CN101646436B - 催产素和/或血管升压素的拮抗剂在辅助生殖中的应用 - Google Patents
催产素和/或血管升压素的拮抗剂在辅助生殖中的应用 Download PDFInfo
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- CN101646436B CN101646436B CN2006800568367A CN200680056836A CN101646436B CN 101646436 B CN101646436 B CN 101646436B CN 2006800568367 A CN2006800568367 A CN 2006800568367A CN 200680056836 A CN200680056836 A CN 200680056836A CN 101646436 B CN101646436 B CN 101646436B
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- oxytocin
- vasopressin
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- uterine
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Abstract
本发明涉及催产素的拮抗剂、催产素和血管升压素的拮抗剂或血管升压素的拮抗剂、或它们的药用盐、或它们与其它药剂的组合用于制备药物的应用,所述药物在哺乳动物的非妊娠子宫中的主要作用模式是抑制催产素和/或血管升压素受体,这导致在胚胎移植中子宫感受性的改善。本发明进一步涉及将这些物质用于制备药物的应用,所述药物用于在人工授精的情形中调节子宫收缩活性。
Description
本发明涉及催产素拮抗剂或催产素和血管升压素拮抗剂或血管升压素拮抗剂或它们的药用盐,例如阿托西班、barusiban或瑞考伐普坦或它们与其它物质的组合用于制备药物的应用,其主要的作用模式是抑制哺乳动物的非妊娠子宫中的催产素和/或血管升压素受体,导致胚胎移植中的子宫感受性的改善。本发明还涉及上述物质用于制备药物的应用,所述药物在经历人工授精程序的受试者中调节子宫收缩性。
将辅助生殖技术应用于人以治疗不育和用于动物以产生妊娠。不育症影响着世界范围内约10%的人类夫妻,可以通过体外受精和胚胎移植(IVF-ET)进行治疗,或在较不复杂的病例中-通过人工授精进行治疗。人类中IVF-ET程序的成功率通常是在每个治疗周期10%到40%妊娠的范围内,对于人工授精则可达到20%的成功率的水平。一般地,胚胎移植的成功取决于子宫感受性,其被定义为子宫提供适当移植和胚胎发育所需要的最适条件的能力。子宫感受性的基本成分是子宫收缩活性和子宫内膜的状态。在胚胎移植过程中发生的过分的子宫收缩性可能会将胚胎从子宫中推出到阴道或输卵管中,由此可能导致治疗失败,或在后者的情形中,会导致宫外孕-一种严重的可能危及生命的并发症。此外,人工授精的成功-除了与精子质量相关外-还与子宫收缩波的强度和方向以及子宫内膜的状态相关。当子宫收缩的方向是从子宫底到子宫颈时,在所述程序中被注入子宫的精子从子宫中移出,这会影响该程序的功效。
在人类中,其中发生子宫内移植的周期可表征为减少的子宫收缩活性。子宫收缩还在饲育动物中影响胚胎移植。已知移植率与子宫收缩的频率成负相关。在高子宫收缩活性和低子宫收缩活性的妇女之间移植的成功率差异可超过50%。除此之外,子宫来源的前列腺素减少了子宫内膜的灌流,损害了子宫的感受性。减少子宫收缩性的药物如β-激动剂的应用与频繁的副作用相关,并且不影响移植的成功率。
