中)表现出官腔的不完全阻隔,或对于缓激肽(BK,10-6M)无法松弛,则将动脉丢弃。
对比子宫肌层动脉中和皮下动脉中雌四醇和PPT([1H]-吡唑-1,3,5-三-三苯酚,选择性***-α-受体激动剂)的松弛反应。PPT被用作阳性对照。在从前的研究中已证明***类固醇***不能引起子宫肌层动脉和皮下动脉的松弛。
图1描述了子宫肌层动脉中雌四醇和PPT的反应曲线。受试者的数量在括号中提到。子宫肌层动脉的大小相当(对于雌四醇,284±41,n=5,而对于PPT,295±37,n=5)。
图2描述了皮下动脉中雌四醇和PPT的反应曲线。受试者的数量再次在括号中提到。皮下动脉的大小相当(对于雌四醇,213±21,n=5,而对于PPT,194±25,n=5)。
图1和2中所描述的浓度反应表明对照化合物(PPT)和雌四醇均能引起子宫肌层动脉和皮下动脉中的松弛。令人惊讶的是,雌四醇看来具有选择性作用,因为与皮下动脉相比,子宫肌层动脉中的松弛显得更加显著。
Claims (11)
1.类固醇在生产用于妊娠高血压病变(HPD)或胎儿生长迟缓的治疗或预防性治疗中的药物组合物中的用途,所述治疗包括对雌性哺乳动物给药选自下组的类固醇:
下式表示的物质
其中,式R1、R2、R3、R4独立地为氢原子、羟基或含有1-5个碳原子的烷氧基;R5、R6、R7各自为羟基;且R1、R2、R3、R4中至多3个为氢原子;
在本治疗中使用时,能够释放前述式的物质的前体,该前体为前述类固醇的衍生物,其中至少一个羟基的氢原子被1-25个碳原子的烃羧酸、磺酸或氨基磺酸的酰基基团、四氢呋喃基、四氢吡喃基、或者每个残基含有1-20个糖苷单元的直链或支链的糖苷残基取代;以及
一种或多种前述物质和/或前体的混合物。
2.权利要求1的用途,其中R3表示羟基或烷氧基。
3.权利要求1或2的用途,其中R1、R2、R3和R4中至少3个表示氢原子。
4.上述权利要求中任一项的用途,其中所述妊娠高血压病变选自先兆子痫、子痫、HELLP综合征以及妊娠高血压。
5.权利要求4的用途,其中所述妊娠高血压病变为先兆子痫。
6.权利要求4或5的用途,其中在发现所述雌性哺乳动物患有高血压后24小时内进行所述类固醇给药。
7.上述权利要求中任一项的用途,其中所述治疗包括静脉内给药、***内给药、直肠给药、皮下给药、肌内给药、子宫内给药或口服给药所述类固醇。
8.上述权利要求中任一项的用途,其中所述雌性哺乳动物是妊娠的,优选至少怀孕20周。
9.上述权利要求中任一项的用途,其中所述治疗不包括孕激素、环氧合酶抑制剂、一氧化氮供体、一氧化氮底物、内皮缩血管肽拮抗剂、内皮缩血管肽合成酶抑制剂、前列环素、前列环素类似物、瓜氨酸或瓜氨酸类似物的联合给药。
10.权利要求9的用途,其中所述治疗不包括除所述类固醇以外的其它药学活性成分的联合给药。
11.上述权利要求中任一项的用途,其中所述类固醇以每kg体重至少2.5μg的剂量给药,优选以每kg体重至少5μg的剂量给药。
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