CN102697785A - 治疗或防治激素变异症状的方法 - Google Patents
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Abstract
一种治疗或预防激素变异症状的方法，包括向有一种或多种激素变异症状的患者给予有效量的受体拮抗剂，其中受体拮抗剂结合选自2A型5-羟色胺2A(5-HT2A)受体或2型多巴胺(D2)受体中的至少一种受体。
Description
本发明专利申请是国际申请号为PCT/IB2007/004514，国际申请日为2007年11月27日，进入中国国家阶段的申请号为200780046351.4，名称为“治疗或防治激素变异症状的方法”的发明专利申请的分案申请。
发明领域
本发明一般地涉及诸如热潮红、盗汗及失眠之类的激素变异症状的治疗或预防。
背景技术
热潮红(又称血管舒缩潮红)是围绝经期或绝经后妇女所经历的最常见症状。热潮红是一种突如其来的热感，常常伴有皮肤泛红、出汗、心悸、焦虑、易怒、甚至恐慌、以及盗汗。由于随后体核温度的下降，热潮红后随之而来的可能是寒战。热潮红有各式各样：可以是每周几次或者一小时一次，其特征可能是微微的温热感觉直至大量出汗，延续的时间可以从几秒钟到60分钟。此等症状会有损睡眠和工作、干扰生活品质。
几乎60-70%的绝经后妇女有热潮红，而全部绝经后妇女中有大约10-20%报告出现包括热潮红在内的无法忍受的症状。有些妇女可能遭受这些症状的折磨最长达15年(Kronenberg F.的论文“Hot flashes:epidemiology andphysiology(热潮红：流行病学与生理学)”，Ann.N.Y.Acad.Sci,592:52-86(1990年))。因而，绝经期症状的识别和正确处理对于保持妇女的生活品质起着决定性作用。
典型的热潮红出现时，突然在胸部有热感，这种热感随后向上扩展到颈部和面部。热潮红可能持续几秒钟到几分钟。然而，这种热感的严重程度在同一名妇女以及不同的妇女之间都会随着时间的变化而有巨大变化。伴随热潮红的可能是头晕、恶心、头痛、心悸、大量出汗及盗汗。妇女经历热潮红的频率同样有所不同，从每天许多次到每周一次或更少。此等症状会有损睡眠和工作、干扰生活品质。在某些妇女，热潮红的诱因有若干因素，比如炎热的天气、压力、饮食、或者饮酒。
虽然热潮红的病例生理学尚未完全明了，但已经提出的假定是热潮红的根源在于下丘脑温度调节设定点的瞬间降低(Steams等,“Hot flushes”，Lancet,360:1851-1861(2002年))。由于性激素浓度的变化与热潮红发作之间在时间上的关联，据信这种症状源于雌激素水平的下降或者促性腺激素浓度的下降。因而，热潮红常见于绝经后妇女，但也出现在服用抗雌激素药物如他莫昔芬的妇女。进行雄激素剥夺处理的男性也可能有此类症状。
虽然雌激素替代疗法可以有效地最大限度地减少或者预防妇女出现热潮红，但许多妇女担心激素替代疗法的潜在风险。对于罹患乳腺癌或者有乳腺癌家族史、和/或有血凝障碍病史的妇女而言尤其如此(Col等，“Patient-specificdecisions about hormone replacement therapy in postmenopausal women(绝经后妇女关于激素替代疗法的患者特异性决定)”，JAMA,277;1140-1 147(1997年)；Gail等，“The menopause(绝经期)”，Lancet,353:571-580(1999年))。
