CN1335772A - 阿扑吗啡在制备治疗男性器质性勃起障碍的药物中的应用 - Google Patents
阿扑吗啡在制备治疗男性器质性勃起障碍的药物中的应用 Download PDFInfo
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- CN1335772A CN1335772A CN99814559A CN99814559A CN1335772A CN 1335772 A CN1335772 A CN 1335772A CN 99814559 A CN99814559 A CN 99814559A CN 99814559 A CN99814559 A CN 99814559A CN 1335772 A CN1335772 A CN 1335772A
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Abstract
一种治疗器质性勃起障碍,尤其是血管原性勃起障碍的方法,包括给需此治疗的男性施用治疗有效量的阿扑吗啡或其可药用盐或其前药。
Description
技术背景
本发明涉及医学治疗方法。更具体地说,本发明涉及阿扑吗啡在治疗男性器质性勃起障碍,尤其是血管原性勃起障碍中的应用。
发明背景
在医学文献中,已使用术语“勃起障碍”来代替不太精确的术语“阳萎”。国立卫生研究院(National Institutes of Health)将该术语定义为男性不能使阴茎引发并维持勃起以足以进行令人满意的性交。J.Am.Med.Assoc.,270(1):83-90(1993)。由于足够的动脉血供应是勃起的关键,减少血流的任何疾病都可能与勃起失败的病因学有关。勃起障碍影响着数百万男性,虽然它被认为是一种良性疾病,但对他们的生活质量却有着极深的影响。据知,在许多男性,即使是勃起障碍的男性的心理愿望中,性兴奋能力和射精能力是完好的。
勃起障碍的病因学起因可划分为心理性的或器质性的。器质性因素包括神经原性起因的和血管原性起因的。神经原性因素包括,例如,可影响产生勃起反射和中断维持勃起所需的触觉的体干神经通路损伤,以及依据其损伤部位和严重程度可导致不同程度勃起障碍的脊髓损伤。
勃起障碍的心理性因素包括诸如抑郁、焦虑和由于性欲降低或感觉意识减弱的其它可影响阴茎功能的性关系问题。这些因素均可能导致无法引发或维持勃起。
血管原性危险因素包括影响血流的因素,包括吸烟、糖尿病、高血压、血管疾病、高血浆胆固醇、低水平高密度脂蛋白(HDL)和其它慢性疾病,如关节炎。马萨诸塞州男性衰老研究会(MMAS,H.A.Feldman等,J.Urol.,151:54-61(1994))发现,例如糖尿病治疗者中完全勃起障碍的经过年龄校准的可能性要比非糖尿病治疗者大三倍。但也存在着一些不同观点,因为糖尿病的许多方面是勃起障碍的直接原因,提及最多是血管疾病。
MMAS还发现了勃起障碍与具有两种相关危险因素的心脏病、高血压和血浆高密度脂蛋白低下(HDL)之间的明显关系。据报道8-10%的所有未治疗的高血压患者在他们被诊断为高血压时患有阳痿。文献记载勃起障碍与血管疾病有着密切的关系,据证实心肌梗塞、冠脉旁路术、心脑血管意外伤害和外周血管病患者的勃起血液动力学都受到损害。MMAS还发现吸烟是血管原性勃起障碍的独立危险因素,吸烟增高了与心血管疾病有关的勃起障碍的危险性。
