CN104524580A - 3-α-雄甾烷二醇结合PDE5抑制剂在治疗性功能障碍中的应用 - Google Patents
3-α-雄甾烷二醇结合PDE5抑制剂在治疗性功能障碍中的应用 Download PDFInfo
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- CN104524580A CN104524580A CN201410844093.6A CN201410844093A CN104524580A CN 104524580 A CN104524580 A CN 104524580A CN 201410844093 A CN201410844093 A CN 201410844093A CN 104524580 A CN104524580 A CN 104524580A
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Abstract
本发明提供了3-α-雄甾烷二醇结合PDE5抑制剂在治疗性功能障碍中的应用。本发明涉及男性和/或女性性功能障碍领域。本发明特别涉及3-α-雄甾烷二醇、优选结合5型磷酸二酯酶(PDE5)抑制剂的应用。
Description
本申请为申请日为2007年11月2日，申请号为200780046242.2，发明名称为“3-α-雄甾烷二醇，可选地结合PDE5抑制剂在治疗性功能障碍中的应用”的发明专利申请的分案申请。
技术领域
本发明涉及男性和/或女性性功能障碍的领域。本发明特别涉及3-α-雄甾烷二醇，优选结合5型磷酸二酯酶(PDE5)抑制剂在需要时的应用。
背景技术
男性性功能障碍(MSD)是指男性性功能的各种障碍或缺陷(衰退)，包括性欲抑制(或性欲不振，ISD)、勃起功能障碍(ED)或阳痿和早泄(PE，也称为快速射精、提前射精、或射精过早)和性快感缺失。利用PDE5抑制剂，如西地那非(sildenafil)、伐地那非(vardenafil)和他达那非(tadalafil)可成功地治疗ED。目前对PE的成功治疗包括降低阴茎感觉的麻醉霜(如利多卡因、丙胺卡因及它们的组合)和SSRI抗抑郁剂，如帕罗西汀、氟西汀和舍曲林。但是对于ISD，目前还没有已知的成功的药物治疗方法。
女性性功能障碍(FSD)是指性功能的各种障碍或缺陷，包括对性活动缺乏兴趣、在获得或保持性冲动上反复失败、充分唤起后不能达到性高潮。近期研究估计美国有43％的女性患有性功能障碍[1]。低性欲(22％患病率)和性唤起问题(14％患病率)属于女性性功能障碍的最常见类型。这些类型便于研究人员和临床医学家给出可行性定义和可普遍采纳的专业词汇。然而，认定这些疾病(或障碍)彼此完全无关可能是不正确的。病例研究和流行病学研究都证明这些疾病(或障碍)可以交叠也可能相互独立。在某些情况中，确定导致其他疾病的原发疾病(primary disorder)是可能的，但在许多情况下，这却是不可能的。
US 6,242,436B1中描述了作为雄激素补充疗法(androgenrepletion therapy)的替代品并用于人类体内雄激素减少/耗损相关问题的3-α-雄甾烷二醇。所描述的该替代的目的在于通过给予3-α-雄甾烷二醇来补充双氢睾酮(DHT)的亚生理血清浓度。而且，根据US 6,242,436B1，减少雄激素减少/耗损相关问题的作用机理在于补充(DHT)。雄激素耗损能够减少性冲动。然而，性冲动减少通常不是由异常的雄激素浓度引起的。
