CN1431899A - 提供抗雄激素作用和抗雌激素作用的比卡鲁胺和他莫昔芬的药物组合 - Google Patents
提供抗雄激素作用和抗雌激素作用的比卡鲁胺和他莫昔芬的药物组合 Download PDFInfo
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- CN1431899A CN1431899A CN01809881A CN01809881A CN1431899A CN 1431899 A CN1431899 A CN 1431899A CN 01809881 A CN01809881 A CN 01809881A CN 01809881 A CN01809881 A CN 01809881A CN 1431899 A CN1431899 A CN 1431899A
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
- A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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Abstract
本发明涉及一种包含4′-氰基-α′,α′,α′-三氟-3-(4-氟苯基磺酰基)-2-羟基-2-甲基丙酰基-间-苯甲胺(化合物I)和他莫昔芬的药品、日剂量或剂量方案。该药品包括25至350∶0.5至100的化合物I和他莫昔芬。本发明还涉及一种为病人提供抗雄激素作用和抗雌激素作用的方法,其中所提供的抗雌激素作用基本不会造成循环雄激素的额外增加。
Description
本发明涉及一种包含4′-氰基-α′,α,α′-三氟-3-(4-氟苯基磺酰基)-2-羟基-2-甲基丙酰基-间-苯甲胺和他昔莫芬的药学产品,日剂量或剂量方案。本发明还涉及一种为病人提供抗雄激素作用和抗雌激素作用的方法,其中所提供的抗雌激素作用基本上不会造成循环雄激素水平的额外增加。此外,本发明涉及4′氰基-α′,α,α′-三氟-3-(4-氟苯基磺酰基)-2-羟基-2-甲基丙酰基-间-苯甲胺和他莫昔芬在用于此目的的药学产品的制造中的应用。
本发明的背景技术
比卡鲁胺,一种非甾体抗雄激素药,是4′-氰基-α′,α,α′-三氟-3-(4-氟苯基磺酰基)-2-羟基-2-甲基丙酰基-间-苯甲胺的消旋体并且通过AstraZeneca的商品名CASODEXTM而已知。EP-100172公开了作为列在实施例6的表中第8个化合物的4′-氰基-α′,α,α′-三氟-3-(4-氟苯基磺酰基)-2-羟基-2-甲基丙酰基-间-苯甲胺(在EP-100172中的名称为4-氰基-3-三氟甲基-N-(3-对-氟苯基磺酰基-2-羟基-2-甲基丙酰基)苯胺)。其相应的结构如式I所示:
4′-氰基α′,α,α′-三氟-3-(4-氟苯基磺酰基)-2-羟基-2-甲基丙酰基-间-苯甲胺可以以不同的R-和S-对映异构体的形式存在。R-对映异构体是(-)异构体并且是在体内具有药理活性的化合物。对映异构体的详细情况,可以参考Tucker和Chesterton,J.Med.Chem.31,pp885-887(1988)。EP-100172公开了(没有实例支持)包含4-氰基-3-三氟甲基-N-(3-对-氟苯基磺酰基-2-羟基-2-甲基丙酰基)苯胺的药物组合物与“一种或几种选自抗雌激素的药物,例如他昔莫芬;芳香酶抑制剂,例如睾内酯或氨基导眠能;孕激素,例如醋酸甲羟孕酮;促性腺激素分泌抑制剂,例如炔睾醇;LH-RH-类似物,例如布舍瑞林;细胞毒性物质,例如环磷酰胺;抗生素,例如青霉素或土霉素;和抗炎药物,例如,尤其是局部应用时,氟轻松”合用。