根据具体患者病症起因的不同,勃起障碍的治疗也不同。治疗模式包括使用精神疗法、手术、机械或药物治疗方法。精神疗法和/或行为治疗常用于某些没有明显器质性原因(精神性)的勃起障碍患者。静脉结扎(litigation)可有效治疗由于从阴茎海绵体的静脉泄漏导致的维持勃起困难的患者。真空压缩装置有时可有效地使勃起障碍患者引发勃起和维持勃起,在治疗无效或患者拒绝其它形式的治疗时,可利用半硬的可伸展的或可膨胀的阴茎假体。
已用于勃起障碍治疗的药物包括直接注射到阴茎体内的血管扩张剂和口服给药的药物。最有效的研究最充分的注射血管扩张剂是盐酸罂粟碱、酚妥拉明和前列地尔,他们可单独或联合使用。但是,阴茎扩张剂的使用对无法耐受短暂性高血压的患者可能是个问题。口服给药的药物包括育亨宾、溴隐亭、氟西汀、曲唑酮(trazadone)、己酮可可碱、西地那非、酚妥拉明和银杏提取物。
美国专利5770606公开了用于治疗男性精神性勃起障碍舌下给药的阿扑吗啡。阿扑吗啡,一种吗啡的衍生物,在1869年首次被用作催吐剂。在20世纪上半叶,阿扑吗啡被用作镇静剂用于精神障碍和用作嗜酒者和瘾君子行为戒断剂。到1967年,认识到了阿扑吗啡的多巴能作用,该化合物被十分看好用于治疗帕金森氏症。从那时起,阿扑吗啡被划分为选择性多巴胺受体激动剂,该激动剂刺激中枢神经系统产生表现为动物和男性张口和阴茎勃起的唤醒反应。
发明概述
本发明发现男性的器质性勃起障碍通过给需此治疗的男性施用治疗有效量的阿扑吗啡或其可药用盐、酯或其前药可以得到有效治疗或缓解。血管原性器质性勃起障碍尤其可通过口服阿扑吗啡得到有效治疗。
根据本发明,阿扑吗啡以足以产生有效阴茎勃起作用、但不足以引发恶心的量施用,典型地是以足以产生优选至高约5.5纳克/毫升的阿扑吗啡血浆浓度水平的量施用。该化合物或其适宜的盐或前药可单独给药,或者如果需要,可以其剂量范围的高限与止吐剂联合给药。
详细描述
本说明书和所附权利要求书中,术语“血管原性勃起障碍”是指由于伴随心血管系统和/或相关危险因素的血流减少,男性不能引发和/或维持阴茎勃起以足以进行令人满意的性交的适应症。这类疾病包括,但不限于,心肌梗塞、心脏病、外周血管病以及由糖尿病、吸烟、心脏旁路术和心脑血管意外伤害导致的循环损害。相关的危险因素包括高血压、血浆低密度脂蛋白(LDL)升高以及血浆高密度脂蛋白(HDL)低下。
术语“敏锐剂量”或“敏锐给药”是指根据患者需要的药物给药方案。
术语两种或多种药物的“共同给药”是指两种或多种药物以一种单位剂量形式给药或者以两种或多种独立的单位剂量形式一种接一种地给药。
术语“有效血管充血唤醒”或“有效勃起”是指足以穿入阴道的男性阴茎的膨胀或胀大。
本发明的治疗方法包括给血管原性勃起障碍的患者施用阿扑吗啡或其可药用的酸加成盐、前药或前药的酯。阿扑吗啡,(R)-5,6,6a,7-四氢-6-甲基-(4H)-二苯并[de,g]喹啉-10,11-二醇,是一种用浓盐酸处理后者(L.Small等,J.Org.Chem.,5:334(1940))或通过加热吗啡和氯化锌(Mayer,Ber.,4:171(1871))得到的吗啡衍生物。该化合物具有如下化学结构式:
阿扑吗啡并在6a位有一个手性中心。其外消旋混合物的全合成记载于J.L.Neumeyer等,J.Pharm.Sci.,59:1850(1970);其对映体单体的合成记载于V.J.Ram和J.L.Neumeyer,J.Org.Chem.,46:2830(1981)。该化合物在6位具有碱性氮原子,因此可以游离碱形式或酸加成盐形式存在。
该化合物可以其游离碱形式或其更易溶的可药用盐或前药衍生物形式给药。本发明还包括以其外消旋形式或任一种对映体形式单独给药或各种形式的结合形式给药。