还对各种非激素药剂进行了测试，比如可乐定。可乐定是一种中枢作用型α2肾上腺素能受体激动剂。它选择性地刺激大脑中监控血液中儿茶酚胺水平的受体。这些受体封闭一个从大脑中控制肾上腺髓质中儿茶酚胺(例如肾上腺素(epinephrine,adrenaline)，以及去甲肾上腺素)产生的交感降神经开始的负反馈环路。通过欺骗大脑使其相信儿茶酚胺水平比真实情况高，可乐定促使大脑减少给肾上腺髓质的信号，导致儿茶酚胺的产生减少。其结果是心跳和血压降低。在随机临床试验中发现，可乐定比安慰剂的效果略强(Goldberg等，“Transdermal clonidine for ameliorating tamoxifen-induced hot flashes(透皮可乐定用于改善他莫昔芬诱导的热潮红)”，J Clin.Oncol,12:155-158(1994年)；Pandya等，“Oral clonidine in postmenopausal patients with breast cancerexperiencing tamoxifen-induced hot flashes(患乳腺癌的绝经后病人口服可乐定时的他莫昔芬诱发的热潮红):a University of Rochester Cancer CenterCommunity Clinical Oncology Program study(罗彻斯特大学癌症中心社区临床肿瘤学项目研究)”，Ann Intern Med.132:788-793(2000年))，但不良反应是普遍的，包括口干、头晕和视力模糊。
最近的随机临床试验还证实，某些选择性5-羟色胺再吸收抑制剂(SSRI)，比如文拉法辛和帕罗西汀,在最大限度地减少热潮红的发生和严重程度方面比安慰剂更有效(Loprinzi等，“文拉法辛在乳腺癌幸存者热潮红管控中的作用：随机受控试验(Venlafaxine in management of hot flashes in survivors of breastcancer:a randomized controlled trial)”，Lancet 356:2059-2063(2000年);Stearns等，“缓释帕罗西汀治疗绝经期热潮红：随机对照试验(Paroxetine controlledrelease in the treatment of menopausal hot flashes:A randomized controlled trial)”，JAMA 289:2827-2834(2003年))。然而，SSRI的不良反应是中等程度的，包括头痛、焦虑、震颤、镇静作用以及性功能障碍。
已知雌激素替代疗法的风险以及现行非激素治疗的边际效益，一直需要治疗或者预防包括热潮红在内的与绝经期有关的症状的其他方法和药物。
发明内容
在一个方面，本发明的实施方式涉及治疗或预防激素变异症状的方法。根据本发明一个实施方式的方法包括：给有一种或多种激素变异症状的对象施用有效量的受体拮抗剂，其中该受体拮抗剂能结合到至少一种选自2A型5-羟色胺(5-HT2A)受体或2型多巴胺(D2)受体的受体。受体拮抗剂选自利培酮、喹硫平、氯氮平、奥氮平、阿立哌唑、齐拉西酮、佐替平或9-羟基利培酮。
阅读以下说明及所附权利要求书就会明白本发明的其他方面和优点。
具体实施方式
本发明的实施方式涉及治疗或预防与激素变异有关的症状的方法，尤其是那些与伴随绝经期的激素变异相关联的症状。在以下说明部分，陈述了大量细节以便更好地理解本发明。但是，本领域技术人员明白，本发明可以在没有这些具体细节的情况下加以实践，可以对所描述的实施方式做出许许多多变型或变更而不会脱离本发明的范围。本发明的方法可涉及通过口服、注射、吸入、透皮贴剂、或者本领域常用的其他途径给予有效量的治疗剂。
此外，以下还描述了几个实施例来说明本发明的实施方式。这些实施例仅用于说明之目的。本领域普通技术人员会了解，这些实施例不是穷举性的，并非旨在限制本发明的范围。除此之外，还应当明白，在整个的说明书中，当描述某个浓度或者数量范围是有用的或合适的等诸如此类时，意在表明已对该范围之内所有的每一个浓度或者数量做了陈述。此外，每个数值应当按有“约”字修饰读一次(除非已经明确地带有这种修饰)，然后再以不带修饰的形式读一次，除非上下文有相反说明。例如，“从1到10的范围”应当解读为指示从大约1连续增加至大约10之间的所有的每一个数字。换言之，当表达一个特定范围时，即使只明文标识或指出了该范围内的几个具体数据点，或者甚至没有指出该范围内的数据点，也应当理解发明人了解且明白是对该范围内的任意的、所有的数据值都已加以指定，而且发明人拥有该整个范围以及该范围内的所有数据点。