本发明的目的是提供增加辅助生殖程序的成功率的药物并且鉴定可以用于生产所述药物的物质,需要考虑的是这些药物应该没有目前使用的药物特有的副作用,并且在辅助生殖中具有改善的临床功效。
本发明的主题是应用和药物,其在后附的权利要求中被定义。具体地,其涉及催产素的拮抗剂、催产素和血管升压素的拮抗剂、或血管升压素的拮抗剂用于制备药物的应用,所述药物用于改善胚胎移植或人工授精中的子宫感受性。
具体地,本发明涉及有效量的催产素的拮抗剂、催产素和血管升压素的拮抗剂、或血管升压素的拮抗剂、或它们的药用盐用于制备药物的应用,所述药物在辅助生殖的程序中应用,并且其可以在胚胎移植之前、期间和之后应用,并且其通过改善子宫感受性来发挥作用。根据本发明,催产素的拮抗剂、催产素和血管升压素的拮抗剂、或血管升压素的拮抗剂、或它们的药用盐以在约0.01mg直至约10g范围内的24小时剂量肠内或肠胃外施用。
催产素的拮抗剂、催产素和血管升压素的拮抗剂、或血管升压素的拮抗剂、或它们的药用盐可以是肽或非肽类物质。特别地,催产素的拮抗剂,催产素和血管升压素的拮抗剂,或血管升压素的拮抗剂是选自下组的物质:阿托西班、barusiban、瑞考伐普坦、TT-235(ANTAG III,1-PMP(S)-2-Trp-6-Pen-8-Arg-催产素)、L-365,209[环(L-异亮氨酰-D-2,3,4,5-四氢-3-哒嗪羰基-L-2,3,4,5-四氢-3-哒嗪羰基-N-甲基-D-苯基丙氨酰-L-脯氨酰-D-苯基丙氨酰]、L-366,509[2-羟基-7,7-二甲基-1-((螺(1H-茚-1,4′-哌啶)-1′-基磺酰基)甲基)二环(2.2.1)庚烷-2-乙酸]、L-371,257[1-(1-(4-((N-乙酰基-4-哌啶基)氧基)-2-甲氧基苯甲酰基)哌啶-4-基)-4H-3,1-苯并噁嗪-2(1H)-酮]、L-372,662[1-(1-4-(1-(2-甲基-1-氧吡啶(oxidopridin)-3-基甲基)哌啶-4-基氧基-2-甲氧基苯甲酰基)哌啶-4-基)-1,4-二氢苯并(d)(1,3)噁嗪-2-酮]、L 368,899[1-(((7,7-二甲基-2-(2-氨基-4-(甲基磺酰基)丁酰氨基)二环(2.2.1)庚-1-基)甲基)磺酰基)-4-(2-甲基苯基)哌嗪]、desGly(NH2)9d(CH2)5{Tyr(Me)2Thr4]OVT、化合物PA1-6酸、ANTAG II(1-PMP-2-Trp-8-Arg-催产素)、ANTAG I(1-PMP-2-Trp-3-Phe-4-Ile-8-Arg-催产素)、L-366,948(环(3-(2-萘基)-D-丙氨酰-L-异亮氨酰-D-2-哌啶羰基-L-2-哌啶羰基-D-组氨酰-L-脯氨酰)、L-366,682(环(D-组氨酰-L-脯氨酰-D-色氨酰-L-异亮氨酰-D-2-哌啶羰基-L-2-哌啶羰基)、OTA(d(CH2)5[Tyr(Me)2Thr4,Tyr-NH2(9)]鸟氨酸加压催产素)、SSR126768A(4-氯-3-[(3R)-(+)-5-氯-1-(2,4-二甲氧基苄基)-3-甲基-2-氧代-2,3-二氢-1H-吲哚-3-基]-N-乙基-N-(3-吡啶基甲基)-苯甲酰胺,盐酸盐),编码为GW405212X的物质和编码为OPC-21268的物质[1-(1-(4-(3-乙酰基氨基丙氧基)苯甲酰基)-4-哌啶基)-3,4-二氢-2(1H)-喹啉酮]。
根据本发明的具体应用涉及治疗人类不育,特别涉及胚胎移植的程序,尤其涉及新鲜的或冷冻/解冻的胚胎的移植。根据本发明的有利应用涉及体外受精-胚胎移植程序(IVF-ET),或涉及胚胎移植,其中卵母细胞或精子-胚胎的成分取自供体。本发明具体涉及在饲育动物中进行的治疗,所述动物如牛、猪、马、羊(绵羊(sheep)),其中进行胚胎移植程序。本发明的实施另外涉及使用可以应用于辅助生殖的其它的药物,尤其是氧化氮供体、氧化氮合酶的底物、孕激素(progestagen)、前列腺素拮抗剂、甲基oxantines、β-激动剂、前列环素激动剂。