本文术语“可药用盐”是指在可靠的医学判断范围内,适于与人体或低等动物的组织接触同时没有过度毒性、刺激性和过敏反应等的,并且具有合理效果/危险比率的那些盐。可药用盐是本领域熟知的。例如S.M.Berge等在J.Pharmceutical Sciences,66:1-19(1977)中详细描述了可药用盐。盐可在分离和纯化本发明的化合物期间就地制备,或者通过游离碱官能团与适宜的有机酸反应单独制备。可药用的、无毒酸加成盐的实例是氨基与例如下列无机酸形成的盐:盐酸、氢溴酸、磷酸、硫酸和高氯酸,或者与例如下列有机酸形成的盐:乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸,或者采用本领域中使用的其它方法,如离子交换法制备的盐。其它可药用盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、葡萄糖二酸盐(digluconate)、月桂基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶脂酸盐、过硫酸盐、3-苄基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐和戊酸盐等。
术语“前药”是指体内,例如通过在血液中水解迅速转化得到母体化合物的化合物。T.Higuchi和V.Stella在″作为新给药体系的前药″,A.C.S.Symposium Series,Vol.14,American ChemicalSociety(1975)中详细论述了前药概念。E.B.Roche编辑的“药物设计中的生物可逆性载体:理论和应用”(Pergamon Press,1987)的14-21页记载了可作为含羧基化合物的酯作为前药的实例。
术语“前药的酯基”是指在生理条件下水解的数种酯形成基团中的任一种。前药的酯基的实例包括新戊酰(pivoyl)氧甲基、乙酰氧甲基、2-苯并[c]呋喃酮基、1,2-二氢化茚基和甲氧基甲基以及其它本领域已知的此类基团。
本文采用的术语阿扑吗啡的“可药用酯”是指与10和11位的一个或两个羟基官能团形成的并且在体内水解,包括在人体内迅速裂解得到母体化合物或其盐的酯。适宜的酯基包括,例如,由可药用脂族羧酸,尤其是烷酸、烯酸、环烷酸和链烷二酸衍生的酯,其中各烷基或烯基部分优选具有至多6个碳原子。优选的酯的实例包括甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯和乙基琥珀酸酯。
为使男性获得最佳的血管充血唤醒反应(勃起),阿扑吗啡的稳态循环血清水平和中脑组织水平应维持在相对狭窄的定义范围内。药物优选以快速释放药物至全身同时维持但不超出药物的理想系统水平的制剂形式给药。可采用药剂领域的配制者已知的可实现这些需求的方法。例如,药物可通过下列形式释放到全身:固体口服制剂、液体制剂,包括舌下滴剂;片剂、锭剂或放入口中的棒棒糖以及经颊或舌下吸收的形式;直肠给药栓剂;或粉末、凝胶或悬浮剂,获知鼻内吸入喷雾剂。药物也可以无菌非胃肠制剂形式经皮下或肌内途径给药,但舌下、颊、鼻内给药形式和栓剂是优选的,因为这些形式较容易给药并且患者接受的可能性也较大。
通常含约2.5-10毫克阿扑吗啡的舌下阿扑吗啡剂型可用于治疗男性的血管原性性功能障碍症状,包括其症状表现,而不具有恶心和不希望的副作用。阿扑吗啡在临性交前的一段时间内给药,通常在性交前约2-120分钟期间给药,优选在性关系发生前约2-约60分钟期间给药,以便在性活动期间使阿扑吗啡维持于足以引发和维持足以进行性交的阴茎勃起(即,“有效血管充血唤醒”)的预定循环血清水平和中脑组织水平,但低于引起恶心的量。优选使阿扑吗啡的血浆浓度维持在约0.3-5.5纳克/毫升,优选约0.3-4纳克/毫升,更优选约1-2纳克/毫升。
