CN100448437C - 抑制女性萎缩或治疗或预防与女性萎缩相关的症状的方法 - Google Patents
抑制女性萎缩或治疗或预防与女性萎缩相关的症状的方法 Download PDFInfo
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Abstract
本发明涉及抑制妇女皮肤萎缩或上皮或粘膜萎缩的方法,或者是治疗或预防与萎缩相关的症状的方法,所述方法包括给予妇女有效量的式(I)化合物或其几何异构体、立体异构体、药学上可接受的盐、酯或其代谢产物。
Description
技术领域
本发明涉及抑制妇女特别是处于绝经期或绝经后妇女的皮肤萎缩、上皮或粘膜萎缩的方法。本发明也涉及预防或治疗与妇女特别是处于绝经期或绝经后妇女的萎缩相关的症状。
背景技术
在此并入本文用于说明发明背景特别是提供涉及实际的额外详细资料的出版物和其它材料作为参考。
绝经期或绝经后,上了年纪的妇女通常表现出由于***缺乏而引起的症状。这些症状包括潮热、背汗、失眠、抑郁、***干燥、尿失禁、恶心、疼痛、骨质疏松、冠心病、***触痛、水肿、疲劳、性行为减退,以及随之而来的社会心理问题(Payer,1990;Rekers,1990)。此外,暗示***具有神经保护作用。因此,***浓度下降可以对年老妇女的精神活动产生负面影响(Schneider & Finch,1997;WicRelgren,1997)。已知***能很好地治疗更年期症状,其在治疗这些症状中的应用也迅速增多。然而,***能增加出现子宫内膜癌和乳腺癌的危险性。通过连续孕激素用药能够降低子宫内膜癌的致癌性,但是孕激素不能降低出现乳腺癌的危险性。这种致癌性的危险限制了***替代疗法的时间长度,尽管它在继续进行长期治疗中非常有用,其原因在于***在骨骼、心血管***、中枢神经***中以及对泌尿症状的保护性作用。
“SEMR”s(选择性***受体调节剂)具有***样和抗***的性质(Kauffman & Bryant,1995)。该作用可以是组织特异性的,如它莫西芬和托瑞米芬,在骨骼中具有***样作用,在子宫和肝脏中具有部分***样作用,在乳腺癌中具有单纯抗***作用。雷洛昔芬和屈洛昔芬与它莫西芬和托瑞米芬相似,除了它们的抗***性质占优势外。基于已公开的资料,所有的SERMs与其预防更年期症状相比更可能引起这些症状。然而,它们在年老妇女中有其它重要的好处:因此它们降低总的和LDL胆固醇,因此减小了出现心血管疾病的危险性,因此它们可以预防绝经后妇女的骨质疏松和抑制绝经后妇女乳腺癌的发展。也有几乎纯的抗***正在研发,它们主要在于治疗乳腺癌(Wakeling & Bowler,1988)。
化合物(去氨基羟基)托瑞米芬,也就是已知的代码FC-1271a或通用名ospemifene,在经典激素实验(Kangas,1990)中显示出相对弱的***和抗***作用。它有抗骨质疏松作用,它在实验模型和人志愿者中能降低总的和LDL胆固醇水平(国际专利公开文本WO96/07402和WO97/32574)。它在动物乳腺癌模型中对乳腺癌发展的早期阶段也显示抗肿瘤活性。Ospemifene是第一个SERM,其已对健康妇女的更年期症状显示出有利作用。欧洲专利申请EP664124 A1提出雷洛昔芬或相关化合物用于抑制皮肤萎缩或***萎缩的用途,特别是在绝经后的妇女中。
发明内容
发明概述
根据一个方面,本发明涉及一种抑制妇女皮肤萎缩或上皮或粘膜萎缩的方法,所述方法包括给予妇女有效量的式(I)化合物
或其几何异构体、立体异构体、药学上可接受的盐、酯或其代谢产物。
根据另一个方面,本发明涉及一种治疗或预防与妇女皮肤萎缩或上皮或粘膜萎缩相关症状的方法,所述方法包括给予妇女有效量的式(I)化合物
或其几何异构体、立体异构体、药学上可接受的盐、酯或其代谢产物。
附图简要说明
图1A到1D显示了每日各自用30mg ospemifene例如FC-1271a(1A),60mgFC-1271a(1B),90mgFC-1271a(1C)和60mg雷洛昔芬(1D)治疗的个体,***上皮(epitelium)的表皮细胞的核碎裂指数(karyopyknosis index)的变化(从开始到治疗12周)。
发明详述
如本发明所述的方法对处于绝经期或绝经后的妇女特别有用。然而,如本发明所述的方法不限于此年龄组的妇女。