为了治疗男性和/或女性性失调，建议并采用了多种不同的疗法，成功程度或大或小。例如WO 2005/107810描述了睾酮和5型磷酸二酯酶(PDE5)抑制剂的应用，其组分必须就性活动以一定的顺序并在一段时间范围内释放。虽然该疗法提供了有前景的结果，但人们认为所采用的时间范围在性活动的期望情境中为不期望地过长。而且，WO 2005/107810中描述的疗法有些复杂，因为依赖于活性成分的剂型，活性成分必须以一定顺序和/或时间范围内给予。对于不能非常精确地在正确的时间点服用正确的活性成分的人，可能不能达到或仅部分达到治疗性功能障碍的目的。
发明内容
本发明披露了给予3-α-雄甾烷二醇可诱导患有MSD的男性和患有FSD的女性增加性冲动和增加对性暗示的注意力。这些给予3-α-雄甾烷二醇的受用者(dependant)冲动增加，而注意力与先前的生理雄激素浓度无关；给予3-α-雄甾烷二醇同样会增加具有正常(即，生理)或具有亚生理雄激素水平的男性和女性的性冲动和对性暗示的注意力。
本发明进一步披露了可通过应用3-α-雄甾烷二醇(与舌下睾酮相比)和PDE5抑制剂使摄入活性成分与性活动之间的时间范围缩短。而且，在一种实施方式中，活性成分可以在同一时间点给予，因此将忘记服用或未及时服用某种成分的风险降至最低。所获得的结果与WO2005/107810中描述的化合物获得的结果相当。这是令人惊讶的，因为与睾酮相比，3-α-雄甾烷二醇是弱得多的雄激素，而且还因为有人指出3-α-雄甾烷二醇对不同受体，GABAA受体[2]有影响(还是与睾酮相比)。3-α-雄甾烷二醇相比睾酮的其他优点是具有较低的雄性化(masculinisation)副作用，并具有较低的致癌风险，这是因为没有给予睾酮因此睾酮不会被还原为雌二醇。
具体实施方式
在第一种实施方式中，本发明提供了3-α-雄甾烷二醇在制备用于治疗性功能障碍的药物中的应用。术语“性功能障碍”是指男性和/或女性性功能障碍。
3-α-雄甾烷二醇也称为5α-雄甾烷3α,17β-二醇，是睾酮代谢物中的一种。睾酮可以通过5α-还原酶而转化为5α-双氢睾酮(DHT)。然后DHT通过3α-羟基类固醇脱氢酶(也称为3-氧化还原酶和3α-羟基类固醇-氧化还原酶，以下称为3α-HSD还原酶)进一步转化为3-α-雄甾烷二醇。从睾酮转化为DHT是单向的；DHT转化为3-α-雄甾烷二醇是双向的：3α-HSD氧化酶也可将3-α-雄甾烷二醇转化为DHT。3α-HSD还原酶/氧化酶的平衡看起来是通过循环甾类激素而自动调节的，该甾类激素例如是睾酮、DHT和3-α-雄甾烷二醇以及雌二醇、生长激素和应激相关的糖皮质激素[3]。存在3α-HSD还原酶的三种人类同种型，其中的两种也存在于脑中(h3α-HSD2和h3α-HSD3，也称为AKR 1C2和AKR 1C3)。
根据本发明，游离3-α-雄甾烷二醇的水平应优选峰值血浆水平为正常血清水平的至少10-100倍、优选5-100倍[4](即，对于女性为0.6-6ng/l且优选0.3-6ng/l而对于男性为2.2-22ng/l且优选1.1-22ng/l)，这通常出现在给予3-α-雄甾烷二醇后的1至60分钟之间。
3-α-雄甾烷二醇优选以在所给予的受治疗者的血液循环中3-α-雄甾烷二醇急剧并快速增加的剂型给予。因此本发明提供了一种应用，其中3-α-雄甾烷二醇以舌下剂型(sublingual formulation)的形式提供，例如包括环糊精作为载体的舌下剂型。合适的给予途径的另一个实例是颊-粘膜(buco-mucosally)或鼻粘膜内给予，这也可通过采用环糊精剂型或其他常用的赋形剂、稀释剂等进行。剂型的典型实例是以羟丙基-β环糊精给出的，但其他的β环糊精和其他常用的赋形剂、稀释剂等也在用于制备包括3-α-雄甾烷二醇的剂型(其在一个短爆发期(short burst)内释放基本上全部的3-α-雄甾烷二醇)的领域的技术范围内。所述爆发通常是在给予后的短时间间隔内(例如在60-120秒内，更优选在60秒内)，导致约1-60分钟后3-α-雄甾烷二醇达到血液峰值水平，并从施用时间起持续至少180分钟。