虽然绝经期是一个自然过程，作为正常老龄化的一部分出现在妇女的生命历程中。虽然有些妇女经过这些过程中鲜有症状，而另一些却有显著的、甚至是病废性的症状，比如热潮红。热潮红一般是全身性的，很可能是缘于位于视前区下丘脑前部的体温调节定点中枢中的改变，涉及到多巴胺、5-羟色胺、去甲肾上腺素及α-肾上腺素能受体。(Steams等，“热潮红(Hot flushes)”，Lancet360:1851-1861(2002年))。
本发明的发明人发现，在各种受体中，多巴胺、5-羟色胺及α肾上腺素能受体的特定亚型是治疗热潮红和与激素变异有关的其他症状的有效靶位。具体来说，研究发现，5-HT2A拮抗剂和/或D2多巴胺拮抗剂可有效地减少或消除与激素变异有关的症状。
因而，根据本发明的实施方式，治疗或预防激素变异症状的方法可包括使用有效量的5-HT2A5-羟色胺受体和/或D2多巴胺受体的拮抗剂。结合5-HT2A和/或D2受体的拮抗剂的有效量取决于给药模式、给药频率、和用于将化合物向病人投药的药物组合物的剂型、以及病人的体重、性别、年龄和身体状况。一般情况下，此类化合物的有效量是每天每千克体重约0.002mg至约0.5mg，优选每天每千克体重约0.005mg至0.1mg，更优选每天每千克体重约0.005至0.034mg。例如，日剂量对于体重50千克(110磅)的成年病人可以在每天约0.1至约25mg的范围内，或者对于体重100千克(220磅)的成年病人可以在每天约0.2至约50mg。虽然个体需要不同，但本领域技术人员能够确定各化合物有效量的最优范围。通过治疗包括热潮红在内的激素变异症状，本发明的实施方式可减少有症状活动的数量(次数或频率)、持续时间和/或严重程度。将本发明的化合物向病人给药可以采用用于向病人施用类似药物的任何适当途径，包括口服、注射、透皮贴剂，仅举此数例。将化合物给药时可以有任意药学上可接受的载体或赋形剂。
5-羟色胺(5-HT)受体包括约15种不同受体。2型(5-HT2)5-羟色胺受体是Gq/G11偶联受体，其通过提升三磷酸肌醇(IP3)和二酰甘油(DAG)的细胞水平来介导细胞效应。根据本发明的部分实施方式，2A型5-羟色胺受体是治疗或预防与激素变异相关的症状的靶位。降低5-HT的水平会提升在体温调节中涉及到的下丘脑中5-HT2A受体的敏感度。因此，5-HT2A受体调节剂可用于激素变异相关症状的管控。
根据本发明的一个实施方式，利培酮可以用于治疗激素变异症状。利培酮(美国市场上的
)是一种抗精神病药，通过干扰脑神经间的通信来发挥作用。利培酮的作用是作为5-HT2A拮抗剂，可以用来在低剂量上快速有效地阻断5-HT2A激动剂的作用。利培酮也是一种高效的2型(D2)多巴胺和α2肾上腺素能受体拮抗剂。因而，利培酮被用来治疗精神疾病，例如精神分裂症。然而，如以下几节中所述，出乎意料地研究发现利培酮可以有效地减少或消除与激素变异相关的症状。
根据本发明的另一个实施方式，可以用9-羟基利培酮治疗激素变异症状。9-羟基利培酮是利培酮的主要活性代谢物，它们具有类似的对5-HT2A受体和D2受体的结合特性和亲和力。(Leysen等，“Risperidone:a novel antipsychoticwith balanced serotonin-dopamine antagonism,receptor occupancy profile,andpharmacologic activity(利培酮：一种均衡地具有5-羟色胺-多巴胺拮抗作用、受体占用特性、以及药理活性的新型抗精神病药)”，J Clin Psychiatry:55增补:5-12(1994))。就像利培酮，9-羟基利培酮因其对5-HT2A和/或多巴胺受体的拮抗剂活性可以有效地治疗或预防与激素变异相关的症状。
除利培酮和9-羟基利培酮外，其他可以结合5-HT2A和/或D2多巴胺受体的受体拮抗剂也可以用来控制与激素变异相关的症状。这些其他的拮抗剂包括例如喹硫平、氯氮平、奥氮平、阿立哌唑、齐拉西酮和佐替平。
根据本发明的另一个实施方式，可以用喹硫平治疗激素变异症状。喹硫平的抗精神病效果是由其对多巴胺和5-HT受体的拮抗剂活性介导的。具体来说，能够拮抗多巴胺受体D1、D2和5-HT受体、5-HT1A及5-HT2亚型。