阿扑吗啡是一种多巴胺受体激动剂,当以约5毫克的剂量皮下给药时,被用作催吐剂。对于本发明的目的而言,阿扑吗啡以足以刺激患者中脑区域的细胞同时又具有最低副作用的量给药。据信该细胞刺激作用是兴奋链反应的一部分,该反应可能包括血清素和催产素的神经传递。
通过给予,优选经舌下给予阿扑吗啡以使阿扑吗啡的血浆浓度不超过约5.5纳克/毫升(5.5ng/ml),可刺激患者中脑区域的多巴胺受体至足以引发勃起反应而不产生恶心的程度。舌下给予一般需约2-10分钟或更长的一段时间。在该段时间内舌下给予阿扑吗啡的量优选为约25微克/公斤(μg/kg)体重至约60μg/kg体重。
在对恶心敏感的患者中,通过控制溶出速率提供低于5.5纳克/毫升的阿扑吗啡的循环血清水平和中脑组织水平来释放阿扑吗啡,可避免或延迟恶心的发作。当阿扑吗啡以上述剂量范围的高限或接近该高限的剂量给药时,通过同时服用神经节阻滞剂(神经节反应抑制剂),例如尼古丁或硫酸洛贝林可降低恶心发作的可能性。为此,阿扑吗啡与神经节阻滞剂的重量比为约10-1。
可与阿扑吗啡结合使用的其它止吐剂是抗多巴胺能药物,例如甲氧氯普胺,和吩噻嗪类,例如氯丙嗪、丙氯拉嗪、匹哌马嗪、硫乙拉嗪和盐酸奥昔喷地等。其它适宜的止吐剂有5-羧色胺(5-羟色胺或5-HT)拮抗剂,如多潘立酮和昂丹司琼(其盐酸盐形式以ZofranTM商标市售)等;组胺拮抗剂,例如盐酸布克利嗪、盐酸赛克力嗪和茶苯海明(DramamineTM)等;副交感神经系统抑制剂,例如东莨菪碱等;以及其它止吐剂,例如美托哌丙嗪、曲美苄胺、benzauinamine盐酸盐和盐酸地芬尼多等。
优选的舌下剂型实例列于下表I中。
表I
150-毫克盐酸阿扑吗啡舌下片
3-mg片
盐酸盐阿扑吗啡 | 2.00wt-% |
甘露醇 | 66.67wt-% |
抗坏血酸 | 3.33wt-% |
柠檬酸 | 2.00wt-% |
Avicel PH 102 | 15.00wt-% |
Methocel E4 | 10.00wt-% |
阿司帕坦 | 0.67wt-% |
硬脂酸镁 | 0.33wt-% |
4-mg片
盐酸盐阿扑吗啡 | 2.66wt-% |
甘露醇 | 66.00wt-% |
抗坏血酸 | 3.33wt-% |
柠檬酸 | 2.00wt-% |
Avicel PH 102 | 15.00wt-% |
Methocel E4M | 10.00wt-% |
阿司帕坦 | 0.67wt-% |
硬脂酸镁 | 0.33wt-% |
5-mg片
盐酸盐阿扑吗啡 | 3.33wt-% |
甘露醇 | 65.34wt-% |
抗坏血酸 | 3.33wt-% |
柠檬酸 | 2.00wt-% |
Avicel PH 102 | 15.00wt-% |
Methocel E4M | 10.00wt-% |
阿司帕坦 | 0.67wt-% |
硬脂酸镁 | 0.33wt-% |
如果需要,为有助于吸收,提高生物利用度,目前设计的剂型除含有压片赋形剂外,还可含有β-环糊精或β-环糊精衍生物,例如羟丙基-β-环糊精(HPBCD)。下面的表II和III中给药含HPBCD的剂型实例。
表II
含羟丙基-β-环糊精的盐酸阿扑吗啡舌下片
成分 | mg/片 |
盐酸盐阿扑吗啡 | 4.0 |
HPBCD | 5.0 |
抗坏血酸 | 10.0 |
PEG 800 | 39.5 |
甘露醇 | 39.5 |
阿司帕坦 | 2.0 |
总计 | 100.0 |
表III