他昔莫芬,一种抗雌性激素药物,通过AstraZeneca的商品名NOLVADEXTM而已知。他莫昔芬是1-(对-β-二甲基氨基乙氧基苯基)-1,2-二苯基丁-1-烯,它在US-4,536,516中被公开。其另外一个名称是(Z)-2-[对-(1,2-二苯基丁-1-烯基)苯氧基乙基二甲基胺。其相应的结构如式II所示:
比卡鲁胺能可与促性腺激素分泌抑制剂结合用于治疗前列腺癌,其中所说的促性腺激素分泌抑制剂例如促黄体生成激素释放激素(LHRH)激动剂如性瑞林、布舍瑞林、亮丙瑞林或曲普瑞林。B J A Fuxr等人,
Urology,1996,
47(Suppl.1A),13-25,和G J C Kolvenbag等人,
Urology,1996,
47(Suppl.1A),70-79,对比卡鲁胺作为抗雄激素的性质和应用进行了综述。
已经注意到用比卡鲁胺单独给药对人进行治疗会引起血液循环中的睾酮数量增加。Blackledge等人,(Urology,1996,47,Suppl.1A),第44-47页)公开了总睾酮的基础水平的约两倍。认为当有足够的抗雄性激素能够进入CNS并阻断丘脑下部的雄激素受体时,就会发生睾酮水平的这种增加。随后的雄激素反馈不足又引起丘脑下部LHRH的额外释放,这又引起脑垂体黄体生成激素(LH)和促卵泡激素(FSH)的释放以及睾丸睾酮的释放。在脂肪及其它组织中的芳香酶将睾酮增加的浓度中的一些转化成雌二醇,这就导致了血液中雌激素浓度的增加。C Mahler等人,Clinical Pharmacokinetics,1998,34(5),第405-417页对此进行了进一步的讨论。
这就产生了一种不良作用。即循环雌激素水平的增加可引起一种或多种男性乳房发育、胸部触痛、热潮红、阳痿和性欲下降的副作用。就男性乳房发育的讨论可见C J Tyrrell,Prostate and ProstaticDiseases,1999,2(4):第167-171页。
正如上面所解释的那样,睾酮和LH水平趋向于增加。Mahler等人解释说增加雌激素水平会逐渐激活正常反馈机制,并且因此LH和睾酮的增加是有限的。在现有技术中广泛认为雌激素水平在控制LH分泌中是十分重要的,并且通过这种方式睾酮分泌,这一点正如Mahler等人所提出的。大量出版物清楚表明给男性和雄性动物服用抗雌激素药物会减少雌激素对下丘脑-垂体轴的负反馈作用,从而导致黄体生成激素(LH)分泌增加。这又使得睾丸产生数量增多的睾酮。在这方面,参考文献参见F H Comhaire等人,Human Reproduction,1995,10(7),第1740-1744页,其中报道成年男性摄取他莫昔芬以增加睾酮和LH。
JJ Spijkstra等人,J.Clinical Endocrinology and Metabolism,1988,66(2),第355-360页,报道了用13名正常男性进行的在服用他莫昔芬前和服用6个星期后的LH分泌研究。在进行他昔莫芬给药后,会观测到平均血清睾酮、雌二醇、LH水平、LH脉冲频率和LH脉冲振幅增加。在给男性服用抗雌激素药物克罗米酚柠檬酸盐后可得到类似的结果。Spijkstra等人提出用他昔莫芬所观测到的结果是由于对垂体雌激素受体负反馈的抑制而造成的。
DI Lewis-Jones等人,Andrologia1987,19(1):第86-90页报道,给男性服用他昔莫芬会升高LH、雌二醇“和尤其是睾酮......的基础血清水平。通过服用他昔莫芬而产生的血清中睾酮水平的显著升高可能是比用其它药理物质如1-甲氢睾酮来升高雄激素水平的方法更成功的方法。”
L van Bergeijk等人,Horm.Metabol.Res.,1986,第558-564页,报道对正常促性腺(normogonadotrophic)精子减少的男性用他昔莫芬治疗三个月能刺激基础LH、FSH和睾酮水平。他们提出雌激素在促性腺激素释放的负反馈调节中扮演了一个角色。
因此,在现有技术中对使用抗雌激素药物来对抗当给男性服用抗雄激素药物时观测到的雌激素水平增加存在着偏见。这是因为由于先前大量的报道,会使人们认为抗雌激素药物会产生LH和睾酮的大量增加,这反过来又能预期的抵消抗雄激素的抗雄激素作用。
