CN1153473A - 使用屈洛昔芬治疗心血管疾病 - Google Patents

使用屈洛昔芬治疗心血管疾病 Download PDF

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CN1153473A
CN1153473A CN95194200A CN95194200A CN1153473A CN 1153473 A CN1153473 A CN 1153473A CN 95194200 A CN95194200 A CN 95194200A CN 95194200 A CN95194200 A CN 95194200A CN 1153473 A CN1153473 A CN 1153473A
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罗兰·洛瑟
迈克尔·施里埃克
戴维·D·汤普森
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Abstract

使用屈洛昔芬治疗心血管疾病。

Description

使用屈洛昔芬治疗心血管疾病
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。
本发明涉及治疗心血管疾病的药物，其包含作为活性成分的具有如下化学式的屈洛昔芬：
Figure A9519420000031
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心血管疾病或血胆固醇过高的症状或疾病的方法，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。“心血管疾病”表示血胆固醇过高或动脉粥样硬化。“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。
本发明用于心血管疾病、血胆固醇过高或动脉粥样硬化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，活性成分可以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)。
与赋形剂组比较，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，而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
对总胆固醇水平的影响
本发明的化合物对血浆中总胆固醇水平的影响采用以下方法测定。麻醉的4-6月龄的雌性Sprague-Dawley鼠被双侧卵巢切除，用屈洛昔芬的柠檬酸盐(5毫克/公斤/天，口服)或赋形剂处理28天，或做假性手术，血样即从这些鼠心脏刺孔获取。血样置于含30微升5％EDTA中(10微升EDTA/1毫升血)。在20℃2500rpm转速下离心后，移出血浆并在-20℃下保存至分析。总胆固醇的分析采用标准酶测定药盒，该药盒来自Sigma Diagnostic，P.O.Box 14508，St。Louis MO 61378(Procedure No.352)。下表表明了屈洛昔芬的柠檬酸盐对总胆固醇的影响。当服用屈洛昔芬的柠檬酸盐后(5mg/kg/天，28天，口服)，血浆总胆固醇显著下降(相对于赋形剂处理的卵巢切除鼠降低30％)。
屈洛昔芬的柠檬酸盐对雌性鼠血浆总胆固醇水平的影响
 血浆胆固醇(mg/dl)  变化％，相对于假性手术＋赋形剂组  变化％，相对于卵巢切除＋赋形剂组
假性手术＋赋形剂组     57        -         -
卵巢切除＋赋形剂组     112     96     -
屈洛昔芬的柠檬酸盐(5mg/kg/天，28天，口服)     78     +36     -30
对雄性Sprague-Dawley鼠(3月龄)进行同样的试验，用赋形剂和屈洛昔芬的柠檬酸盐(10毫克/公斤/天，14天，口服)治疗处理假性手术和睾丸切除的鼠。如下表所示，屈洛昔芬的柠檬酸盐显著降低了血浆总胆固醇，相对于假性手术组降低48％，相对于睾丸切除的赋形剂处理的动物降低59％。
屈洛普芬的柠檬酸盐对雄性鼠血浆总胆固醇水平的影响
 血浆胆固醇(mg/dl)  变化％，假性手术＋赋形剂组  变化％，睾丸切除＋赋形剂组
假性手术＋赋形剂组     72      -      -
睾丸切除＋赋形剂组     91      -      -
屈洛昔芬的柠檬酸盐(10mg/kg/天，14天，口服)     37      -48      -59
这些数据表明屈洛昔芬的柠檬酸盐在治疗例如血胆固醇过高和动脉粥样硬化的心血管疾病方面是有效的。
实施例3
屈洛昔芬的柠檬酸盐片剂屈洛昔芬的柠檬酸盐        100克乳糖                      1190克低级取代的羟丙基纤维素    250克聚乙烯基吡咯烷酮          50克硬脂酸镁                  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 (5)

1、一种治疗良性前列腺增生的方法，包括给药于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盐。
2、一种治疗或预防心血管疾病的方法，包括给药于待治的哺乳动物一定量的有效治疗或预防所述心血管疾病的屈洛昔芬或其药学可接受盐。
3、权利要求2的方法，其中，所述心血管疾病为动脉粥样硬化。
4、权利要求2的方法，其中，所述心血管疾病为血胆固醇过高。
5、权利要求2的方法，其中，所述药学可接受盐为柠檬酸盐。
CN95194200A 1994-07-19 1995-05-26 使用屈洛昔芬治疗心血管疾病 Expired - Fee Related CN1076967C (zh)

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FI970215A (fi) 1997-01-17
KR100221854B1 (ko) 1999-09-15
US5902830A (en) 1999-05-11
MX9700538A (es) 1997-04-30
JP2930424B2 (ja) 1999-08-03
FI970215A0 (fi) 1997-01-17
CA2195093A1 (en) 1996-02-01
US5827892A (en) 1998-10-27
EP1029540A3 (en) 2001-05-16
EP1029540A2 (en) 2000-08-23
NZ285158A (en) 2000-07-28
WO1996002242A1 (en) 1996-02-01
MY113079A (en) 2001-11-30
ZA955964B (en) 1997-01-20
US5852059A (en) 1998-12-22
AU2417095A (en) 1996-02-16
CA2195213A1 (en) 1996-02-01
JPH09507860A (ja) 1997-08-12
ZA955963B (en) 1997-01-20
MX9700534A (es) 1997-04-30
US5441986A (en) 1995-08-15
IL114586A0 (en) 1995-11-27
FI970214A0 (fi) 1997-01-17
HU9700163D0 (en) 1997-03-28
AU689257B2 (en) 1998-03-26
NZ285159A (en) 2000-10-27
KR100212352B1 (ko) 1999-08-02
KR970704429A (ko) 1997-09-06
EP0769941A1 (en) 1997-05-02
IL114586A (en) 2000-06-29
AU2416995A (en) 1996-02-16
KR970704430A (ko) 1997-09-06
CN1076967C (zh) 2002-01-02
IL114585A (en) 2000-01-31
WO1996002243A1 (en) 1996-02-01
HUT77391A (hu) 1998-04-28
CA2195213C (en) 2000-03-14
IL114585A0 (en) 1995-11-27
HUT77392A (hu) 1998-04-28
AU694220B2 (en) 1998-07-16
EP0771194A1 (en) 1997-05-07
JPH09507859A (ja) 1997-08-12
FI970214A (fi) 1997-01-17
HK1000697A1 (en) 2002-05-10
TW403649B (en) 2000-09-01
CA2195093C (en) 2000-03-07
HU9700162D0 (en) 1997-03-28
CN1152868A (zh) 1997-06-25

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