特别地,根据本发明生产的药物可以在辅助生殖的程序期间使用,特别用于调节子宫收缩活性,其在人工授精后改善雌性生殖道的精子的运输。在本专利的具体实施中,其涉及在人类中进行的治疗或在饲育动物-牛、猪、羊、马中的治疗,其中进行了人工授精。最后,本发明的另外的物质构成了根据以上定义的本申请生产的药物。
本发明的主题是应用有效量的催产素的拮抗剂,催产素和血管升压素的拮抗剂,或血管升压素的拮抗剂,或它们的药用盐,例如阿托西班、barusiban或瑞考伐普坦用于制备药物的应用,所述药物应用于辅助生殖的程序,特别用于胚胎移植或人工授精。在胚胎移植之前和/或期间和/或之后以及在人工授精之前和/或期间和/或之后,以肽(例如阿托西班)或非肽(例如瑞考伐普坦)的形式应用本发明的药物。将这些药物以约0,01mg直至约10g的24小时剂量进行肠内或肠胃外施用。这些药物的应用涉及在人中治疗不育,尤其用于体外受精和新鲜胚胎的移植,或新鲜/解冻胚胎的移植,在该情形中一个或两个配子取自供体或两个配子(卵母细胞和精子)取自配偶。还在饲育动物-牛、猪、马、羊中进行用催产素的拮抗剂、催产素和血管升压素的拮抗剂或血管升压素的拮抗剂,或它们的药用盐,例如阿托西班、barusiban或瑞考伐普坦的治疗,并且所述治疗包括胚胎移植,其中假定约0.01mg直至约10g的每日剂量的有效应用。
用肽或非肽物质形式的催产素的拮抗剂,催产素和血管升压素的拮抗剂或血管升压素的拮抗剂或它们的药用盐进行的治疗涉及在人类中和在饲育动物-牛、猪、马、羊中的人工授精的程序,其中这些在所述程序之前和/或期间和/或之后进行应用。在所述治疗中,将本发明定义的药物用于调节子宫收缩性,改善精子在雌性生殖道中的运输,其中假定约0,01mg直到约10g的24小时剂量。
催产素的拮抗剂,催产素和血管升压素的拮抗剂或血管升压素的拮抗剂或它们的药用盐,例如阿托西班、barusiban或瑞考伐普坦用于制备用于辅助生殖程序的药物的应用是与下列物质中的一种或多种的应用组合进行:氧化氮供体、氧化氮合酶的底物、孕激素、前列腺素拮抗剂、甲基oxantines、β激动剂、前列环素激动剂。
良好的安全曲线(profile)是包含催产素的拮抗剂,催产素和血管升压素的拮抗剂,或血管升压素的拮抗剂,或它们的药用盐,例如阿托西班、barusiban或瑞考伐普坦的药物的一个有利性质,尤其因为这些物质的高特异性和选择性,通常将这些药物的作用限于子宫。
抑制子宫中的催产素和/或血管升压素受体导致以数种途径改善子宫感受性-首先,通过减少子宫收缩性,第二,通过抑制局部前列腺素释放(该释放减少子宫内膜的灌流)来达到对子宫内膜状态的有利影响。在子宫收缩方向是由子宫底向子宫颈的时候,在人工授精之前、期间或之后抑制催产素和/或血管升压素受体将阻止精子从子宫排出到阴道中。
催产素的拮抗剂,催产素和血管升压素的拮抗剂,或血管升压素的拮抗剂,或它们的药用盐与其它物质(例如β-激动剂)的组合抑制子宫收缩性,发挥超加成(hyperadditive)作用。所述作用可以用于减少活性物质在组合药物中的剂量,并且这与在所述组合物中使用的物质的作用的增强有关。结果,其还减少不利的药物反应的可能性。氧化氮供体、氧化氮合酶底物、前列腺素抑制剂、甲基oxantines、前列环素模拟物或孕激素是物质的实例,其可以与催产素的拮抗剂或催产素和血管升压素的拮抗剂或血管升压素的拮抗剂或它们的药用盐组合,改善子宫感受性并且调节子宫收缩性,和减少药物不利反应的可能性。