含β-环糊精的盐酸阿扑吗啡舌下片
成分 | mg/片 |
盐酸盐阿扑吗啡 | 5.0 |
β-环糊精 | 20.0 |
抗坏血酸 | 5.0 |
甘露醇 | 68.9 |
硬脂酸镁 | 1.0 |
D&C黄色10铝色淀 | 0.1 |
总计 | 100.0 |
下表IV说明含尼古丁和含多潘立酮的剂型。
表IV
含止吐剂的盐酸阿扑吗啡舌下片
含尼古丁片
成分 | mg/片 |
盐酸盐阿扑吗啡 | 5.0 |
抗坏血酸 | 5.0 |
甘露醇 | 67.9 |
硬脂酸镁 | 1.0 |
尼古丁 | 1.0 |
β-环糊精 | 20.0 |
D&C黄色铝色淀 | 0.1 |
总计 | 100.0 |
含多潘立酮片
成分 | mg/片 |
盐酸盐阿扑吗啡 | 5.0 |
抗坏血酸 | 5.0 |
甘露醇 | 58.9 |
硬脂酸镁 | 1.0 |
多潘立酮 | 10.0 |
β-环糊精 | 20.0 |
D&C黄色铝色淀 | 0.1 |
总计 | 100.0 |
优选的舌下剂型在约10分钟内溶化。溶出时间基本上是瞬时的,或者,如果需要,可使阿扑吗啡血浆浓度维持需要长的时间。目前设计的剂型在水中的溶出时间是约3-5分钟。
对被诊断患男性勃起障碍的患者进行多中心的、双盲的、随机的、安慰剂对照的三臂(three-armed)研究。各顺序是,患者在一个治疗期间接受安慰剂,在其它治疗期间接受一种剂量(2mg,4mg,5mg或6mg)的阿扑吗啡。这种安排导致约三分之一的患者接受三种阿扑吗啡剂量之一。
在研究的治疗期间,指示患者和其性伙伴尝试性交,至少每两周一次。每次服用研究的药物,由患者完成问卷表并寄至研究倡议者。问卷表记录服用药物的日期和时间、对勃起的评价、是否发生了性交,以及每次尝试的满意程度。患者还完成记录与服用研究药物和止吐剂有关的潜伏期和勃起时间以及伴随的药物服法和任何副作用的日记。如果患者服用研究药物后发生勃起,患者日记中还记录勃起的时间长短和勃起时间。对这些研究的数据进行分析,并对从被诊断为患高血压的患者或服用高血压药物的患者得到的结果作表。研究结果示于表V-VII。
表V显示了接受安慰剂或四种剂量(2mg,4mg,5mg或6mg)的阿扑吗啡之一的研究参与者对问卷问题“勃起的坚挺性是否足以进行性交?”的反应。
表V
勃起坚挺足以进行性交
(基于尝试次数*)
*″尝试″定义为服用研究药物并完成适合的问卷的功效问题。
阿扑吗啡 安慰剂 | |||||||
剂量 | 患者数量 | 反应 | 尝试次数 | (百分数) | 尝试次数 | (百分数) | P值 |
2mg | 65 | 是 | 210 | 43.30 | 162 | 34.11 | 0.028 |
2mg | 否 | 275 | 56.70 | 309 | 65.61 | ||
4mg | 53 | 是 | 202 | 52.60 | 105 | 27.06 | <0.001 |
4mg | 否 | 182 | 47.40 | 283 | 72.94 | ||
5mg | 26 | 是 | 95 | 49.48 | 62 | 30.85 | 0.022 |
5mg | 否 | 97 | 50.52 | 139 | 69.15 | ||
6mg | 50 | 是 | 233 | 62.13 | 119 | 32.96 | <0.001 |
6mg | 否 | 142 | 37.87 | 242 | 67.04 |
表V中的数据表明各种试验剂量的阿扑吗啡都明显提高了报告足以进行性交的坚挺勃起的百分数。不希望限于一种理论而排除其它理论,据信与4mg剂量相比,5mg剂量作“是”反应的稍有减少反映了接受5mg剂量研究的患者数量较少。