因此需要能提供抗雄激素作用并能对抗雌激素水平升高的治疗,从而能抑制男性乳房发育、胸部触痛、热潮红、阳痿和性欲下降的副作用,而基本不造成上述的由于单独使用抗雄激素药物而产生的循环雄激素水平额外增加。
本发明概述
本发明通过提供一种给病人服用的能为病人提供抗雄激素作用和抗雌激素作用的药品满足了这种需要,该产品包括式I的化合物或其可药用的盐或溶剂化物和他莫昔芬或其可药用的盐或溶剂化物,其中式I的化合物和他莫昔芬的比例分别为25至350∶0.5至100。他莫昔芬优选以其柠檬酸盐的形式被应用。
作为本发明的一个结果,所提供的抗雌激素作用基本不造成循环雄激素水平的额外增加。这时,我们希望病人的雄激素水平(例如,用血液中的总或游离睾酮表示)的增加基本不超过上面所述的当给病人只服用抗雄激素药物时常常观测到的水平。
本发明还提供了一种给病人服药以给病人提供抗雄激素作用和抗雌激素作用的每日给药剂量,该剂量包括式I的化合物或其可药用的盐或溶剂化物和0.5至100mg的他莫昔芬或其可药用的盐或溶剂化物。
此外,本发明提供了达到该目的的剂量方案,该方案包括给病人同时或相继服用式I的化合物或其可药用的盐或溶剂化物(例如150mg的量)和0.5至100mg的他莫昔芬或其可药用的盐或溶剂化物。
在另一方面,本发明提供了一种给病人服用为病人提供抗雄激素作用和抗雌激素作用的药品,该产品包括式I的化合物或其可药用的盐或溶剂化物和他莫昔芬柠檬酸盐。
本发明的其它方面涉及为了同时或相继给药,式I的化合物或其可药用的盐或溶剂化物和他莫昔芬或其可药用的盐或溶剂化物在药品的制造中的应用,该药物用于;
(a)给病人提供一种抗雄激素作用和抗雌激素作用,其中所提供的抗雌激素作用基本不造成循环雄激素水平的额外增加;或
(b)给病人提供一种抗雄激素作用并抑制男性乳房发育、胸部触痛、热潮红、阳痿和性欲下降副作用的发病率或严重程度的增加,基本不造成循环雄激素水平的额外增加。
通过“抑制副作用的发病率或严重程度的增加”,我们希望提供一种比单独给药用抗雄激素药物时产生的副作用的发病率或严重程度更低的副作用发病率或严重程度,或消除该副作用。
本发明进一步提供了一种给病人提供抗雄激素作用的方法,该方法包括给病人同时或相继服用式I的化合物或其可药用的盐或溶剂化物和他莫昔芬或其可药用的盐或溶剂化物,其中该方法进一步向病人提供了一种基本不引起循环雄激素水平额外增加的抗雌激素作用。
本发明的详细描述
我们现在令人吃惊的发现,在病人体内既可以产生抗雄激素作用,又可以产生抗雌激素作用,其中所提供的抗雌激素作用基本不引起循环雄激素水平的额外增加。这一点可以通过给病人服用包含式I的化合物或其可药用的盐或溶剂化物和他莫昔芬或其可药用的盐或溶剂化物的产品来达到,其中式I的化合物和他莫昔芬的使用比例分别为25至350(优选的该范围的较低端点为50,优选的该范围的较高端点为300、150或50;在该范围内适宜的值为150或50):0.5至100(优选的该范围的较低端点为1或5,优选的该范围的较高端点为40、20或10;在该范围内适宜的值为20)。“产品”的定义指的是式I的化合物和他莫昔芬的混合物(例如,包含这两种化合物的胶囊或片剂的产品)或包括分开的一定量化合物的试剂盒(例如,一组他莫昔芬片剂和另外一组其它化合物的片剂)。后面的产品可用于将化合物同时或相继(即短暂时间间隔)给予病人,而预先混合的化合物适用于同时给药。诸如每种物质的吸收速率、代谢和排泄速率等因素都会影响它们在肿块部位的存在。当医生在为了得到有利作用而需要用两种物质结合给药进行治疗时,他一般会考虑这类因素,并且这一判断一般是医生周知的常用技能。
式I的化合物被用于提供抗雄激素作用,在该作用中这种化合物阻断了雄激素的活性。他莫昔芬被用于提供抗雌激素作用,在该作用中这种化合物预防了雌激素活性。