本发明将导致在胚胎移植和人工授精后妊娠率的提高。在人类中,它对于人口具有直接的社会学价值,另外减少了治疗不育的费用。本发明在饲育动物中的应用将减少育种的费用。
与在专利WO 9609824中公开的催产素拮抗剂的备选应用相反,在所述专利中其声称通过延长黄体功能增加了畜牧动物的生育力和胚胎存活,所述黄体提供孕酮的来源并且支持妊娠,而本发明涉及辅助生殖程序而不涉及自发分娩。另外,本发明不涉及黄体的形成或维持,因为在胚胎移植周期中不存在黄体。因此,在胚胎移植和人工授精两种情形中,根据本发明的妊娠率的提高是通过不同的改善子宫感受性的机制来实现。
为了更好地举例说明本发明,本发明提供了下列的附图。
图1表示通过在患者中进行经阴道的超声检查来评估关于子宫收缩活性的图,该病例在实施例1中进行描述。关于图B和图C的子宫收缩用浅颜色标记以更好的观察。在数字图像分析方法中,由于高图像质量的需要,选择总共记录的5分钟中4分钟的阶段进行分析。
A)子宫收缩性的非侵入性评估的原理的示意图(与Fanchin等类似进行,[Hum.Reprod(人类生殖).1998;13(7):1968-74]))描述:U-子宫,En-子宫内膜(子宫的内层)-在子宫收缩的过程中,观察到子宫内膜的结构和外形的变化,My-子宫肌膜(子宫的中层,平滑肌组织的构造),T-测试部分,评估其中表示子宫收缩活性的子宫内膜轮廓的运动。
B)在应用催产素拮抗剂阿托西班之前表示子宫收缩活性的图。观察到收缩活动过强。图例:↑-子宫收缩,1分钟-表示数字记录的1分钟的部分,T-测试部分,其中评估反映子宫收缩活性的子宫内膜轮廓的运动;C)在催产素拮抗剂阿托西班的最大作用的时间内表示子宫收缩活性的图。子宫收缩活性显著减少。图例:↑-子宫收缩,1分钟-代表1分钟数字记录的部分,T-测试部分,其中评估反映子宫收缩活性的子宫内膜轮廓的运动。
图2,其基于实施例2绘制,表示在对照样品和在暴露于3种浓度的阿托西班(300nM,1000nM i 3000nM)的样品中的人类精子游动性的参数比较。该图包括3张图表:A-代表与暴露于阿托西班(0nM,300nM,1000nM i 3000nM)和暴露时间相关的活跃游动的精子百分比的图。B-代表暴露于阿托西班(0nM,300nM,1000nM i 3000nM)和暴露时间相关的游动精子的百分比的图。C-代表与暴露于阿托西班(0nM,300nM,1000nM i3000nM)和暴露时间相关的活动过强的游动精子的百分比的图。在对照(0nM)组和实验组(阿托西班300nM,1000nM lub 3000nM)之间没有观察到显著的差异。精子游动性随时间的减少(在实验的第8和第24小时)取决于精子细胞能量储备的逐渐减少并且在所有的评估组中都是相当的。在统计学分析(方差分析-ANOVA)中,没有观察到精子游动性参数的显著差异。图例:活性%-活跃游动的精子细胞百分比;游动性%-游动的精子细胞的百分比;过强%-活动过强的游动精子细胞的百分比。
图3,根据实施例2绘制,代表在对照样品中和在实验组样品中(暴露于3种浓度的阿托西班:300nM,1000nM i 3000nM)精子细胞的运动参数(速率)的比较。图3包括3张图表:A-表示与暴露于阿托西班(0nM,300nM,1000nM i 3000nM)和暴露时间相关的总的精子速率的变化的图;B-代表与暴露于阿托西班(0nM,300nM,1000nM i 3000nM)和暴露时间相关的直线精子速率的变化的图;C-表示与暴露于阿托西班(0nM,300nM,1000nM i 3000nM)和暴露时间相关的在精子细胞的精子头侧摆幅度((amplitude of lateral head displacements))中的变化的图;图例:VSL-直线速率,VCL-总速率,ALH-精子头侧摆幅度。在统计学分析(方差分析-ANOVA)中,在对照(0nM)和实验样品(阿托西班300nM,1000nM,3000nM)之间没有观察到显著差异。