评估喹硫平的D2多巴胺占用情况的连续PET扫描显示，喹硫平快速地从D2受体解离。理论上，这样就可以得到正常的多巴胺生理起伏，以引发其在诸如黑质纹状体及结节漏斗部途径等区域中的正常效应，因而最大限度地降低副作用的风险，比如假性帕金森综合征和催乳激素的上升。喹硫平对H1组胺受体也有拮抗作用。这可能就是该药物镇定作用的原因。
根据本发明的部分实施方式，可以用氯氮平治疗激素变异症状。氯氮平属于“非典型性”抗精神病药，因为其多巴胺受体结合特性及其对各种多巴胺介导的行为的作用与更加典型的抗精神病药物所表现的有差异。特别地，氯氮平对D4受体的亲和力高，且其对多巴胺与D1、D2、D3和D5多巴胺受体结合的干扰程度较低。但是，氯氮平不会诱发僵住症，它也不会有见于“常规”安定药的对动物模型中阿扑吗啡诱发表型的抑制作用。这一证据表明氯氮平有选择地对缘多巴胺受体比对纹状体多巴胺受体的活性更高，而且也可以解释其相对温和的锥体束外副作用及其强劲的抗胆碱能活性。氯氮平还是肾上腺素能、胆碱能、组胺能和5-羟色胺能受体不同亚型的强效拮抗剂。
根据本发明的部分实施方式，可以用奥氮平治疗激素变异症状。奥氮平在结构上类似于氯氮平，对多巴胺和5-羟色胺受体的亲和力高。奥氮平对组胺、胆碱能、毒覃碱和α-肾上腺素能受体的亲和力低。奥氮平的作用机理尚不得而知。然而，据信奥氮平的抗精神病活性主要是由多巴胺受体，具体是D2多巴胺受体的拮抗作用介导的。5-HT拮抗作用对于奥氮平的效果也有影响。然而，研究人员对于5-HT2A拮抗作用的意义是有争论的。
根据本发明的部分实施方式，可以用阿立哌唑治疗激素变异症状。阿立哌唑(施贵宝公司(Bristol-Myers Squibb)的Abilify品牌)是一种新型非典型性抗精神病药物，等待美国食品药品管理局FDA批准用于治疗精神分裂症。阿立哌唑已得到FDA批准用于治疗双相性精神障碍的急性躁狂发作和混合发作。阿立哌唑似乎主要是通过作为D2受体的部分激动药来介导其抗精神病效应的。D2受体的部分激动药具有分别在多巴胺活性可能高也可能低的区域调节多巴胺能活性的能力，比如在精神分裂症患者大脑中的中脑边缘区及中脑皮层(mesocortical)区。除了D2受体的部分激动活性，阿立哌唑还是5-HT1A受体的部分激动药。就像其他非典型性抗精神病药，阿立哌唑对5-HT2A受体表现出拮抗剂活性。阿立哌唑对组胺和α-肾上腺素能受体有中等亲和性，但对胆碱能毒蕈碱受体无明显亲和力。
根据本发明的部分实施方式，可以用齐拉西酮治疗激素变异症状。齐拉西酮对多巴胺、5-羟色胺和α-肾上腺素能受体的亲和力高，而对组胺受体的亲和力中等。齐拉西酮在“非典型性药”中有点独特性，因为它还能够抑制5-羟色胺和去甲肾上腺素的突触再摄取，虽然其临床意义尚不得而知。齐拉西酮作用机理尚不得而知。然而，其抗精神病活性据信主要是由对多巴胺受体，具体是D2多巴胺受体的拮抗作用介导的。5-羟色胺拮抗作用可以也对齐拉西酮的有效性有影响,但齐拉西酮的5-HT2A拮抗作用的意义在研究人员中有争论。类似地，对组胺及α肾上腺素能受体的拮抗作用可解释齐拉西酮的部分副作用，比如镇定作用及静态平衡位(orthostasis)。
根据本发明的部分实施方式，可以用佐替平治疗激素变异症状。佐替平对D1和D2多巴胺受体亲和力高。它还影响5HT2A、5HT2C、5HT6和5HT7受体。除此之外，它还抑制去甲肾上腺素的再摄取。
临床实施例
提供以下实施例是为了说明本发明的实施方式能够减少包括热潮红、盗汗以及血压波动在内的激素变异症状。本发明的实施方式对于各种状况下的病人有效。然而，本领域普通技术人员可以了解，这些实施例仅是说明性的，并非旨在以任何方式限制本发明的范围。
本发明的实施方式涉及给予治疗有效量的5-HT2A和/或D2多巴胺受体拮抗剂(比如利培酮或9-羟基利培酮)，以缓解与激素变异相关的症状。例如，利培酮被用在若干病人身上成功缓解了热潮红或其他激素变异症状的出现。以下描述了四位不同病人的四个具体例子，以说明利培酮在缓解激素变异相关症状中的有效性。本领域普通技术人员会了解，这些具体例子并非旨在限制本发明的范围。例如，本发明的实施方式可以使用其他用药方案，包括其他的5-HT2A和/或D2多巴胺受体拮抗剂在内。