抗雄激素作用能用于治疗癌症,例如前列腺癌。特定实例是晚期前列腺癌和早期前列腺癌。为了减少病人前列腺癌发生的危险,该抗雄激素作用可被用于预防。这对于基因倾向于前列腺癌的男性特别有用。可用一般的方法根据其患前列腺癌的危险将病人进行分类,其中所说的一般方法例如通过家族史的评估和对特定血液蛋白如前列腺特定抗原(PSA)的超时测定。对抗雄激素作用的其它应用包括前列腺非恶性疾病(例如,良性前列腺增生或肥大)和痤疮的治疗。
抗雌激素作用能用于抑制男性乳房发育、胸部触痛、热潮红、阳痿、性欲下降、恶心、呕吐、疲劳和腹泻的副作用的发病率或严重程度的增加。在用抗雄激素单独治疗时可观察到该类副作用。优选地,该类副作用是男性乳房发育和胸部触痛中的一种或两种。
适合的剂量方案或每天药物剂量包含式I的化合物或其可药用的盐或溶剂化物和0.5至100mg的他莫昔芬或其可药用的盐或溶剂化物。优选的,该范围内他莫昔芬的较低端点值为1或5mg;优选的该范围的较高端点值为40、20或10mg;该范围内的适宜值为20mg。该剂量或方案优选地包含25至350mg的式I的化合物或其可药用的盐或溶剂化物。优选的,该范围内的较低端点值为50mg;优选的该范围的较高端点值为300、150或50mg;该范围内的适宜值为150或50mg。
对于该方案而言,每一化合物优选的被每天给药。另一种可能的方案是式I的化合物交替给药并且他莫昔芬也交替(相同或不同)给药。为此,该方案可包括给药说明。优选地,式I的化合物的剂量被每隔3、4、5、6或7天给药并且他莫昔芬每隔3、4、5、6或7天给药(例如,与式I的化合物在同一天)。
在本发明的一个实施方案中,式I的化合物由其90至100%的R-对映异构体和10至0%的S-对映异构体组成。在优选的实施方案中,使用100%的R-对映异构体。
在另一个实施方案中,式I的化合物由其R和S-对映异构体的外消旋混合物组成。
病人可以是男性病人,例如成人,但是也适用于其它哺乳动物(大鼠除外)的治疗。
本发明的产品、剂量和方案可以以适用于口服(例如片剂、胶囊剂、水性或油性混悬液、乳剂或可分散粉末或颗粒)、局部应用(例如霜剂、药膏、凝胶、或水性或油性溶液或混悬液;例如用于经皮膏药中)、非胃肠道给药(例如静脉、皮下、肌肉或血管内给药的无菌水性或油性溶液或混悬液)的形式被应用,或以直肠给药栓剂的形式被应用。优选的本发明的组合物以适于口服应用的形式被使用,例如片剂或胶囊剂。
本发明的产品、剂量和方案可以使用一般的现有技术中众所周知的可药用的稀释剂或载体通过常用的方法获得。
用于片剂制剂的适宜的可药用的稀释剂或载体包括,例如惰性稀释剂,如玉米淀粉或海藻酸;粘合剂如明胶或淀粉;润滑剂如硬脂酸镁、硬脂酸或滑石粉;防腐剂如乙基或丙基对-羟基苯甲酸酯,和抗氧剂,如抗坏血酸。为了改变其崩解及随后活性物质在胃肠道内的吸收,或改善其稳定性或外观,该片剂可以是未包衣或包衣的片剂,在两种情况中都使用现有技术中众所周知的包衣物质和方法。
用于口服的组合物可以是硬明胶胶囊的形式,在这种形式中将活性成分与惰性固体稀释剂混合,其中所说的惰性稀释剂例如碳酸钙、磷酸钙或高岭土,用于口服的组合物还或者可以是软胶囊的形式,在这种形式中活性成分与水或油例如花生油、液体石蜡或橄榄油混合。
当我们提到提供一种不引起循环雄激素水平额外增加的抗雌激素作用时,我们指的是病人的雄激素水平(例如,用血液中的总或游离睾酮表示)基本不高于上面所述的当单独使用抗雄激素对病人进行给药时观察到的最大水平。用下面给出的人的临床试验进行说明。
人的临床试验
用下面的临床试验来测定CASODEXTM与NOLVADEXTM结合给药6星期对健康男性志愿者游离睾酮水平的影响。
方案
主要包含标准:男性,65岁或65岁以上,在常规血液学和生物学检验中在临床没有表现出显著异常并且具有在正常限度内的内分泌和前列腺特定抗原结果。
