CN1568183A - 用于治疗升高的血压的西酞普兰 - Google Patents
用于治疗升高的血压的西酞普兰 Download PDFInfo
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- CN1568183A CN1568183A CNA038012936A CN03801293A CN1568183A CN 1568183 A CN1568183 A CN 1568183A CN A038012936 A CNA038012936 A CN A038012936A CN 03801293 A CN03801293 A CN 03801293A CN 1568183 A CN1568183 A CN 1568183A
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Abstract
本发明涉及西酞普兰或其可药用盐在制备适于治疗升高的(高)血压、使血压正常化或降低升高的血压和/或预防升高的血压的药物组合物中的应用。
Description
发明领域
本发明涉及西酞普兰(citalopram)的新应用。
发明技术背景
已知1-(3-二甲氨基-丙基)-1-(4-氟-苯基)-1，3-二氢-5-异苯并呋喃-腈(INN西酞普兰)是众所周知的抗抑郁药物活性成分(DE 2,657,103)。在EP 346,066中描述了光学活性的(S)-西酞普兰也具有抗抑郁活性。
已知若干用于制备西酞普兰的合成方法(WO 98/19512和WO98/19513)。
从包含西酞普兰的产品信息宣传品(例如“Celexa Side EffectsCelexa Drug Interactions Citalopram-Rx List Monographs”)中得知，在用西酞普兰治疗抑郁的过程中，血压过低作为不合需要的副作用会发生。
然而，这并不意味着西酞普兰被宣称作为使高血压患者血压正常化的产品。第一：上面提及的参考文件没有涉及高血压患者。第二：它公开了“虽然在用CelexaTM进行治疗的过程中发生了报导的病例，但是由CelexaTM引起的所述副作用不是必然的(“CelexaTM”是包含西酞普兰的产品的商标)”。第三：事实是高血压(即与低血压相反)也被作为不合需要的副作用提出，强烈地支持了此陈述，即参考文献没有包含明显的由西酞普兰引起低血压的教导。第四：不合需要的血压过低的诱导不是血压正常化效应，因为低血压本身是不正常的血压。基于上述理由，所引用的参考文献没有教导或公开应用西酞普兰来分别治疗高血压、使血压正常化或降低升高的血压。
前面所述的参考文献也涉及信息宣传品“SEROPRAM product，active ingredient CITALOPRAM”，其中提及作为不合需要的副作用的体位性低血压的情况。
发明概述
本发明的目标是研究西酞普兰或其可药用盐的新应用。
在本发明的帮助下，上述目标以出乎意料的方式被解决了。
本发明涉及西酞普兰或其可药用盐在制备适于治疗升高的(高)血压、使血压正常化或降低升高的血压和/或预防血压升高的药物组合物中的应用。
发明详细说明
在本专利说明书中使用的术语的定义如下：
术语“可药用盐”涉及与可药用无机酸或有机酸形成的盐。这些盐是盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、醋酸盐、酒石酸盐、马来酸盐、富马酸盐、乳酸盐、马来酸盐、苯基磺酸盐等等。
术语“高血压”指血压为180/110Hgmm或更高值。
术语“正常血压”指血压为130/80Hgmm±10Hgmm。
可以使用西酞普兰的外消旋化合物或光学活性形式，例如(S)-西酞普兰。
西酞普兰具有众多超过已知抗高血压剂的优点。通常，在临床实践中使用抗高血压剂不能达到血压的正常化，部分是因为血压的波动，部分是由于血压降到了低于正常水平。大多数已知的抗高血压剂的缺点是诱导失眠、疲劳、特别是在清晨的激惹现象、注意力不集中、记忆和心情问题、运动减少。另一方面，西酞普兰不引起焦虑和情感障碍，其主要的适应症降低恰恰是治疗了这种障碍。