循环中的3-α-雄甾烷二醇被SHBG(甾类激素结合球蛋白)和白蛋白结合。重要的是，如本发明中所限定的3-α-雄甾烷二醇的峰值血浆水平是存在的并且以游离的3-α-雄甾烷二醇计算，游离的3-α-雄甾烷二醇恰好就是没有被白蛋白和SHBG结合的一部分。因此，3-α-雄甾烷二醇的剂量应足够高以使白蛋白和SHBG饱和(即，3-α-雄甾烷二醇的浓度必须足够高从而克服3-α-雄甾烷二醇被SHBG或白蛋白完全结合)，或者必须设计另一种方式以避免与白蛋白或SHBG结合，例如采用针对SHBG上3-α-雄甾烷二醇结合位点的竞争物(competitor)。
与基于3-α-雄甾烷二醇的其他性功能障碍疗法相比，本文中所述的应用(和方法)旨在暂时增加治疗对象体内的3-α-雄甾烷二醇水平。其他方法旨在恢复/替代/补充3-α-雄甾烷二醇水平(或其代谢物，如DHT的水平)到如正常受治疗者体内测定的正常(即，生理)水平。在一种优选的实施方式中，施用3-α-雄甾烷二醇，使得在所给予的受治疗者的血液循环中获得3-α-雄甾烷二醇的较短持续时间(几个小时)超生理峰值。然后，该水平返回到基线(即，给药前的水平)。
在第二种实施方式中，本发明提供了3-α-雄甾烷二醇和5型磷酸二酯酶(PDE5)抑制剂在制备用于治疗性功能障碍的药物中的应用。术语“性功能障碍”是指男性和/或女性性功能障碍。
如上所述，与目前的疗法相关的问题之一是活性成分的摄入和性活动之间的长时间延迟。通过本发明的3-α-雄甾烷二醇的实施方式，时间延迟从约4小时缩短到约1小时。这导致减少了约3小时。
多种PDE5抑制剂是可用的。PDE5抑制剂的一个实例是盐酸伐地那非，其被化学命名为哌嗪,1-[[3-(1,4-二氢-5-甲基-4-氧代-7-丙基咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基苯基]磺酰基]-4-乙基-,单盐酸盐。除了活性成分之外，每片盐酸伐地那非还含有微晶纤维素、交聚维酮、胶态二氧化硅、硬脂酸镁、羟丙甲纤维素、聚乙二醇、二氧化钛、黄氧化铁、和红氧化铁。另一个实例以枸橼酸西地那非给出，其被化学命名为1-[[3-(6,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)-4-乙氧苯基]磺酰基]-4-甲基哌嗪枸橼酸盐。除了活性成分之外，每片枸橼酸西地那非还含有以下成分：微晶纤维素、无水磷酸氢钙、交联羧甲基纤维素钠、硬脂酸镁、羟丙基甲基纤维素、二氧化钛、乳糖、甘油醋酸酯、和FD&C蓝色#2铝色淀。其他的实例为他达那非(他达拉非)，其化学命名为吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-1,4-二酮,6-(1,3-苯并二噁茂-5-基)-2,3,6,7,12,12a-六氢-2-甲基-,(6R,12aR)-。除了活性成分之外，每片他达那非还含有以下成分：交联羧甲基纤维素钠、羟丙基纤维素、羟丙甲纤维素、氧化铁、乳糖一水合物、硬脂酸镁、微晶纤维素、硫酸月桂酯钠、滑石、二氧化钛、和甘油醋酸酯。
PDE5抑制剂的数目仍在增加，且其他非限制性实例是：E-4021、E-8010、E-4010、AWD-12-217(苯氮嘌呤酮(扎普司特，zaprinast))、AWD 12-210、UK-343,664、UK-369003、UK-357903、BMS-341400、BMS-223131、FR226807、FR-229934、EMR-6203、Sch-51886、IC485、TA-1790、DA-8159、NCX-911或KS-505a或在WO 96/26940中披露的化合物。