病人1:利培酮在做了子宫切除术的病例中消退热潮红
一位68岁的妇女因热潮红、高血压和坐立不安于2004年12月入院。在16年里她都被告知她患了原发性高血压并且已用抗高血压药若干年。然而，她的血压仍然在波动，而且在因高血压突然发作舌下给予硝苯吡啶(adalate(l0mg))后经常性地下降到低于临界值。除在45岁时做了腹式全子宫切除术外，她没有精神病或全身性疾病史。入院后，观察到她的热潮红发作每天出现许多次、持续几分钟，而且常常随后发生最高达180-200/84-96mmHg的高血压、全身战栗、焦虑达20-60分钟。这种临床症状从50岁左右开始且日益恶化。
她的生化及血液检查结果都在正常范围之内，比如钠和钾的水平分别是140mmol/L和4.0mmol/L。血浆考的松水平在正常范围内，而且呈现昼夜节律。血浆肾上腺素、去甲肾上腺素、VMA、肾上腺素和多巴胺水平以及甲状腺激素，包括T3、T4、和TSH在内，也都正常。分别评估交感神经及副交感神经功能的SSR和RRIV试验显示她的植物神经系统正常。EEG显示，没有局限型癫痫样放电，也没有异常背景活动。脑MRI显示老龄化大脑改变，但下丘脑或脑干中没有损伤。24小时的霍特尔描记显示正常的窦性心律。超声心动描记术显示心腔大小正常、左心室收缩性能及壁运动正常。
在观察了一个月之后，该病人接受了每天0.625毫克
每天20毫克
和每天20毫克
的治疗，各为期1-2个月，取得有限的成功。因为雌激素戒断能通过提高下丘脑5-HT2A受体的敏感性而改变下丘脑中的体温调整设定点，5-HT2A拮抗剂方案可以为诸如热潮红等激素变异症状提供有效疗法。因而，该病人用利培酮(2毫克/天)进行了治疗。治疗三天之后，她的热潮红显著地降低到了每1-2周一次的频率。相关症状，比如心悸和焦虑，同样得到显著改善。之后即减少了抗高血压药的剂量。得到病人允许后，停止了利培酮治疗，在停止治疗后的2-3天内热潮红再次出现。恢复利培酮治疗后的3-4天症状再次得到缓解。
病人2：利培酮消退自然绝经期的热潮红
病人2是一名57岁的妇女，她于7年前出现自然绝经期之后开始有不能忍受的热潮红及盗汗。虽然她对激素替代疗法响应良好(毫克/天)，但她因担心乳腺癌风险而在本研究之前的一年停止了该疗法。在停止激素替代疗法一个月之后，她出现了每天最多达10次的热潮红、影响其睡眠的每夜最多达3次的盗汗、以及头痛。于是该病人寻求神经学会诊。该病人还患有一天两次的头痛和血压波动。利培酮开始时的剂量是每天2毫克，病人报告利培酮治疗开始两天后热潮红的出现即显著减少，第7天即完全消除。此外，她睡眠良好而且血压稳定。为评估利培酮疗法与热潮红消除之间的关系,用两天的时间逐渐撤除了利培酮。在利培酮治疗完全停止之后两天，病人再次出现热潮红及盗汗。恢复每天2毫克的利培酮，病人自此之后再无热潮红出现。
病人3：利培酮消退围绝经期热潮红
病人3是一名46岁的妇女，基于促卵泡激素水平升高、月经周期长度变化增大、热潮红发病以及失眠，她被诊断处于围绝经期。该病人出现这种症状已有两年。她对雌激素疗法响应良好。由于健康风险，病人停止了雌激素治疗而寻求辅助疗法，比如大豆异黄酮，但未成功。开始进行利培酮治疗(每晚1毫克)。当时，病人每天经历7次热潮红。利培酮疗法开始后3天，病人报告其热潮红频率和强度显著降低。得到她允许后，在两天内逐渐撤除了利培酮，三天之后热潮红再次发病。恢复利培酮治疗(日剂量1毫克)，病人再未经历热潮红，其睡眠和生活质量得到改善。三个月后，利培酮剂量降至每天0.25毫克，病人的热潮红仍然显著地得到消除。
病人4：利培酮消退了激素替代疗法病例的残存热潮红
病人4是一名56岁的妇女，她有频率为每小时一次的热潮红、心悸、失眠症、头痛、不安、以及血压不稳等已达7年。起初，该病人因睡眠障碍去看精神病学家，因高血压去看心血管专家。一年之后，她因无法忍受的热潮红及其他绝经期症状而接受了激素替代疗法