主要排除标准:以前用CASODEXTM进行过临床试验中;用除对乙酰氨基酚外的任何药物同时进行治疗;曾有过或正存在任何的睾丸异常;曾患有或正患有胃肠道、肝或肾疾病,或具有其它已知能干扰药物吸收、分布、代谢或排泄的情况;在试验开始前2周内患有重大的临床疾病;确定或怀疑有严重的个人或家族不良药物反应史或对CASODEXTM或NOLVADEXTM有任何过敏性;在之前3个月内用任何一种已经确认可能具有肝毒性或肝干扰作用的药物进行过治疗。
剂量:CASODEXTM以每天150mg的剂量给药,NOLVADEXTM以每天20mg的剂量给药。所有的治疗都采用片剂形式并每天给药一次。每天用CASODEXTM加NOLVADEXTM进行治疗,持续治疗6周,选择这段治疗时间作为获得药物稳态血浆浓度的最小时间。另一志愿者组只服用CASODEXTM,日剂量为150mg,连续服药4周。所有的治疗都采用片剂的形式,并且每天服用一次。
主要评估:在试验期间测定游离睾酮浓度。
结果
在治疗期间游离睾酮浓度的概况见表1(CASODEXTM与NOLVADEXTM合用),表2是单独使用CASODEXTM的情况。
表1用CASODEX TM 加NOLVADEX TM 进行治疗后的游离睾酮浓度参数 第1天 第8天 第22天 第43天 跟踪检测睾酮(nmol/l)N 7 7 7 7 7gmeam 0.045 0.059 0.077 0.063 0.056CV 11.970 18.628 34.582 34.303 22.686最小值 0.04-0.05 0.05-0.08 0.04-0.10 0.04-0.09 0.04-0.07与第1天 - 1.30 1.69 1.38 1.23的比
CV=变异系数 gmean=几何平均值 n=观测数
在给药前将第1天的样本抽出,将其作为基础测定值。
用CASODEXTM加NOLVADEXTM的治疗组没有志愿者经历过男性乳房发育。
表2单独用CASODEX
TM
进行治疗后的游离睾酮浓度
参数 第1天 第29天
睾酮
(nmol/l)
n 7 7
gmeam 0.048 0.076
CV 30.415 26.219
最小值 0.03-0.07 0.00-0.12
与第1天的比 - 1.58
CV=变异系数 gmean=几何平均值 n=观测数
在给药前将第1天的样本抽出,将其作为基础测定值。
结论
当CASODETM单独给药时,在治疗结束时平均睾酮浓度增加58%。用CASODEXTM连续给药超过第4周时,这一数值会预期的升高(相当于平均总睾酮浓度的约2倍)。在这一方面,可参见由Verhelst,J等人所报道的试验(“在前列腺癌中服用新型非甾体抗雄激素药物卡索地的内分泌图线”,Verhelst,J等人,Clin.Endocrinol。(0xf)1994,Oct.,41(4),第525-30页),该试验报道在用CASODEXTM以每天150mg的剂量单独给药24周后,平均游离睾酮浓度增加57%。
表1表明NOLVADEXTM与CASODEXTM共同给药在临床上不产生游离睾酮浓度的额外显著变化。实际上,在治疗结束时平均浓度的增加为38%。
因此,该结果支持了我们在本发明中令人吃惊的发现,即他莫昔芬并不抵消式I化合物的抗雄激素药物的抗雄激素作用,与本领域技术人员根据现有技术所作出的前述偏见性的看法相反,使用他莫昔芬并不会造成雄激素水平额外增加超出当抗雄激素药物单独应用时所预期的水平。
Claims (11)
1.用于给病人给药以为病人提供抗雄激素作用和抗雌激素作用的药品,该药品包含式I的化合物或其可药用的盐或溶剂化物和他莫昔芬或其可药用的盐或溶剂化物,其中式I的化合物和他莫昔芬的使用比例分别为25至350∶0.5至100。
2.一种给病人给药以为病人提供抗雄激素作用和抗雌激素作用的每日药物剂量,该剂量包括式I的化合物或其可药用的盐或溶剂化物和0.5至100mg的他莫昔芬或其可药用的盐或溶剂化物。