表VI显示了接受安慰剂或四种剂量(2mg,4mg,5mg或6mg)的阿扑吗啡之一的研究参与者对问卷中“成功”的反应。在治疗时,如果最开始的8次尝试的至少50%产生足以进行性交的坚挺勃起,则患者认为治疗“成功”。表VI显示了以治疗成功性划分的患者百分比。结果表明在6mg剂量下,药物的成功率为68.0%,而安慰剂的成功率为38.8%;5mg剂量下,药物的成功率为53.8%,而安慰剂的成功率为38.5%;4mg剂量下,药物的成功率为62.3%,而安慰剂的成功率为26.9%;2mg剂量下,药物的成功率为44.6%,而安慰剂的成功率为38.5%。在4mg和6mg剂量下,结果具有统计学显著意义;但2mg和5mg剂量也显示了有益的成功率,它们缺乏统计学显著意义可能是由于采样的数量较小。
表VI
“成功”勃起坚挺足以进行性交
阿扑吗啡2mg | 安慰剂 | |||
成功 | 不成功 | 合计 | ||
成功 | 21(32.3%) | 8(12.3%) | 29(44.6%) | |
不成功 | 4(6.2%) | 32(49.2%) | 36(55.4%) | |
合计 | 25(38.5%) | 40(61.5%) | 65(100%) |
阿扑吗啡4mg | 安慰剂 | |||
成功 | 不成功 | 合计 | ||
成功 | 12(22.6%) | 21(39.6%) | 33(62.3%) | |
不成功 | 3(5.7%) | 17(32.1%) | 20(37.7%) | |
合计 | 15(28.3%) | 38(71.7%) | 53(100%) |
阿扑吗啡5mg | 安慰剂 | |||
成功 | 不成功 | 合计 | ||
成功 | 8(30.8%) | 6(23.1%) | 14(53.8%) | |
不成功 | 2(7.7%) | 10(38.5%) | 12(46.2%) | |
合计 | 10(38.5%) | 16(61.5%) | 26(100%) |
阿扑吗啡6mg | 安慰剂 | |||
成功 | 不成功 | 合计 | ||
成功 | 18(36.0%) | 16(32.0%) | 34(68.0%) | |
不成功 | 1(2.0%) | 15(30.0%) | 16(32.0%) | |
合计 | 19(38.0%) | 31(62.0%) | 50(100%) |
最后,表VII显示了研究参与者在问卷表上报告的实际进行性交的尝试次数。
表VII
进行性交尝试
(基于最初的8次尝试*)
*″尝试″定义为服用研究药物并完成适合的问卷的功效问题。
阿扑吗啡 安慰剂 | |||||||
剂量 | 患者数量 | 反应 | 尝试次数 | (百分数) | 尝试次数 | (百分数) | P值 |
2mg | 65 | 是 | 185 | 38.22 | 148 | 31.36 | 0.080 |
2mg | 否 | 299 | 61.78 | 324 | 68.64 | ||
4mg | 52 | 是 | 183 | 47.66 | 87 | 22.96 | <0.001 |
4mg | 否 | 201 | 52.34 | 292 | 77.04 | ||
5mg | 26 | 是 | 100 | 52.08 | 62 | 30.85 | 0.012 |
5mg | 否 | 92 | 47.92 | 140 | 69.65 | ||
6mg | 50 | 是 | 205 | 56.01 | 96 | 26.67 | <0.001 |