虽然热潮红降低至每天两次，但头痛依旧，而且尽管用抗高血压药治疗，血压还是在波动，从180至210/110至90毫米汞柱。病人开始利培酮治疗，头两天上床时给药1毫克，然后每晚2毫克，用于治疗残存热潮红。在利培酮疗法开始后三天，病人的热潮红完全消除。另外，该病人能够每天用激素四次，并且停用了抗高血压药，因为血压稳定在正常范围内。
以上数据清楚地显示，利培酮或类似的受体拮抗剂对于缓解诸如热潮红及血压波动等激素变异相关症状是有效的。另据设想，施用本发明的化合物用于缓解激素变异相关症状，可以和可用于治疗包括热潮红在内的激素变异症状的其他适当治疗方法联合进行。
尽管无意受限于这些受体拮抗剂缓解激素变异症状的机理，但本发明人相信，这些药物可能是通过抑制5-HT2A5-羟色胺受体、D2多巴胺受体、和/或α1-肾上腺素能受体发挥作用的。
绝经期是一个自然过程，作为正常老龄化的一部分出现在妇女的生命历程中。大约三分之一的妇女很少或没有症状，而其余的人可能有显著的，甚至病废性的症状，比如严重的热潮红。热潮红一般是全身性的，很可能是缘于位于视前区下丘脑前部的体温调节定点中枢的改变，涉及到多巴胺、5-羟色胺、去甲肾上腺素及α-肾上腺素能受体(Steams等，“Hot flashes(热潮红)”，Lancet360;1851-1861(2002年))。
利培酮是一种苯并异噁唑衍生物，是一种非典型性抗精神病药物，其能够高亲和性地结合2A型5-羟色胺5-HT2A、2型多巴胺(D2)及α1-肾上腺素能受体。利培酮结合α2-肾上腺素能和H1组胺受体的亲和性低。利培酮不结合D1多巴胺受体，对毒蕈碱胆碱能受体没有亲和力(在浓度>10-5M测试时)。(Grant和Fitton，“Risperidone，A review of its pharmacology and therapeutic potential in thetreatment of schizophrenia(利培酮：其用于治疗精神分裂症的药理学及治疗潜力综述)”，Drug,48:253-273(1994年)；Ota等，“Peripheral injection of risperidone,an atypical antipsychotic,alters the body weight gain of rats(非典型性抗精神病药利培酮外周注射改变大鼠体重增加)”，Clin Exp pharmacol.physiol,29:980-989(2002年))。
试验数据表明，刺激5-HT2和多巴胺受体可以提高体温。例如，直接刺激5-HT2A受体还可以在动物模型中诱发体温过高，而给予5-HT2A拮抗剂可以预防5-羟色胺综合征动物模型中的体温过高。然而，给予啮齿动物和人类5-HT1A激动剂会导致核心体温下降。这些结果表明，两个5-HT受体亚型，5-HT1A和5-HT2A，与体温控制密切相关(Oether等，“Involvement of 5-HT1A and 5-HT1Breceptors for citalopram-induced hypothermia in the rat(5-HT1A和5-HT1B受体在西酞普兰诱发的大鼠体温过高中的作用)”，Psychopharmacology，154:429-434(2001年)；Salmi和Ahlenius，“Evidence for functional interactions between5-HT1A and 5-HT2A receptors in rat thermoregulatory mechanisms(大鼠体温调节机制中5-HT1A和5-HT2A受体功能互动的证据)”，Pharmacol.Toxicol.,82:122-127(1998年))。
在绝经期内，性激素，特别是雌激素水平的显著下降可能导致血中5-羟色胺(5-HT)水平的显著降低。5-羟色胺水平下降提高了下丘脑中5-HT2A受体的敏感性(Berendsen HH，“The role of serotonin in hot flashes(5-羟色胺在热潮红中的作用)”，Maturiatas,36:155-164(2000年))。因而，当诸如焦虑等内部或外部刺激诱发5-羟色胺释放以刺激5-HT2A受体敏感性提高时，体温的设定点改变并出现热潮红。