技术人员明了的是，优选给予/释放活性成分，以便它们的峰值效果(即，它们的活性)至少部分重叠/重合，并优选完全重叠。对于睾酮和3-α-雄甾烷二醇，峰值效果意味着对性欲刺激的注意力和性冲动的最大限度的增加。对于PDE5抑制剂，峰值效果是自律神经系统的NANC(非肾上腺素能非胆碱能)路径的活性的最大限度的增加。该目标可通过采用不同策略而实现。下面提供一个非限制性实例。
在一种优选的实施方式中，所述3-α-雄甾烷二醇和所述PDE5抑制剂基本同时释放。术语“基本同时”应理解为意指优选3-α-雄甾烷二醇和PDE5抑制剂在30分钟内、优选在25-30分钟内、更优选在20-25分钟内，甚至更优选在15-20分钟或10-15分钟内在治疗对象体内彼此达到它们的峰值血清水平，并且最优选这两种化合物彼此在0至10分钟内在受治疗者体内释放。
如上文所概述的，为了实现3-α-雄甾烷二醇和PDE5抑制剂的最优效果，期望两种化合物的峰值效果重叠。然而，即使峰值效果仅部分重叠，也仍会带来所需的效果(例如，治疗FSD)。对于3-α-雄甾烷二醇的生效，有约1-60分钟的时间滞后(而口服3-α-雄甾烷二醇会更加延长该时间滞后)，且3-α-雄甾烷二醇的效果持续约3小时。PDE5抑制剂(如伐地那非和西地那非)通常在给予后约1小时后达到它们的峰值血浆浓度(西地那非应为至少约35ng/ml，伐地那非为2μg/l而他达那非为40μg/l)并且峰值过后它们的效果也存在。通过基本同时释放3-α-雄甾烷二醇和PDE5抑制剂，它们的效果至少部分重叠。技术人员明了的是，可将3-α-雄甾烷二醇和PDE5抑制剂配制为使它们延迟释放。例如，活性成分具有或包裹有2小时后溶解的涂层。在这种情况下，必须在性活动前2-3小时服用活性成分。其他变化可由技术人员容易地实施并包括在本发明的范围内。
本文中提到的性功能障碍包括男性和/或女性性功能障碍。提到的男性性功能障碍包括性欲抑制(ISD)、勃起功能障碍(ED)和早泄(PE)。提到的女性性功能障碍包括机能减退的性欲障碍(HSDD)、女性性唤起障碍(FSAD)和女性性高潮障碍(FOD)。
对于本发明，所选择的给予途径为侵入性最小的那些(例如，口服、颊-粘膜或鼻内)。侵入性给予途径不应对性行为的冲动造成不利影响。
本文中所描述的应用可替换地表述为：3-α-雄甾烷二醇和PDE5抑制剂在用于治疗性功能障碍的方法中应用。
在一种优选的实施方式中，本发明提供了3-α-雄甾烷二醇和5型磷酸二酯酶(PDE5)抑制剂在制备用于治疗女性性功能障碍的药物中的应用。在另一种优选的实施方式中，所述女性性功能障碍是女性性唤起障碍(FSAD)和/或机能减退的性欲障碍(HSDD)和/或女性性高潮障碍(FOD)。
在另一种优选的实施方式中，所述性功能障碍是男性性功能障碍。
本发明还提供了一种包含3-α-雄甾烷二醇的药物组合物。
3-α-雄甾烷二醇优选以舌下剂型的形式提供，例如包含作为载体的环糊精的舌下剂型。合适的给予途径的另一个实例是颊-粘膜或鼻内给予，这也可通过使用环糊精剂型或其他常用的赋形剂、稀释剂等进行。在一种优选的实施方式中，将药物设计为用于舌下给予，且甚至更优选所述组合物包含环糊精，如羟丙基-β环糊精。所制得的3-α-雄甾烷二醇样品的典型非限制性实例(0.1-0.5mg的3-α-雄甾烷二醇)由0.1-0.5mg的3-α-雄甾烷二醇、5mg羟丙基-β环糊精(载体)、5mg乙醇、和5ml水组成，但这些物质中每一种的量可更高或更低。