6mg | 否 | 161 | 43.99 | 264 | 73.33 |
表VII显示的结果与表V平行,在6mg药物剂量下,服用药物进行性交的尝试百分比为56.01%,而服用安慰剂为26.67%;在5mg药物剂量下,服用药物进行性交的尝试百分比为52.08%,而服用安慰剂为30.35%;在4mg药物剂量下,服用药物进行性交的尝试百分比为47.66%,而服用安慰剂为22.96%;在2mg药物剂量下,服用药物进行性交的尝试百分比为38.22%,而服用安慰剂为31.36%。
表V-VII的数据证明给患高血压(一种代表性血管原性勃起障碍的原因)的男性服用阿扑吗啡可成功治疗或缓解症状。
虽然这里给出并描述了被认为是本发明的优选实施方案,但本领域技术人员应该清楚,在不超出所附权利要求书限定的范围内,在本发明的实践中可进行各种改变。
Claims (20)
1、一种治疗男性器质性勃起障碍的方法,包括给需此治疗的男性施用治疗有效量的阿扑吗啡或其可药用盐、酯或前药。
2、权利要求1的方法,其中所述器质性勃起障碍是与心血管系统疾病有关的血管原性起因的。
3、权利要求1的方法,其中所述器质性勃起障碍是相关于心血管系统疾病有关的危险性因素的血管原性起因的。
4、权利要求2的方法,其中所述心血管系统疾病是心肌梗塞、心脏病或外周血管疾病。
5、权利要求2的方法,其中所述心血管系统疾病是与糖尿病、心脏旁路术、脑血管损伤或吸烟有关的循环损害。
6、权利要求3的方法,其中所述相关于心血管系统疾病的危险性因素是高血压、高血清低密度脂蛋白(LDL)和低血清高密度脂蛋白(HDL)。
7、权利要求1的方法,其中所述阿扑吗啡以足以使所述男性产生有效阴茎勃起作用、但不足以引起恶心的量施用。
8、权利要求1的方法,其中所述阿扑吗啡与呕吐抑制有效量的止吐剂联合给药。
9、权利要求1的方法,其中所述阿扑吗啡以约25-60微克/千克体重的量施用。
10、权利要求1的方法,其中所述阿扑吗啡以足以产生约0.3-5.5纳克/毫升的阿扑吗啡血浆浓度的量施用。
11、权利要求10的方法,其中虽说阿扑吗啡的血浆浓度范围为约0.3-4纳克/毫升。
12、权利要求11的方法,其中所述阿扑吗啡的血浆浓度范围为约1-2纳克/毫升。
13、权利要求8的方法,其中所述止吐剂选自尼古丁、硫酸洛贝林、甲氧氯普胺、氯丙嗪、丙氯拉嗪、匹哌马嗪、硫乙拉嗪、盐酸奥昔喷地、多潘立酮、昂丹司琼、盐酸布克利嗪、盐酸赛克力嗪、茶苯海明、东莨菪碱、美托哌丙嗪、曲美苄胺、benzauinamine盐酸盐和盐酸地芬尼多。
14、一种治疗患高血压男性勃起障碍的方法,包括给需此治疗的男性施用治疗有效量的阿扑吗啡或其可药用盐、酯或前药。
15、权利要求14的方法,其中所述阿扑吗啡与呕吐抑制有效量的止吐剂联合给药。
16、权利要求14的方法,其中所述阿扑吗啡以约25-60微克/千克体重的量施用。
17、权利要求14的方法,其中所述阿扑吗啡以足以产生约0.3-5.5纳克/毫升的阿扑吗啡血浆浓度的量施用。
18、权利要求17的方法,其中所述阿扑吗啡的血浆浓度范围为约0.3-4纳克/毫升。
19、权利要求18的方法,其中所述阿扑吗啡的血浆浓度范围为约1-2纳克/毫升。
20、权利要求15的方法,其中所述止吐剂选自尼古丁、硫酸洛贝林、甲氧氯普胺、氯丙嗪、丙氯拉嗪、匹哌马嗪、硫乙拉嗪、盐酸奥昔喷地、多潘立酮、昂丹司琼、盐酸布克利嗪、盐酸赛克力嗪、茶苯海明、东莨菪碱、美托哌丙嗪、曲美苄胺、benzauinamine盐酸盐和盐酸地芬尼多。
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