在图2和图3中呈现以及在实施例2中进一步提及的人类精子游动性生物评估研究的结果证实,催产素和血管升压素的拮抗剂-阿托西班并没有抑制人类精子的体外游动性,这证实了阿托西班缺乏胚胎毒性的潜力,这是其用于辅助生殖所需要的。
图4举例说明了在子宫收缩活性和胚胎移植成功率之间的相关性。在高收缩活动的情形(>5.0次收缩/分钟)中,临床妊娠率达到14%,在低子宫收缩活性的患者中,其增加超过3倍,达到53%(根据Fanchin等出版物的图[Hum.Reprod.1998;13(7):1968-74])。
图5表示在生物中在不存在和存在催产素和血管升压素拮抗剂瑞考伐普坦的情况中在血管升压素刺激的过程中,关于非妊娠人类的子宫收缩活性的图(使用在子宫内压力曲线下面积参数评估)。
图示描述:
安慰剂-参照子宫收缩活性(在接受安慰剂的患者中);VAS-1,VAS-2,VAS-3-在给药瑞考伐普坦的患者中的相对(于安慰剂)的子宫收缩活性:各个数字对应于各种血管升压素施用。
在该图中呈现的数据显示血管升压素和催产素受体抑制的作用(血管升压素和瑞考伐普坦还作用在催产素受体上),降低了子宫收缩性。考虑到瑞考伐普坦的受体模式-与催产素受体比较,针对血管升压素V1a受体具有更大的亲和力,以及与妊娠子宫相比,在非妊娠子宫中V1a表达更多的事实,瑞考伐普坦是在胚胎移植和人工授精之前应用的有前景的候选物(根据Bossmar等的出版物的图,[BJOG 1997,104;471-477])。
图6(根据等[JSGE 2004,11(6):384-387])举例说明了在施用催产素拮抗剂barusiban之前和之后,人妊娠子宫肌膜的收缩活动。
图例P-参照氯化钾(KCl)收缩W-洗涤
OT-一系列累积催产素注射用于刺激子宫收缩性(在施用催产素拮抗剂之前和之后重复),W-洗涤,BSB-施用催产素拮抗剂barusiban
在此项体外研究中,评估barusiban对催产素刺激的子宫平滑肌收缩性的作用。在施用barusiban后,显著减少了子宫平滑肌(子宫肌膜)收缩活动,并且在所述催产素浓度范围内观察到对人中发生的收缩活动的总抑制。在该研究中显示,与阿托西班相比,barusiban是更有效的子宫收缩抑制剂。尽管在妊娠和非妊娠子宫之间存在生理差异,考虑到barusiban的延长的作用模式(单剂量估计的半衰期-7小时),其是用于辅助生殖技术的有前景的候选物。
本发明涉及催产素的拮抗剂,催产素和血管升压素的拮抗剂或血管升压素的拮抗剂,例如阿托西班,barusiban或瑞考伐普坦或它们的药用盐用于制备药物的应用,所述药物以约0,01mg直至约10g之间的24小时剂量包含活性物质。这些药物的应用改善子宫感受性,其通过减轻催产素和/或血管升压素对子宫肌膜和子宫内膜(子宫的平滑肌和最内层,其中发生移植)的影响而实现。这样的作用导致子宫静止期(就收缩性而言)并且另外停止对子宫中前列腺素合成的刺激(前列腺素在正常情况下增加子宫的收缩性并且减少子宫内膜灌流)。随后,子宫内环境变得更“胚胎友好”,这又增加胚胎移植成功率。在子宫收缩方向是从子宫底到子宫颈时,本发明所述的药物在人工授精前施用时将通过防止精子从子宫中排出到子宫颈而增强该程序的功效。