西酞普兰可以被极好地应用于使血压正常化。在用通常使用的抗高血压剂治疗的过程中很常见的是，先前是正常血压或低血压的并从抑郁或焦虑性障碍中康复的患者在数月或数年后变为了高血压。在这些病例中，用西酞普兰替代迄今使用的抗高血压剂除了使血压正常化外，还消除了情感性和焦虑性疾病。
按照本发明的优选的具体实施方式，西酞普兰或其可药用盐被用来治疗和/或预防不稳定性血压升高。
按照本发明进一步优选的具体实施方式，西酞普兰或其可药用盐被用来治疗和/或预防在惊恐性障碍患者身上发生的血压升高。
不稳定性高血压不仅仅是20岁左右的年轻一代所特有的。实践证明，不稳定性高血压在儿童期至老年期都存在，并且经常呈现惊恐性障碍的最初迹象。然而，这只是外表上的观察。广泛的既往病史揭示，情感障碍或惊恐性障碍，有时仅是一、两次零星的惊恐发作，在老龄患者的医学史上已有发生。
基于上述理由，西酞普兰尤其适用于并且优选来治疗上述类型的升高的血压。
伴随惊恐性障碍发生的不稳定性高血压在经过一段时间后会转变成严重的固定高血压。已经出乎意料地发现，西酞普兰在治疗上述疾病方面是有用的，也就是使同时伴随惊恐性障碍所有症状的不稳定性血压正常化，包括惊恐性发作、期待焦虑、广场恐怖、和半数与抑郁相关的惊恐性障碍病例。
在上述疾病的情况下，高血压的发生指示施用西酞普兰的必要性。
按照本发明另外优选的具体实施方式，西酞普兰或其可药用盐被用来治疗和/或预防原发性升高的血压。
80％血压升高的患者是原发性高血压。假定术语“原发性”是指在大多数病例中(相关的高血压小组)对西酞普兰(应激性)完全响应。
按照本发明另外优选的具体实施方式，西酞普兰或其可药用盐被用来预防和/或治疗中风。
已知众多中风患者属于高血压患者。中风是世界范围内严重的有害因素。全世界约有五千五百万人患有不稳定性高血压，但是从不稳定性高血压起源的固定高血压患者的数目则要高若干倍。
在匈牙利，1979年有170,000名年龄低于40岁的患者患有中风并死亡。
西酞普兰能被用来长期单独或是与其它抗高血压剂结合治疗高血压。
西酞普兰在单独治疗中已经改善了温和的或中度的高血压。在更多严重的病例中，西酞普兰也显示明显的抗高血压作用，即另外的抗高血压剂可以较低的剂量给药。相应地，在每天的医疗实践中，西酞普兰使血压正常化。
按照本发明另外的优选具体实施方式，制备药物组合物，其包含西酞普兰或它的可药用盐以及另外的抗高血压剂。为此，例如可以使用如下的抗高血压剂：具有中枢性作用的抗高血压剂，优选甲基多巴、氯压定、胍法新、氯压胍；β-阻断剂，优选醋丁酰心安、氨酰心安、倍他洛尔、比索洛尔、喹酮心安、心得安、美多洛尔、纳多洛尔、喷布洛尔、吲哚洛尔、噻吗洛尔、布新洛尔、拉贝洛尔、卡维洛尔、nevibolol；α-阻断剂，优选哌唑嗪、特拉唑嗪、多沙唑嗪、三甲氧唑嗪、酚苄明、酚妥拉明；直接血管扩张剂，优选肼苯哒嗪、长压定、氯甲苯噻嗪、非诺多巴；钙通道阻滞剂，优选维拉帕米、地尔硫、硝苯地平、尼莫地平、费乐地平、尼卡地平、伊拉地平、氨氯地平、尼索地平、拉西地平；ACE-抑制剂，优选卡托普利、依那普利、赖诺普利、喹那普利、雷米普利、贝那普利、福森普利、甲硫普利、喹那普利、哌道普利、雷米普利、群多普利；血管紧张素II受体拮抗剂，优选氯沙坦、坎地沙坦、阿比沙坦、缬沙坦、替米沙坦、依普罗沙坦；咪唑啉受体激动剂，优选莫索尼定、利美尼定。上述列举只是作为范例的目的，而不构成限制。
本发明的抗高血压药物组合物优选除包含西酞普兰或其可药用盐外还包含至少一种可药用惰性载体和/或辅剂。
按照本发明制备的包含西酞普兰的抗高血压药物组合物优选口服或肠胃外给药。用于口服给药的，例如片剂、包衣片剂、硬或软明胶胶囊。也可以使用糖衣丸、溶液剂、混悬剂或乳剂。胃肠外药物组合物例如可以是静脉内、肌内或腹膜内注射液。
口服给药的固体药物组合物除包含活性成分外还包含常用的药用赋形剂。出于此目的，例如可以使用粘合剂(例如明胶、山梨醇和/或聚乙烯吡咯烷酮)，载体(例如乳糖、葡萄糖、淀粉和/或磷酸钙)，压片辅剂(例如硬脂酸镁、滑石粉和/或二氧化硅)和/或润湿剂(例如十二烷基硫酸钠)。