本发明特别涉及***受体调节剂ospemifene在绝经期或绝经后妇女中的应用。Ospemifene是式(I)化合物的Z-异构体,它是托瑞米芬的一个主要代谢产物,是已知的***激动剂和拮抗剂(Kangas,1990;国际专利公开文本WO96/07402和WO97/32574)。
术语“代谢产物”应该理解为涵盖了任意已发现或有待发现的(去氨基羟基)托瑞米芬代谢产物。涉及这种代谢物的实例有在Kangas(1990)第9页(TORE VI,TORM VII,TORE XVIII,TORE VIII,TOREXIII)提到的氧化代谢产物,尤其是TORE VI和TORE XVIII,以及所述化合物的其它代谢产物。
用语“抑制皮肤萎缩或上皮萎缩或粘膜萎缩”不限于对所述病症的完全抑制。它应该被理解为也包括对所述病症的基本缓解。
化合物(I)异构体的混合物的用途也应包括在本发明内。
能被抑制的具体形式的萎缩是泌尿生殖器萎缩。可以将与泌尿生殖器萎缩相关的症状划分为两个小组:泌尿症状和***症状。
泌尿症状的实例可提及的有排尿障碍、排尿困难、血尿、尿频、尿急感、尿道感染、尿道炎症、夜尿症、尿失禁、紧迫性失禁和无意识遗尿(involuntary urinary leakage)。
***症状的实例可提及的有刺激、瘙痒、灼烧、恶臭性(maladorous)分泌物、感染、白带、外阴瘙痒、压迫感和***后出血。
皮肤萎缩的影响是外表上的,但也能与病理疾病相关,例如经历伤口愈合皮肤性能的下降。皮肤的萎缩或老化表现为光滑度和纹理的变化,这使得看上去和感觉皮肤外表面很粗糙,皮肤弹性的变化影响皮肤的物理性质,皮肤色素沉着的变化。绝经后妇女皮肤的老化也能从角化细胞的有丝***速度,皮肤厚度的变化和与皮肤水分含量有关的葡萄糖胺聚糖和可溶性胶原的减少测定出。
在临床研究中发现了ospemifene新的和令人惊奇的效果。在这个研究中,给予年老妇女志愿者不同剂量的雷洛昔芬(60mg/天)或ospemifene 3个月。在每天30、60和90mg ospemifene的剂量水平下,观察到***萎缩显著减少。这些性质在已知的选择性***受体调节剂(SERMs)中是新颖且独特的,说明ospemifene在每天25mg到稍低于100mg的剂量下,尤其是每天30到90mg,能够成功地用于缓解源于绝经期或绝经后妇女萎缩特别是泌尿生殖器萎缩的症状。此外,与任何已知的抗***或SERM化合物相比,ospemifene具有较好的***和抗***作用谱。
如本发明所述的化合物(I)能通过各种途径给予,例如口服、局部、经皮、***内或皮下途径,其中口服或经皮给药途径是最优选的。
适宜的制剂形式包括有例如片剂、胶囊剂、颗粒剂、粉末、混悬剂、糖浆和经皮制剂,膏剂、乳膏或凝胶。也可使用皮下植入剂来延长使用时间。
对***局部给药来说,优选***乳膏、凝胶、***栓(vagitories)、***片、***托或***环。
具体实施方式
实验
进行临床I-II期研究以考察ospemifene对年龄在55到69岁的健康绝经后妇女志愿者子宫内膜厚度、子宫内膜病理(按照Vuopala等,1982记载的刮除术进行活组织切片检查)和子宫颈涂片的影响。对耐受性和药物动力学也进行评定。用雷洛昔芬(60mg每天)作为参考。每天口服给予30、60和90mg剂量的Ospemifene。每一个剂量水平有29名志愿者,雷洛昔芬组也一样。Ospemifene以明胶较囊的形式给予,胶囊含有30、60或90mg的ospemifene。用Hitachi EUB-405仪器通过超声波检查法评定子宫内膜的厚度。用核碎裂指数这一本领域技术人员公知的评价方法来评定***上皮。在这个方法中,以不同层:基底细胞层;中间细胞层和表面细胞层细胞数的百分比来评定子宫颈涂片的***分数。动情力(estrogenicity)可通过向表面细胞分数的迁移看出。在绝经后的妇女中,该分数通常接近于零,***治疗使该分数提高到接近于100。于治疗前和治疗后(三个月)取样本。ospemifene******作用的评定
下述表1显示了给予不同剂量的ospemifene或雷洛昔芬3个月后,副基底(parabasal)细胞(MI 1)成熟指数的变化和表面细胞(MI3)成熟指数的变化。
表1.给予不同剂量的ospemifene或雷洛昔芬3个月后,副基底细胞(MI 1)成熟指数的变化和表面细胞(MI 3)成熟指数的变化。(MI 1:指数100没有动情力;指数0全***,MI 3:指数100全***;指数0没有动情力)。
化合物与剂量 | MI 1平均值 | MI 1Sd | MI 3平均值 | MI 3sd |
