CN1152868A - 使用屈洛昔芬治疗前列腺疾病、子宫内膜异位和肥胖症 - Google Patents

使用屈洛昔芬治疗前列腺疾病、子宫内膜异位和肥胖症 Download PDF

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CN1152868A
CN1152868A CN95194196A CN95194196A CN1152868A CN 1152868 A CN1152868 A CN 1152868A CN 95194196 A CN95194196 A CN 95194196A CN 95194196 A CN95194196 A CN 95194196A CN 1152868 A CN1152868 A CN 1152868A
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戴维·D·汤普森
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Abstract

使用屈洛昔芬治疗前列腺癌、子宫内膜异位和肥胖症。

Description

使用屈洛昔芬治疗前列腺疾病、子宫内膜异位和肥胖症
这是1994年7月19日递交的美国专利申请流水号08/276,969的部分继续申请。
本发明涉及治疗前列腺疾病、子宫内膜异位和肥胖症的药物，其包含作为活性成分的具有如下化学式的化学结构的屈洛昔芬：或其药学上可接受的盐。
屈洛昔芬是美国专利5,047,431公开的一种已知化合物，在该专利中，屈洛昔芬是一种抗肿瘤药物，尤其是用于乳腺癌的治疗和防治。屈洛昔芬对由于雌激素或类似物缺乏引起的骨骼疾病的缓解也很有用，该病在妇女绝经或子宫切除后比较常见。美国专利5,254,594。
在Gill-Sharma等人，J.Reproduction and Fertility(1993)99，395中公开了使用200和400毫克/千克/天的它莫西芬减少了雄性鼠的睾丸和第二性器官的重量。
Neubauer等人，The Prostate 23：245(1993)报道了雷洛昔芬治疗雄性鼠可导致腹侧的前列腺的退化。
本发明提供了治疗哺乳动物的选自子宫内膜异位、肥胖症、良性前列腺肥大和前列腺癌的症状或疾病的方法，该方法包括给药于所述哺乳动物一定量的有效治疗所述症状或疾病的屈洛昔芬或其药学上可接受的盐。
制备屈洛昔芬(1-[4′-(2-二甲基氨基乙氧基)苯基]-1-(3′-羟苯基)-2-苯基丁-1-烯)及其药学上可接受的盐的方法记载于美国专利5,047,431，在此引入本文作为参考。
在本说明书中，“前列腺疾病”表示良性前列腺增生或前列腺癌。“治疗”表示对疾病或病症的症状的治愈、减轻或防止疾病的发生。
本发明用于治疗前列腺疾病、子宫内膜异位和肥胖症的药物包括作为活性成分的屈洛昔芬及其盐。屈洛昔芬的药学上可接受的盐是那些常用的无毒类型的盐，例如有机酸(如甲酸、乙酸、柠檬酸、马来酸、酒石酸、甲磺酸、苯磺酸和甲苯磺酸)的盐，无机酸(如盐酸、氢溴酸、硫酸或磷酸)的盐，以及氨基酸(如天冬氨酸或谷氨酸)的盐。这些盐可以由本领域熟练化学师用公知的方法来制备。
本发明的用于治疗疾病和病症的药物可以口服或非肠道给药于包括人的动物，制剂可以采用常规剂型，例如胶囊剂、微胶囊剂、片剂、颗粒剂、粉剂、锭剂、丸剂、栓剂、注射液、悬浮液和糖浆。
本发明用于疾病或病症的药物可以由常用方法来制备，使用常规的有机或无机的添加剂，例如赋形剂(如蔗糖、淀粉、甘露糖醇、山梨醇、乳糖、葡萄糖、纤维素、滑石粉、磷酸钙或碳酸钙)，粘合剂(如纤维素、甲基纤维素、羟甲基纤维素、聚丙基吡咯烷酮、聚乙烯基吡咯烷酮、明胶、阿拉伯胶、聚乙二醇、蔗糖或淀粉)，分解剂(如淀粉、羧甲基纤维素、羟丙基淀粉、低级取代的羟丙基纤维素、碳酸氢钠、磷酸钙或柠檬酸钙)，润滑剂(如硬脂酸镁、轻质无水硅酸、滑石粉或月桂基硫酸钠)，矫味剂(如柠檬酸、甲醇、甘氨酸或橘子粉)，防腐剂(如苯甲酸钠、亚硫酸氢钠、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯)，稳定剂(如柠檬酸、柠檬酸钠或乙酸)，悬浮剂(如甲基纤维素、聚乙烯基吡咯烷酮或硬脂酸铝)，分散剂(如羟丙基甲基纤维素)，稀释剂(如水)和基质蜡(如可可油、白凡士林或聚乙二醇)。在医药组合物中，活性成分的量可为达到所需治疗效果的量，例如，口服和非肠道给药的单剂含量为1～100毫克。
活性成分每单剂含0.25～100毫克，通常每天对病人给药一到四次，但是上述剂量可以根据病人年龄、体重、病情和给药方式适当有所变化。优选每天一剂。
以下实施例用于说明本发明，而非限定本发明的权利要求书的保护范围。
实施例1
对前列腺重量的影响
三月龄雄性Sprague-Dawley鼠，14天内每天皮下注射给药赋形剂(水中10％乙醇)、雌二醇(30微克/公斤)、睾酮(1毫克/公斤)或屈洛昔芬的柠檬酸盐(10毫克/公斤)(n＝6/组)。14天后处死动物，取出前列腺并称量其湿重。测定平均重量并且用Student试验法确定相对于赋形剂治疗组的统计学显著性(p＜0.05)。
与赋形剂比较，10毫克/公斤/天的屈洛昔芬的柠檬酸盐显著降低了前列腺的重量(p＜0.05)。睾酮组没有效果，30微克/公斤的雌激素显著地降低了前列腺的重量。
这些数据表明屈洛昔芬的柠檬酸盐在治疗良性前列腺肥大和前列腺癌方面是有用的。
实施例2
对身体脂肪重量的影响
10月龄的体重450克的雌性Sprague-Dawley鼠被施以假性手术(sham)或卵巢切除(OVX)，用赋形剂、30微克/公斤/天的17α乙炔基雌二醇或1.0、2.5或5毫克/公斤/天屈洛昔芬的柠檬酸盐口服处理八周。每小组有6至7只鼠。在试验的最后一天，采用配有全身扫描软件的双道X射线能量吸收法(Hologic QDR-1000/W)测定所有鼠的身体物质组成。参考Faulkner等人，Calcified Tissue 53，7(1993)。我们的结果表明乙炔基雌二醇和所有剂量的屈洛昔芬对身体的瘦肉质量(克)没有影响。但是，与sham或OVX对照试验组比较，用乙炔基雌二醇或屈洛昔芬(所有剂量)处理的OVX鼠的脂肪质量(克)均明显降低(40-60％)。这些结果表明了屈洛昔芬是治疗肥胖症的有效物质。
实施例3
对子宫内膜异位的控制和预防
关于手术引起子宫内膜异位的原始记录与Jones，Acta Endocrinol(Copenh)106：282-8中所述内容一致。使用成年Charles River Sprague-DawleyCD雌性鼠(200-240克)。体腔壁的皮肤和肌肉系统被腹侧斜切开。切取一片右子宫角质切片，从子宫内膜上剥离子宫肌层并纵向切割该切片。一片5mm×5mm的子宫内膜切片，将其上皮层面紧贴体腔壁在四个角上用聚酯braid(Ethiflex，7-0)缝合于肌肉。移植物存活的条件是类同于子宫内发生的作为雌激素刺激结果的液体积累。
子宫内膜组织移植后三周(+3周)，动物被剖腹，用测径器测量移出物的体积(长×宽×高，mm3)，然后试验开始。给动物皮下注射式I化合物10～1000微克/公斤/天三周。作为对照，给带有子宫内膜移植物的动物皮下注射玉米油0.1毫升/天三周。治疗三周后(+6周)，动物被剖腹并测量移出物的体积。停止试验后八周(+14周)，动物被处死，再次测量移出物的体积。移出物体积的统计分析采用方差分析。
实施例4
屈洛昔芬的柠檬酸盐片剂
    屈洛昔芬的柠檬酸盐乳糖低级取代的羟丙基纤维素聚乙烯基吡咯烷酮硬脂酸镁     100克1190克250克50克10克
上述所列成分采取常用方法混合，如此所得混合物压成10,000片，每片含活性成分屈洛昔芬柠檬酸盐10毫克。