本发明用于治疗,提高在人和饲育动物中的胚胎移植中的子宫感受性。用催产素的拮抗剂,催产素和血管升压素的拮抗剂或血管升压素的拮抗剂或它们的药用盐进行的治疗可以使用肽药物,其按照催产素和血管升压素的结构,如阿托西班或barusiban,以及非肽药物,如瑞考伐普坦。由于它们的消化作用,肽药物可能不通过口服施用,然而,当应用用于药物释放的专门系统时,这种施用也是可能的。催产素的肽拮抗剂,催产素和血管升压素的肽拮抗剂或血管升压素的肽拮抗剂,例如阿托西班或barusiban或它们的药用盐可以静脉内、肌内、皮下或鼻内施用。催产素的非肽拮抗剂,催产素和血管升压素的非肽拮抗剂或血管升压素的非肽拮抗剂,例如瑞考伐普坦,或它们的药用盐也可以肠内施用。包含肽或非肽药剂的本发明所述的药物将以单剂量、重复剂量或作为连续/间歇输注方式以约0,01mg至约10g/24小时的剂量进行给药。药物施用将最多在胚胎移植之前一周开始,并且将最多持续直到移植后一周。这将容许消除子宫收缩反射反应从而引入移植导管,并且减少子宫收缩性同时改善子宫感受性直到胚胎的植入,在人类中,所述植入在移植后约一周发生。
本发明的另一个方面涉及制备药物,所述药物用于在人工授精之前、期间和之后调节子宫收缩性。在子宫收缩方向是从子宫底到子宫颈情形中,该情形可以将精子通过子宫颈从子宫排出,施用催产素的拮抗剂,催产素和血管升压素的拮抗剂或血管升压素的拮抗剂或它们的药用盐。本发明所述的药物的应用将最多(maximally)在授精前一周开始并且将最多持续直到所述程序后的一周。在进行一系列授精的情况中,所述治疗可以以最多持续直到最后一次授精后一周。催产素的拮抗剂,催产素和血管升压素的拮抗剂或血管升压素的拮抗剂或它们的药用盐,如阿托西班,barusiban或瑞考伐普坦将以约0,01mg到10g/24小时的剂量,肠内或鼻内、静脉内、肌内或皮下给药。用于这些药物的施用的形式的实例是片剂、dragettes、胶囊、丸剂、混悬剂、糖浆剂、颗粒剂和溶液剂。每个给药单位,例如片剂或一匙溶液可以包含例如0,1-1000mg的每种活性成分。
包含催产素的拮抗剂,催产素和血管升压素的拮抗剂或血管升压素的拮抗剂或它们的药用盐的药物可以与其他药物联合施用,所述其他药物可以减少子宫收缩性,例如与氧化氮供体、氧化氮合酶底物、孕激素、前列腺素的拮抗剂、甲基oxantines、β-激动剂、前列环素激动剂或孕激素联合施用。
催产素的拮抗剂、催产素和血管升压素的拮抗剂或血管升压素的拮抗剂或它们的药用盐与其他上述提及的物质的组合可以肠内或肠胃外,以产生适当功效的剂量进行施用,所述剂量减少子宫收缩性并且可能具有减少不利药物反应的另外的作用。
实施例1包含阿托西班-催产素和血管升压素的拮抗剂的药物用于在IVF-ET(体外受精-胚胎移植)辅助生殖程序过程中增加胚胎移植时的子宫感受性中的临床应用。
临床描述:具有15年不育史的42岁女性,从未妊娠,伴随临床上需要治疗的被称为不育的阴性产科/妇产科史。开始,在月经过程中进行的激素实验室结果如下:FSH-5,1IU/ml(正常范围3,2-10,0),LH-1,8mIU/ml(正常范围1,2-12,5),PRL-23,4ng/ml(正常范围3,3-24,5),E2 95,7pg/ml(正常范围12,0-48,0),T-0,43(正常范围0,1-0,96ng/ml)。在生理和超声检查评估后,显示肌瘤性子宫和左卵巢囊肿。在首次访问后一个月以外科手术治疗患者,通过剖腹术和摘除子宫肌瘤并且摘除左卵巢囊肿,没有伴随的并发症。
手术后7个月,开始专门治疗不育,并对患者进行IVF-ET程序。在2003年9月进行第一个治疗程序,应用长期的刺激排卵方案。在该治疗过程中,患者接受了总共44安瓿的重组FSH(Gonal 75IU)和8安瓿的绝经促性腺素HMG(Menogon 75IU),这诱导了3个Graaf滤泡生长。在经阴道吸出滤泡后,收集1个MII卵母细胞。由于发现患者的丈夫患有精子无力(这进一步通过睾丸活组织检查证实),体外受精使用了匿名供体的精子。在卵母细胞收集后的第3天,将一个4卵裂球的胚胎移植到子宫,得到了阴性结果。