在另一种实施方式中，本发明提供了一种包含3-α-雄甾烷二醇和PDE5抑制剂的药物组合物。该包含PDE5抑制剂的药物组合物优选包含至少25mg西地那非(或5mg伐地那非、或5mg他达那非)至最多100mg西地那非(或20mg伐地那非、或20mg他达那非)，或相当剂量的其他PDE5抑制剂。这些剂量可随患者的体重不同而不同，并优选由医生确定。
在一种优选的实施方式中，本发明提供了一种其包含3-α-雄甾烷二醇和PDE5抑制剂的药物组合物，其中所述组合物被设计成基本同时释放所述3-α-雄甾烷二醇和所述PDE5抑制剂。该药物组合物可设计为使得3-α-雄甾烷二醇和PDE5抑制剂在给予后(直接)释放，或使得3-α-雄甾烷二醇和PDE5抑制剂在经过一定时间(例如2小时)后释放。这取决于两种成分所采用的剂型。
活性成分(例如3-α-雄甾烷二醇和PDE5抑制剂)可以任何合适的形式提供，如片剂、胶囊、多颗粒(multi-particulate)、凝胶剂、膜剂、溶液或混悬液的形式，并且可包含稀释剂和/或赋形剂和/或粘合剂和/或崩解剂和/或润滑剂和/或着色剂。也可以采用不同类型的释放模式，如直接释放或延迟释放。
因为不同活性成分的效果必须至少部分重合，并优选完全重合，本发明优选还提供关于给药的说明。因此，本发明还提供了一种套装试剂盒(套装药剂盒，kit of parts)，其包括至少一种包含3-α-雄甾烷二醇的药物组合物和至少一种包含PDE5抑制剂的组合物，其中所述试剂盒进一步包括关于给予所述组合物的说明。
本发明还提供了一种套装试剂盒，其包括本文所述的药物组合物，即包含3-α-雄甾烷二醇和PDE5抑制剂的药物组合物。
为了进一步增强本发明的套装试剂盒的效果，所述试剂盒可进一步包括用于认知干预和刺激的工具。这些信息可以存在于任何数据载体(纸张、CD、DVD)上，或可以被动或交互地链接到至少部分地设计用于所述认知刺激目的的网站。有时优选下意识地，如潜意识地提供所述认知刺激性信息。
本文所述的有效成分的组合可进一步伴随有其他合适的有效成分。
本发明进一步提供了一种通过为患性功能障碍的男性或女性提供有效量的3-α-雄甾烷二醇和PDE5抑制剂的组合来治疗患性功能障碍的男性或女性的方法。
以下将通过非限制性实例来更详细地解释本发明。
实验部分
实验1 FSD中的3-α-雄甾烷二醇和西地那非
组合给予3-α-雄甾烷二醇和PDE5抑制剂-西地那非对患有FSD的女性响应于色情影片片段的VPA的功效
在双盲、随机分配的安慰剂对照的交叉设计中，一组16名患有女性性功能障碍(FSD)的女性将在三个独立的实验日接受：
1.3-α-雄甾烷二醇(0.1mg)和西地那非(10mg)
2.仅3-α-雄甾烷二醇(0.1mg)
3.安慰剂
在给药后立即，和给药后1小时，测量响应于中性和色情影片片段的阴道搏动振幅。3个实验日间隔(至少)3天时间。关于所有的给药，受治疗者将接受一种由西地那非、或安慰剂构成的胶囊，和一种含有3-α-雄甾烷二醇或安慰剂的液体制剂。胶囊和液体制剂在测试前1小时同时服用。舌下3-α-雄甾烷二醇的效果与高西地那非血清浓度交叠(西地那非的Tmax为30-120min；T1/2＝3.5小时)，这是由于它们的时间滞后类似(0-1小时)。
在实验期间，必须在受治疗者阴道内插入卫生棉条状的阴道探针(光体积描记器)以测量VPA。然后，受治疗者将观看10分钟中性片段，然后观看5分钟色情影片片段。在这些基线测量(baselinemeasurement)后，受治疗者接受上述四种药物组合中的一种。给药后，播放另一组中性(5分钟)和色情(5分钟)影片片段。然后抽出阴道探针。在4小时后，再一次进行响应于中性(5分钟)和色情(5分钟)影片片段的VPA测量。在整个实验日内监测血压(仰卧和站立)、心率、呼吸率、和体温。