脉冲式促黄体激素(LH)分泌理论是热潮红发病的另一种常见解释，因为LH-RH激动剂给药可能产生热潮红。多巴胺能系统似乎在脉冲式促黄体激素(LH)分泌和绝经后妇女热潮红中都涉及到。抗多巴胺能药(anti-dopaminergicdrugs)可通过直接降低对体温调节核的肾上腺素能影响而作用于体温调节核以降低热潮红，或间接地通过诸如由高催乳素血症对具有继发性类多巴胺活性的结节-漏斗部多巴胺神经元产生的短回路反馈作用等机理、或通过刺激阿片类系统(Melis GB等，“Effects of the dopamine antagonist veralipride on hot flashesand luteinizing hormone secretion in postmenopausal somen(多巴胺拮抗剂维拉必利对绝经后妇女热潮红及促黄体激素分泌的影响)”，Obstet.Gynecol.72:688-692(1988年)；Wesel等，“Veralipride versus conjugated oestrogens:adouble-blind study in the management of menopausal hot flashes(维拉必利与偶联雌激素对比：绝经期热潮红管控中的双盲试验)”，Curr.Med.Res.Opin.,8:696-700(1984年))。
利培酮对5-HT2A和D2受体亲和性高。利培酮可以抵消5-HT活性的提高、以及降低5-羟色胺综合征中下丘脑前部的去甲肾上腺素活性(Nisijima等，“Risperidone counteracts lethality in an animal model of the serotoninsyndrome(利培酮抵消5-羟色胺综合征动物模型中的致死)，Psychopharmacology150:9-14(2000年))。除此之外，利培酮可提升健康受试者及精神分裂症患者的循环催乳激素水平(Markianos等，“Neuroendocrine serotonergic anddopaminergic responsivity in male schizophrenic patients during treatment withneuroleptics and after switch to risperidone(用神经镇静药治疗期间和转换至利培酮之后，男性精神分裂症患者的神经内分泌5-羟色胺能和多巴胺能响应)”，Psychopharmacology，157:55-59(2001年))。利培酮还可以通过对结节-漏斗部多巴胺神经元回路的抗多巴胺能作用以及对下丘脑前部中去甲肾上腺素活性的抗多巴胺能作用减少或预防热潮红。
本发明实施方式的优点包括以下的一项或多项。本发明的实施方式可以提高用于治疗包括热潮红和盗汗在内的激素变异症状的组合物和方法。此外，这些方法和组合物还可以实现血压的正常化以及消除/减少心悸。本发明的组合物可以包含2A型5-羟色胺(5-HT2A)受体、2型多巴胺(D2)受体、和/或α1-肾上腺素能受体拮抗剂，且可以提供多多的治疗选择，用于改善经历激素变异症状妇女的生活质量。
尽管本发明结合数量有限的实施方式进行了描述，本领域技术人员会了解，可以设计出其他实施方式而不会背离在此所揭示的本发明的范围。因此，本发明的范围仅由所附权利要求书限定。
Claims (11)
1.化合物在制备用于治疗与绝经后的激素变异相关联的一种或多种症状的药物中的应用，其中，所述化合物选自9-羟基利培酮；所述症状选自热潮红、盗汗和心悸。
2.化合物在制备用于治疗与围绝经期的激素变异相关联的热潮红的药物中的应用，其中，所述化合物选自9-羟基利培酮。
3.如权利要求1所述的应用，其特征在于，所述症状是热潮红和/或盗汗。
4.如权利要求3所述的应用，其特征在于，所述症状是热潮红。
5.如权利要求2或4所述的应用，其特征在于，所述药物是包含0.1-50毫克9-羟基利培酮的剂型。
6.如权利要求2或4所述的应用，其特征在于，所述9-羟基利培酮的量是每天每千克体重0.002-0.5毫克。