Claims (6)

1、一种治疗良性前列腺增生的方法，包括给药治疗患有良性前列腺增生症的哺乳动物有疗效用量的屈洛昔芬或其药学可接受的盐。
2、一种治疗选自子宫内膜异位、前列腺癌和肥胖症的疾病或病症的方法，包括给药于待治的哺乳动物一定量的有效治疗所述疾病或病症的屈洛昔芬或其药学可接受的盐。
3、权利要求2的方法，其中，所述疾病或病症为子宫内膜异位。
4、权利要求2的方法，其中，所述疾病或病症为前列腺癌。
5、权利要求2的方法，其中，所述疾病或病症为肥胖症。
6、权利要求2的方法，其中，所述药学可接受的盐为柠檬酸盐。
CN95194196A 1994-07-19 1995-05-26 使用屈洛昔芬治疗前列腺疾病、子宫内膜异位和肥胖症 Pending CN1152868A (zh)

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US08/276,969 US5441986A (en) 1994-07-19 1994-07-19 Estrogen agonists as remedies for prostate and cardiovascular diseases

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ZA955963B (en) 1997-01-20
CN1153473A (zh) 1997-07-02
NZ285158A (en) 2000-07-28
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AU2416995A (en) 1996-02-16
CA2195093A1 (en) 1996-02-01
CA2195213C (en) 2000-03-14
HUT77392A (hu) 1998-04-28
IL114586A (en) 2000-06-29
KR100212352B1 (ko) 1999-08-02
WO1996002242A1 (en) 1996-02-01
AU689257B2 (en) 1998-03-26
CN1076967C (zh) 2002-01-02
MX9700534A (es) 1997-04-30
KR100221854B1 (ko) 1999-09-15
JP2930424B2 (ja) 1999-08-03
WO1996002243A1 (en) 1996-02-01
US5441986A (en) 1995-08-15
FI970214A (fi) 1997-01-17
HU9700162D0 (en) 1997-03-28
MY113079A (en) 2001-11-30
AU694220B2 (en) 1998-07-16
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JPH09507860A (ja) 1997-08-12
IL114586A0 (en) 1995-11-27
MX9700538A (es) 1997-04-30
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