在实验之前进行筛查走访。在筛查走访中，受治疗者会见Almere的Flevo医院妇科的医生并接受检查以便诊断FSD并判断是否适于参与研究。受治疗者将被要求填写调查问卷；女性性功能指数(Female Sexual Function Index，FSFI)。对受治疗者进行筛选以排除怀孕或哺乳期、阴道感染、阴道和/或外阴大手术、未发现的主要妇科病或不清楚的妇科问题的受治疗者。测量体重、身高、血压(仰卧和站立)。检测心血管状况并检查ECG是否有明显异常。有内分泌、神经或精神病史和/或治疗史的受治疗者。进行标准血液化学和血液学测试。参试者被要求不能在实验当天和前一天晚上饮用酒精或服用精神药物。月经期间，受治疗者不能测试。
实验2 MSD中的3-α-雄甾烷二醇和西地那非
组合给予3-α-雄甾烷二醇和PDE5抑制剂-西地那非对患有MSD的男性响应于色情影片片段的男性性功能的功效
在双盲、随机分配的安慰剂对照的交叉设计中，一组16名患男性性功能障碍(MSD)的男性将在三个独立的实验日接受：
1.3-α-雄甾烷二醇(0.5mg)和西地那非(10mg)
2.仅3-α-雄甾烷二醇(0.5mg)
3.安慰剂
在给药后直接、和给药后1小时，测量响应于中性和色情影片视听刺激(VSTR)的阴茎膨大和坚硬度，然后直接测量震动触觉刺激射精等待时间(VTS-ELT)和射精后勃起持续时间。3个实验日间隔(至少)3天时间。关于所有的给药，受治疗者将接受一种由西地那非、或安慰剂构成的胶囊，和一种含有3-α-雄甾烷二醇或安慰剂的液体制剂。胶囊和液体制剂在测试前1小时同时服用。舌下3-α-雄甾烷二醇的效果与高西地那非血清浓度交叠(西地那非的Tmax为30-120min；T1/2＝3.5小时)，这是由于它们的时间滞后类似(0-1小时)。
在实验之前要进行筛查走访。在筛查走访中，受治疗者将会见Almere的Flevo医院妇科医生并接受检查以便诊断MSD并判断是否适于参与研究。受治疗者将被要求填写调查问卷；阴茎勃起功能国际指数问卷(IIEF)。测量体重、身高、血压(仰卧和站立)。检查心血管状况并检查ECG是否有明显异常。参试者被要求不能在实验当天和前一天晚上饮用酒精或服用精神药物。
实验3动物模型FSD
组合给予3-α-雄甾烷二醇、和PDE5抑制剂对雌性性功能的功效。
研究给予3-α-雄甾烷二醇和西地那非对大鼠雌性性行为的影响。具体地，在注射并放置单只性活跃雄性大鼠后3小时内，记录雌性大鼠的邀配行为(proceptive behaviour)(引诱、社交时间、嗅舔)和受配行为(receptive behaviour)(脊柱前凸)。
以单盲、随机分配的安慰剂对照的交叉设计，对一组32只建康的、性活跃的成年雌性大鼠进行实验。雌性和雄性大鼠应在它们(第一个)测试日前分开饲养两周。所有药物和安慰剂应通过单次腹膜内注射而给予。药物剂量是基于文献确定的。每只大鼠接受不超过两次的治疗，间隔一周。
实验4动物模型MSD
组合给予3-α-雄甾烷二醇和PDE5抑制剂对雄性性功能的功效。
研究给予3-α-雄甾烷二醇和西地那非对大鼠雄性性行为的影响。具体地，在注射并放置单只性活跃雌性大鼠后3小时内，对雄性大鼠的爬胯等待时间、爬胯频率、插入等待时间、插入频率、射精等待时间和射精后间隔进行评分。
以单盲、随机分配的安慰剂对照的交叉设计，对一组32只建康的、性活跃的成年雄性大鼠进行实验。雌性和雄性大鼠应在它们(第一个)测试日前分开饲养两周。所有药物和安慰剂应通过单次腹膜内注射给予。药物剂量是基于文献确定的。每只大鼠接受不超过两次的治疗，间隔一周。
参考文献
1.Laumann,E.O.,A.Paik,and R.C.Rosen,Sexual dysfunction in theUnited States:prevalence and predictors.Jama,1999.281(6):p.537-44.