3个月后进行下一个(第二次)IVF程序。在受控的卵巢刺激过程中,施用了总共74安瓿的重组FSH(Gonal 75IU)和3安瓿的人绝经促性腺素(Menogon 75IU)。在该治疗周期中,证实了3个滤泡的生长。经阴道吸出滤泡,导致收集了3个MII卵母细胞,其随后用匿名供体的精子进行受精。在卵母细胞收集后的第三天,将2个2-卵裂球的胚胎移植到子宫,得到阴性结果。
在6个月后进行的第三个IVF程序还使用长期卵巢刺激方案。在该治疗周期过程中,施用58amp的重组FSH(Gonal 75IU)和2amp的绝经促性腺素HMG(Menogon 75IU)。结果,观察到8个滤泡的生长。在经阴道的滤泡吸出后,收集2个MII卵母细胞,其随后用匿名供体的精子进行受精。将2个4-卵裂球胚胎移植到子宫腔中,得到阴性结果。一个月后,进行了旨在提供关于可能的子宫腔病理学数据的宫腔镜检查,得到阴性结果。
鉴于患者卵母细胞存在低发育潜力的高度可能性,再经过两个月后,决定改变治疗方式使用供体的卵母细胞。卵母细胞由另一个健康的患者匿名捐赠,所述健康的患者是由于男性不育而在IVF程序中进行治疗。在将2个捐赠的卵母细胞与匿名供体的精子体外受精后,进行胚胎移植,得到阴性结果。随后在接下来的7个月中,进行了3个连续的供体卵母细胞-供体精子胚胎的周期,得到阴性结果。
在治疗的第8个周期,决定应用包含阿托西班(催产素和血管升压素的拮抗剂)的药物,旨在改善子宫感受性。将所述药物通过静脉内输注给药,所述给药在移植前60分钟开始,并且在移植后持续2小时。在开始施用前10分钟(在移植前70分钟),进行经阴道超声检查,伴随子宫收缩的5分钟的数字记录。在移植前60分钟,静脉内给药6,75mg的阿托西班的快速推注(bolus)剂量,没有不利反应。紧随其后,使用输注泵进行18mg/小时的阿托西班的连续输注,并且在整个接下来的60分钟持续。在开始输注后的45分钟,重复经阴道的超声检查,伴随数字图像记录。在输注的第55和第60分钟之间,进行超声检查引导的2个胚胎的移植。移植后,将阿托西班的剂量改变为6mg/小时。在移植后2小时结束输注,施用的总剂量是37,5mg。
上述应用阿托西班的模式在胚胎移植时提供了最大效果(证实了在开始输注后约1小时达到稳定的阿托西班浓度)。患者保持水平位置直到在终止输注后一小时,并且在当天限制她的活动。在胚胎移植后2周进行的监督访问,进行了妊娠测试,显示为阳性结果。在下一次访问(移植后4周),通过经阴道的超声检查证实了子宫内正常双胎妊娠,在两个胎囊中均观察到胎心跳动。
在该患者中治疗不育的阳性结果证实:催产素和血管升压素的拮抗剂在胚胎移植时改善子宫感受性的有利作用。因为不可能证实在移植过程中阿托西班的另外方面的作用(其在子宫内膜灌流或局部前列腺素生产方面的作用),所述作用的证据是基于其在减少子宫收缩活性上的作用,这在阿托西班显示最大作用的时刻进行非侵入性地显示。使用超声图像序列通过两种方法进行子宫收缩性的分析:通过在加速的胶片序列(acceleratedfilm sequence)上检查和人工记录收缩(方法I),和通过数字分析子宫内膜轮廓的移动(方法II,与由R.Fanchin等所述方法[Fanchin R i wsp.HumReprod(人类生殖)1998;13(7):1968-74]类似地进行)。在没有作用的情况下和在稳定血液水平的阿托西班的情况下进行子宫收缩活性的分析证实其显著的减少(方法I:在施用阿托西班前的15次收缩/5分钟对比在施用阿托西班后的8次收缩/5分钟。方法II:在施用阿托西班前的11次收缩/4分钟对比在施用阿托西班后的7次收缩/4分钟)。方法II在图1中进行了举例说明。应用包含阿托西班的药物以数种途径改善了子宫感受性:直接地-通过减少子宫收缩活性,以及间接地-通过减少子宫收缩性的刺激和减缓减少子宫内膜灌流的作用,这是由抑制子宫腔中前列腺素的生产/分泌导致的。