口服给药的液体药物组合物例如可以是溶液剂、混悬剂或乳剂。这种组合物可以包含混悬剂(例如明胶和/或羧甲基纤维素)，乳化剂(例如失水山梨糖醇单油酸酯)，溶剂(例如水、油、甘油、聚乙二醇和/或乙醇)和/或防腐剂(例如甲基-p-羟基-苯甲酸酯)。
肠胃外给药的药物组合物优选是活性成分与水或等渗氯化钠溶液形成的无菌溶液。
用作抗高血压剂的西酞普兰的每日剂量优选为约0.01mg/kg体重-约2mg/kg体重，尤其为约0.07mg/kg体重-1mg/kg体重。西酞普兰的初始剂量优选是约5mg/天，在其后的数月，稳定剂量是约20-60mg/天。(S)-西酞普兰的剂量大约是上述值的一半。
在口服治疗的情况下，以输注形式给西酞普兰可能是必须的(初始“负荷”剂量)。
按照本发明的另一方面，其提供了治疗升高的(高)血压、使血压正常化或降低升高的血压和/或预防血压升高的方法，包括向需要此治疗的患者施用药学有效量的西酞普兰和/或其可药用盐。
按照本发明优选的具体实施方式，所述治疗方法被用于治疗患不稳定性升高的血压的患者。
按照本发明另一优选的具体实施方式，所述治疗方法被用来治疗患不稳定性血压合并惊恐性障碍的患者。
按照本发明的另一优选的具体实施方式，所述治疗方法被用来治疗患原发性升高的血压的患者。
按照本发明另一优选的具体实施方式，所述治疗方法被用来治疗患中风或易患中风的患者。
通过下面的试验来证明西酞普兰的抗高血压作用。
I.研究
西酞普兰抗高血压作用验证
254名患者参与此研究。所有患者都有高血压。在此高血压组中，120名患者患有惊恐性障碍和广场恐怖，70名患者患有惊恐性障碍合并广场恐怖及抑郁，64名患者患有惊恐性障碍合并广场恐怖及社交恐怖症和/或合并强制性障碍(OCD)。
在第一个星期以5mg/天的剂量给患者施用西酞普兰，在第二个星期10mg/天，在第三和第四个星期20mg/天。
经过4星期治疗，170名患者(67％)完全康复。这些患者血压正常，焦虑性和情感性障碍症状完全消失。
继续以20mg/天的口服剂量用西酞普兰治疗剩余的84名患者。在所述84名患者中，64名患者另外用美多洛尔以2×50mg/天的剂量口服治疗3个星期，20名患者以2×12.5mg/天的剂量给予卡托普利。6星期后获得完全康复，患者血压正常，焦虑性和情感性障碍症状完全消失。
治疗的结果是患不稳定性高血压的患者康复。
上述结果清楚地显示西酞普兰使升高的血压复原，使不稳定性高血压正常化，恢复患者的正常血压状态并另外治愈高血压患者的各种焦虑和抑郁症状。
II.研究
预先用抗抑郁药治疗的不稳定性高血压患者的研究
参予此研究的13名不稳定性高血压患者还患有各种焦虑性障碍和抑郁症。这些患者中3名患有惊恐性障碍，1名患有强制性障碍，9名患有惊恐性障碍合并抑郁。在用下面的抗抑郁药治疗初期，这些患者血压正常。
口服帕罗西丁40mg/天、或舍曲林100mg/天、或氟西汀20mg/天、或三氟戊肟胺150mg/天来治疗患者。在6个月后60％的患者，在12-30个月后40％的患者，除他们的精神病状态恢复正常以外，变成了高血压。
此后用西酞普兰替代上述提及的抗抑郁药。在第一个星期西酞普兰的口服剂量是5mg/天，在第二个星期是10mg/天，在第三个星期是20mg/天。出乎意料地，在治疗结束时，患者变得血压正常。
上述试验结果证明，与参考的抗抑郁剂相反，西酞普兰能够使伴随焦虑和情感性障碍出现的不稳定性高血压正常化。从上述出乎意料的结果清楚地得出，强烈建议开始用西酞普兰来治疗患高血压的焦虑和抑郁患者。
III研究
患有高血压但是无焦虑或抑郁症的患者的研究
在此试验中，有102名高血压患者参与，他们自述有下列症状：攻击样头疼，眩晕，颤抖，出汗，流汗，惧怕死亡，对热和冷敏感及胃肠道疾病。患者认为他们的疾病是惊恐发作的结果，但是这没有以明确的方式得到他们的精神病学既往病史的支持。
在第一个星期，以5mg/天的剂量口服西酞普兰来治疗患者，在第二个星期10mg/天，在第三个星期20mg/天。在三个星期的治疗后，47名患者(46％)康复并变得血压正常。