2.Reddy,D.S.,et al，A high-performance liquidchromatography-tandem mass spectrometry assay of theandrogenic neurosteroid 3alpha-androstanediol(5alpha-androstane-3alpha,17beta-diol)in plasma.Steroids,2005.70(13):p.879-85.
3.Jin,Y.and T.M.Penning,Steroid 5alpha-reductases and3alpha-hydroxysteroid dehydrogenases:key enzymes in androgenmetabolism.Best Pract Res Clin Endocrinol Metab,2001.15(1):p.79-94.
4.Wudy,S.A.,et al,Androgen metabolism assessment by routine gaschromatography/mass spectrometry profiling of plasma steroids:Part 1,Unconjugated steroids.Steroids,1992.57(7):p.319-24。
Claims (11)
1.3-α-雄甾烷二醇和5型磷酸二酯酶(PDE5)抑制剂在制备用于根据需要治疗性功能障碍的药物中的应用，其中，所述3-α-雄甾烷二醇和所述PDE5抑制剂基本上同时释放，从而使得它们的峰值效果至少部分重叠。
2.根据权利要求1所述的应用，其中，所述性功能障碍是男性性功能障碍。
3.根据权利要求1所述的应用，其中，所述性功能障碍是女性性功能障碍。
4.根据权利要求1-3中任一项所述的应用，其中，所述3-α-雄甾烷二醇和所述PDE5抑制剂在单独的药物组合物中提供。
5.根据权利要求1-3中任一项所述的应用，其中，所述3-α-雄甾烷二醇和所述PDE5抑制剂以套装试剂盒提供，所述套装试剂盒包含至少一种包含3-α-雄甾烷二醇的药物组合物和至少一种包含PDE5抑制剂的组合物。
6.根据权利要求1-3中任一项所述的应用，其中，所述3-α-雄甾烷二醇和所述PDE5抑制剂在性活动之前约1小时释放。
7.根据权利要求1-3中任一项所述的应用，其中，所述PDE5抑制剂选自西地那非、伐地那非和他达那非。
8.一种药物组合物，包含3-α-雄甾烷二醇和PDE5抑制剂，其中，所述组合物被设计成基本上同时释放所述3-α-雄甾烷二醇和所述PDE5抑制剂，从而使得它们的峰值效果至少部分重叠。
9.根据权利要求8所述的组合物，其中，所述PDE5抑制剂选自西地那非、伐地那非和他达那非。
10.一种套装试剂盒，包含至少一种包含3-α-雄甾烷二醇的药物组合物和至少一种包含PDE5抑制剂的组合物，其中，所述试剂盒进一步包括关于根据需要给予所述组合物的说明，从而使得所述3-α-雄甾烷二醇和所述PDE5抑制剂的峰值效果至少部分重叠。
11.根据权利要求10所述的套装试剂盒，其中，所述PDE5抑制剂选自西地那非、伐地那非和他达那非。
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| EP06076976A EP1925307A1 (en) | 2006-11-03 | 2006-11-03 | Use of 3-alpha-androstanediol in the treatment of sexual dysfunction |
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| CN201310556256.6A Pending CN103599536A (zh) | 2006-11-03 | 2007-11-02 | 3-α-雄甾烷二醇在治疗性功能障碍中的应用、可选地与5-HT1A激动剂联合应用 |
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