3.一种给病人提供抗雄激素作用和抗雌激素作用的剂量方案,该方案包括给病人同时或相继服用式I的化合物或其可药用的盐或溶剂化物和0.5至100mg的他莫昔芬或其可药用的盐或溶剂化物。
4.如权利要求2所述的剂量,或如权利要求3所述的方案,包括25至350mg的式I的化合物或其可药用的盐或溶剂化物。
5.一种为病人提供抗雄激素作用和抗雄激素作用的剂量方案,该方案包括给病人同时或相继服用150mg式I的化合物或其可药用的盐或溶剂化物和0.5至100mg的他莫昔芬或其可药用的盐或溶剂化物。
6.用于给病人给药以为病人提供抗雄激素作用和抗雌激素作用的药品,该药品包含式I的化合物或其可药用的盐或溶剂化物和他莫昔芬柠檬酸盐。
7.在给病人同时或相继给药的药品的制造中式I的化合物或其可药用的盐或溶剂化物和他莫昔芬或其可药用的盐或溶剂化物的的应用,该药品用于为病人提供抗雄激素作用和抗雌激素作用,其中所提供的抗雌激素作用基本不造成循环雄激素水平的额外增加。
8.在给病人同时或相继给药的药品的制造中式I的化合物或其可药用的盐或溶剂化物和他莫昔芬或其可药用的盐或溶剂化物的应用,该药品用于为病人提供抗雄激素作用并抑制男性乳房发育、胸部触痛、热潮红、阳痿和性欲下降的副作用中至少一种副作用的发病率或严重程度,基本不造成循环雄激素水平的额外增加。
9.一种为病人提供抗抗雄激素作用的方法,该方法包括给病人同时或相继服用式I的化合物或其可药用的盐或溶剂化物和他莫昔芬或其可药用的盐或溶剂化物,其中该方法进一步为病人提供了一种基本不造成循环雄激素水平额外增加的抗雌激素作用。
10.前面任意一项权利要求所述的产品、剂量、方法、应用或方案,其中式I的化合物由其90至100%的R-对映异构体和其10至0%的S-对映异构体组成。
11.权利要求1至9中任意一项权利要求所述的产品、剂量、方案、应用或方法,其中式I的化合物由其R-和S-对映异构体的外消旋混合物组成。
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US20060269611A1 (en) * | 2001-11-29 | 2006-11-30 | Steiner Mitchell S | Prevention and treatment of androgen-deprivation induced osteoporosis |
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US20080249183A1 (en) * | 2001-11-29 | 2008-10-09 | Steiner Mitchell S | Treatment of androgen-deprivation induced osteoporosis |
US20070197664A1 (en) * | 2001-11-29 | 2007-08-23 | Steiner Mitchell S | Prevention and treatment of androgen-deprivation induced osteoporosis |
US20050080143A1 (en) * | 2001-11-29 | 2005-04-14 | Steiner Mitchell S. | Treatment of androgen-deprivation induced osteoporosis |
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WO2001089515A1 (en) | 2001-11-29 |
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HUP0302276A3 (en) | 2005-06-28 |
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