7.如权利要求2或4所述的应用，其特征在于，所述9-羟基利培酮的量是每天每千克体重0.005-0.1毫克。
8.如权利要求2或4所述的应用，其特征在于，所述9-羟基利培酮的量是每天每千克体重0.005-0.034毫克。
9.如权利要求1所述的应用，其特征在于，所述9-羟基利培酮的量是每天2毫克。
10.如权利要求2所述的应用，其特征在于，所述9-羟基利培酮的量是每天1毫克。
11.如权利要求1，2或3所述的应用，其特征在于，所述药品是选自口服剂、注射剂、吸入剂或透皮贴剂的剂型。
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| MX2009006672A (es) * | 2006-12-19 | 2009-10-26 | Univ Virginia | Efectos combinados de topiramato y ondansetron sobre el consumo de alcohol. |
| CA2697990A1 (en) * | 2007-08-27 | 2009-03-05 | University Of Virginia Patent Foundation | Medication combinations for the treatment of alcoholism and drug addiction |
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| EP2255184B1 (en) | 2008-02-28 | 2013-04-24 | University Of Virginia Patent Foundation | Serotonin transporter gene and treatment of alcoholism |
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| US8461102B2 (en) | 2010-03-02 | 2013-06-11 | George E. Royster, JR. | Methods and compositions for treating and preventing symptoms of hormonal variations |
| US20130190299A1 (en) * | 2010-06-30 | 2013-07-25 | Victoria Link Ltd. | Methods and compositions for treatment of multiple sclerosis |
| EP2801625B1 (en) | 2010-07-02 | 2017-11-01 | University Of Virginia Patent Foundation | Molecular genetic approach to treatment and diagnosis of alcohol and drug dependence |
| US20140030329A1 (en) * | 2011-05-10 | 2014-01-30 | Chui Yu Liu | Methods for Treating Insomnia |
| EA027743B1 (ru) | 2011-09-09 | 2017-08-31 | Юниверсити Оф Вирджиния Пэтент Фаундейшн | Молекулярно-генетический подход для лечения и диагностики алкогольной и наркотической зависимости |
| CN105744835A (zh) | 2013-07-22 | 2016-07-06 | 俄亥俄州国家创新基金会 | 用于减少热潮红发生的方法 |
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