扼要重述,该病例证实了将包含催产素的拮抗剂,催产素和血管升压素的拮抗剂或血管升压素的拮抗剂或它们的药用盐的药物在辅助生殖中,尤其是在胚胎移植的程序中用于治疗改善子宫感受性的原理。此外,在具有相似临床特征的第二个患者中也实现了妊娠。
实施例2.催产素拮抗剂在辅助生殖中的安全性
到目前为止,包含阿托西班的药物是被注册用于人的唯一的一种催产素和血管升压素的拮抗剂。其是一种肽物质,注册用于在完全不同于辅助生殖的情况-在早产中用于静脉内应用,在早产中其用于延长妊娠。阿托西班的临床安全性在注册前的研究中已经得到了完全的证实。阿托西班被认为是唯一安全的,导致最小的副作用。然而,在辅助生殖中没有胆敢应用,因为尚未进行关于阿托西班的胚胎毒性研究。
为了证实阿托西班的胚胎毒性,进行了关于阿托西班对于人类精子游动性参数的影响的研究(人精子游动性生物测定)。在所述研究中所用的技术是在IVF实验室中进行质量控制和评估胚胎毒性的标准技术。显示该技术与小鼠或兔胚胎生物测定相当,所述小鼠或兔胚胎是用于胚胎毒性的动物模型[Miller,JW等Fertil Steril 2001:76(3),增刊;S104]。人精子游动性生物测定的特异性和敏感性与在胚胎上进行的测试相当并且目前其由于低成本和复杂性而成为最普遍的。据显示,当在人精子环境中的某因子限制其游动性时,所述因子将也是胚胎毒性的。
所述研究在取自15个健康供体的新鲜人精子样品上进行,所述供体具有理想的精液学参数。在选择活性的和游动群体(精子上游迁移方法(swim-up ascending migration method))后,将精子样品转移到包含单独的人精子制备培养基或还有300nM,1000nM,3000nM浓度的阿托西班的无菌Eppendorf管中,最后的浓度是在治疗早产过程中在人中获得的最大浓度的10倍。在暴露于阿托西班的第1,第8和第24小时,用计算机辅助的精子分析器Hobson精子追踪器(Hobson Sperm Tracker)进行精子游动性评估。
分析下列参数:
a)活跃游动的精子细胞的百分比(活性%);b)游动精子细胞的百分比(游动性%);c)活动过强的游动精子细胞的百分比(过强%),d)VSL-直线速率,e)VCL-总速率,f)ALH-精子头侧摆幅度。结果显示在图2和图3中。在统计学分析中,应用方差分析(ANOVA)。然而,在对照样品和暴露于阿托西班的样品之间没有发现显著差异。证实了不存在阿托西班的胚胎毒性,这是其用于辅助生殖所需要的。
Claims (9)
1.巴芦西班(barusiban)用于制备用于在辅助生殖中改善子宫感受性的药物的应用。
2.根据权利要求1所述的应用,其中所述制备的药物在胚胎移植之前、期间和之后被应用于子宫腔。
3.根据权利要求1所述的应用,其中巴芦西班以0.01直至10g的24小时剂量应用。
4.根据权利要求1所述的应用,其中制备的药物用于治疗人不育,
或用于动物的辅助生殖,其涉及胚胎移植和/或人工授精。
5.根据权利要求4所述的应用,其中胚胎移植是新鲜或冷冻/解冻的胚胎的移植。
6.根据权利要求1所述的应用,其中它涉及体外受精-胚胎移植(IVF-ET)的程序。
7.根据权利要求1所述的应用,其中它涉及在饲育动物中的辅助生殖的程序,在所述辅助生殖中进行胚胎移植或人工授精。
8.根据权利要求7所述的应用,其中饲育动物选自如下的组:牛、猪、羊和马。
9.根据权利要求1所述的应用,其中巴芦西班与其它药物应用联合施用于辅助生殖的治疗中,所述其它药物选自如下的组:氧化氮供体、氧化氮合酶底物、孕激素、前列腺素拮抗剂、甲基oxanthines、β激动剂、前列环素激动剂。
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