Ospemifene,30mg,(n=21) | -40 | 42 | +12.4 | 13.6 |
Ospemifene,60mg,(n=20) | -26 | 39 | +5.5 | 13.4 |
Ospemifene,90mg,(n=22) | -48 | 44 | +12.5 | 14.0 |
Raloxifene,60mg,(n=19) | -2 | 34 | -0.3 | 4.1 |
在图1A到1D中,显示了每天各自给予30mg ospemifene(1A)、60mg ospemifene(1B)、90mg ospemifene(1C)和60mg雷洛昔芬(1D)的个体,***上皮表面细胞的核碎裂指数的变化(从开始到治疗12周)。图中,代码FC-1271a用来替代通用名ospemifene。
子宫颈涂片评定表明在雷洛昔芬组(图1D)中,表面细胞核碎裂指数从基线到治疗后没有一个有显著变化。Ospemifene组中绝大多数个体的指数有微弱增加,但在剩下的个体中***作用非常微弱,如果根本能测定的话。在所有的实例中,与已知能实际增加指数100的***相比,该增加是比较小的(<40,除了一个90mg组的为45的情形以外)。因此这证明了在子宫颈涂片中有虽微弱但具统计学显著性的***作用。在任何一个样本中均没有见到病理改变。
Ospemifene子宫内膜***作用的评定
Ospemifene对子宫内膜的组织结构显示微弱的***作用。该作用明显比***替代疗法中见到的更微弱。在子宫内膜中没有恶性发现物。由超声波检查法评定的子宫内膜厚度显示,分别在30、60和90mg剂量水平下,仅有小的、统计学不显著的厚度增长(平均0.2mm,0.5mm和0.5mm)。该测量值总是小于8mm,其被认为是表示对SERMs样它莫西芬生理学显著动情力的厚度(Hann等,1997;OLahti等,1993)。对泌尿生殖器萎缩及其相关症状的作用
在临床I和II期研究中,有241名绝经后妇女接受了ospemifene治疗。77名给予日剂量25-30mg的ospemifene,78名给予50-60mg,78名给予90-100mg,8名给予200mg。在对照组中,47名给予了安慰剂,29名给予了雷洛昔芬。一些人报告与泌尿生殖器萎缩有关的症状得到了自发缓解。该症状包括***和泌尿器的症状例如刺激性***不适、瘙痒、灼烧、刺痛、***后出血、外阴瘙痒和/或恶臭性分泌物和白带。个别人中缓解的泌尿症状包括尿失禁、复发尿道感染、排尿障碍、尿频、夜尿症、尿急感、紧迫性失禁和无意识遗尿。临床医生也报告了ospemifene缓解了泌尿生殖器萎缩的症状,特别是***苍白(pallor)、瘀斑、脆弱、***粘膜萎缩和溃疡的情形。
基于目前的数据,最佳临床剂量预期要高于25mg每天,低于100mg每天。发现特别优选的日剂量是在30到90mg范围内。在较高的剂量中(100和200mg每天),ospemifene显示了与那些它莫西芬和托瑞米芬更为相似的性质。Ospemifene是一种特别有价值的药物,因为它有良好的耐受性。此外,ospemifene降低了总的和LDL胆固醇,提高了HDL胆固醇,预防了骨质疏松和早期乳腺癌。本发明建议ospemifene和其它式(I)化合物也能在绝经期作为激素替代疗法代替***使用,已知***能增加乳腺和子宫内膜癌的危险性。
可以理解本发明的方法能以不同形式的实施方案并入,其中在此公开的仅有一些。对本领域技术人员来说,显然还存在其它实施方案,但这并不背离本发明的精神。因此,所描述的实施方案是说明性的,不应被解释为限制性的。
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Claims (5)
2.如权利要求1所述的应用,其中化合物(I)是2-[p-[(Z)-4-氯-1,2-二苯基-1-丁烯基]苯氧基]乙醇。
4.如权利要求3所述的应用,其中化合物(I)是2-[p-[(Z)-4-氯-1,2-二苯基-1-丁烯基]苯氧基]乙醇。
5.权利要求1或3的应用,其中所述立体异构体是几何异构体。
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US8758821B2 (en) | 2004-05-04 | 2014-06-24 | Hormos Medical Ltd. | Oral formulations of ospemifene |
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