对于55名无反应的患者，除给予西酞普兰20mg/天以外，40名患者(39％)以100mg/天的口服剂量给美多洛尔，15名患者(15％)以2×12.5mg/天的剂量给卡托普利。在六个星期的治疗后，获得完全康复，并且患者变得血压正常。
上述结果充分显示西酞普兰使高血压正常化，并且也消除了由高血压诱导的惊恐样症状。在这些病例中也强烈建议开始用西酞普兰来治疗。
因此，西酞普兰适合于单独治疗或结合治疗伴随非情感障碍发生的高血压。
IV研究
患惊恐性障碍和/或情感障碍的患者的研究，他们的病例报告包含至少一次高血压发作
25名患有惊恐性障碍和/或情感障碍的患者参与了此项研究。在这些患者的医疗历史中显示有至少一次高血压发作。在第一个星期，以5mg/天的剂量让患者口服西酞普兰，在第二个星期10mg/天，在第三个星期20mg/天。患者完全响应治疗，惊恐性障碍和情感障碍的综合症状彻底停止并且血压维持在正常范围。
上述结果显示，对于患有惊恐性障碍和/或情感障碍且他们的病例记录包含至少一次高血压发作的患者，西酞普兰是极好的选择。即高血压发作可以被认为是必须使用西酞普兰的生物学标志。
V研究
父母患有高血压或中风的抑郁症患者研究
患有焦虑或情感障碍的患者参与此研究，他们父母中的至少一位患有高血压或中风。已经发现，在用西酞普兰以上面公开的口服剂量治疗患者后，在较长的时期内血压维持正常，并且焦虑和抑郁症状也消失。利用任何其它抗抑郁药进行的治疗都不能产生完全的响应。因此，利用西酞普兰治疗上述组的患者是高度优选的。
Claims (15)
1.西酞普兰或其可药用盐在制备适于治疗升高的(高)血压、使血压正常化或降低血压和/或预防升高的血压的药物组合物中的应用。
2.根据权利要求1的应用，制备适于治疗和/或预防不稳定性升高的血压的药物组合物。
3.根据权利要求1或2的应用，制备适于治疗和/或预防惊恐性障碍患者的升高的血压的药物组合物。
4.根据权利要求1的应用，制备适于治疗和/或预防原发性升高的血压的药物组合物。
5.根据权利要求1的应用，制备适于预防和/或治疗中风的药物组合物。
6.根据权利要求1-5中任一项的应用，其中使用外消旋西酞普兰。
7.根据权利要求1-5中任一项的应用，其中使用(S)-西酞普兰。
8.根据权利要求1-7中任一项的应用，其中将西酞普兰或其可药用盐与另外的抗高血压剂一起使用。
9.根据权利要求8的应用，其中使用至少一种下述的抗高血压剂：具有中枢性作用的抗高血压剂，优选甲基多巴、氯压定、胍法新、氯压胍；β-阻断剂，优选醋丁酰心安、氨酰心安、倍他洛尔、比索洛尔、喹酮心安、心得安、美多洛尔、纳多洛尔、喷布洛尔、吲哚洛尔、噻吗洛尔、布新洛尔、拉贝洛尔、卡维洛尔、nevibolol；α-阻断剂，优选哌唑嗪、特拉唑嗪、多沙唑嗪、三甲氧唑嗪、酚苄明、酚妥拉明；直接血管扩张剂，优选肼苯哒嗪、长压定、氯甲苯噻嗪、非诺多巴；钙通道阻滞剂，优选维拉帕米、地尔硫、硝苯地平、尼莫地平、费乐地平、尼卡地平、伊拉地平、氨氯地平、尼索地平、拉西地平；ACE-抑制剂，优选卡托普利、依那普利、赖诺普利、喹那普利、雷米普利、贝那普利、福森普利、甲硫普利、喹那普利、哌道普利、雷米普利、群多普利；血管紧张素II受体拮抗剂，优选氯沙坦、坎地沙坦、阿比沙坦、缬沙坦、替米沙坦、依普罗沙坦；咪唑啉受体激动剂，优选莫索尼定、利美尼定。
10.根据权利要求1-9中任一项的应用，其中制备包含至少一种可药用惰性载体和/或辅剂的药物组合物。
11.治疗升高的(高)血压、使血压正常化、或降低高血压和/或预防高血压的方法，包括向需要此治疗的患者施用药学有效量的西酞普兰和/或其可药用盐。
12.根据权利要求11的方法，其包括治疗患有不稳定性升高的血压的患者。
13.根据权利要求11的方法，其包括治疗患有不稳定性血压的惊恐性障碍患者。
14.根据权利要求11的方法，其包括治疗患有原发性升高的血压的患者。
15.根据权利要求11的方法，其包括治疗患有或易患中风的患者。
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2004
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