CN1325304A - 用于治疗偏头痛的5ht1受体激动剂和甲氧氯普胺 - Google Patents
用于治疗偏头痛的5ht1受体激动剂和甲氧氯普胺 Download PDFInfo
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- CN1325304A CN1325304A CN99812756A CN99812756A CN1325304A CN 1325304 A CN1325304 A CN 1325304A CN 99812756 A CN99812756 A CN 99812756A CN 99812756 A CN99812756 A CN 99812756A CN 1325304 A CN1325304 A CN 1325304A
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- metoclopramide
- treatment
- administration
- migrainous
- stimulating agent
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract
本发明涉及在哺乳动物、包括人中治疗偏头痛的方法,该方法包括,将5HT1受体激动剂、特别是伊利曲坦与甲氧氯普胺联合向哺乳动物给药。本发明还涉及含有可药用载体、5HT1受体激动剂和甲氧氯普胺的药物组合物。
Description
本发明涉及通过向哺乳动物联合施用5HT1受体激动剂和甲氧氯普胺在哺乳动物、包括人中治疗偏头痛的方法。本发明还涉及含有可药用载体、5HT1受体激动剂和甲氧氯普胺的药物组合物。5HT1受体激动剂的例子是5HT1A、5HT1B、5HT1C、5HT1D、5HT1E和5HT1F受体中的一种或多种的激动剂。
将甲氧氯普胺和5HT1激动剂(例如伊利曲坦(eletriptan)、利扎曲坦(rizatriptan)、那拉曲坦、舒马普坦,但不包括唑米曲坦(zolmitriptan))联用对偏头痛进行急性治疗可以比目前采用的疗法产生更强的效力而较少出现恶心。
1975年,Volans证实了甲氧氯普胺有助于缓解偏头痛发作所伴随的胃停滞(参见Volans,G.N.,《英国药理学杂志》(British Journalof Pharmacology),1975年2月;2(1):67-73和Volans,G.N.,《临床药动学》(Clinical Pharmacokinetics),1978年7月;3(4):313-318)。他对该效应进行了研究,并证实口服给药的阿斯匹林和对乙酰氨基酚(扑热息痛)的血液水平在正经历偏头痛发作的患者中降低,并且该水平在偏头痛发作的间期恢复至正常。将甲氧氯普胺与阿斯匹林或对乙酰氨基酚一起使用可以增加这些药物的血液水平,使它们在治疗偏头痛时更为有效。
鉴于甲氧氯普胺可以增加口服5HT1激动剂的血液水平以及甲氧氯普胺的止吐和抗偏头痛作用,据信在与甲氧氯普胺联合给药时5HT1激动剂将会显示出明显更强的治疗偏头痛的效力。
甲氧氯普胺是苯甲酰胺衍生物,虽然它与精神安定剂有关,但却没有明显的抗精神病或镇定特性。甲氧氯普胺是多巴胺和5HT3受体拮抗剂,并且还具有某些5HT4激动剂活性。甲氧氯普胺的作用包括对阿朴吗啡或麦角胺引起的呕吐的拮抗作用。它还可以引起高催乳素血症,这是多巴胺能阻断的特点。甲氧氯普胺对多巴胺-2(D2)受体的亲和性相对较低。
发明概述
本发明涉及用于在哺乳动物、包括人中治疗偏头痛的药物组合物,该组合物含有甲氧氯普胺;5HT1受体激动剂或其可药用盐,其中不包括唑米曲坦;以及可药用载体。
本发明还涉及在哺乳动物、包括人中治疗偏头痛的方法,该方法包括,向所述哺乳动物施用治疗偏头痛有效量的含有甲氧氯普胺;5HT1受体激动剂或其可药用盐,其中不包括唑米曲坦;以及可药用载体的药物组合物。
本发明还涉及在哺乳动物、包括人中治疗偏头痛的方法,该方法包括,向所述哺乳动物施用可以使两种活性成分的组合在偏头痛的治疗或预防中有效之量的甲氧氯普胺;5HT1受体激动剂或其可药用盐,其中不包括唑米曲坦。
本发明的优选实施方案涉及上述治疗偏头痛的药物组合物和治疗偏头痛的方法,其中的5HT1受体激动剂选自伊利曲坦、那拉曲坦、利扎曲坦、舒马普坦、阿莫曲坦(almotriptan)、阿维曲坦(avitriptan)、氟伐曲坦(frovatriptan)、阿尼地坦(alniditan)、LY334370、LY306258、BMS-180048和BMS-181885。特别优选的实施方案是伊利曲坦和甲氧氯普胺的药物联用,预期伊利曲坦的药动学也将会改善。
其中R3、R4和Z彼此独立地选自氢、卤素(例如氯、氟、溴或碘)、任选性地被1-3个氟原子取代的(C1-C4)烷基、任选性地被1-3个氟原子取代的(C1-C4)烷氧基和其中的各烷基部分可以任选性被1-3个氟原子取代的(C1-C4)烷氧基-(C1-C4)烷基;
W是-CH2-O-(C1-C6)烷基,其中的烷基部分可以是直链或支链的;或者W是-CH2NR1R2,其中R1和R2彼此独立地选自氢和直链或支链的(C1-C6)烷基;
或者R1和R2与它们所连接的氮合在一起形成饱和的4元单环或饱和或不饱和的非芳香性5-7元单环或饱和或不饱和的非芳香性7-10元二环,除NR1R2的氮之外,这些环还可以任选性地含有一个或两个其它杂原子,其中所述杂原子彼此独立地选自氧、氮和硫,并且其中的1-3个环碳原子或环氮原子之一可以任选性地并且彼此独立地被直链或支链的(C1-C4)烷基、直链或支链的(C1-C6)烷氧基、直链或支链的(C1-C3)烷基-(C3-C7)环烷基、羟基、氨基、氰基、卤素、芳基-(直链或支链的(C1-C3)烷基)或杂芳基(直链或支链的(C1-C3)烷基)所取代,其中所述芳基选自苯基和萘基并且所述杂芳基选自噁唑基、异噁唑基、噻唑基、异噻唑基、呋喃基、吡唑基、吡咯基、四唑基、三唑基、噻吩基、咪唑基、吡嗪基、吡唑基、吲哚基、异吲哚基、吡嗪基、噌啉基、吡啶基和嘧啶基;
条件是在由NR1R2所形成的任何环中:(a)环氧原子不能超过一个;(b)不能有羟基、烷氧基、烷氧基烷基、氰基、氨基或烷基氨基部分直接与任何环氮原子相连;和(c)与另一个环碳原子以双键连接并且不是芳香族环系一部分的环碳原子不能与环氧原子或环氮原子相连。
发明详述
在以下专利和专利申请中举例说明了可在本发明的药物组合物和方法中与甲氧氯普胺联合使用的5HT1激动剂,并提到了其制备方法:美国专利5,545,644,1996年8月13日授权;欧洲专利776,323,1998年2月11日授权;美国专利5,618,834,1997年4月8日授权;世界专利申请PCT/EP98/04176(指定了美国),1998年7月1日申请;欧洲专利503,440,1998年6月18日授权;美国专利4,816,470,1989年3月28日授权;日本专利9,423,197,1994年3月30日授权;加拿大专利1,241,004,1988年8月23日授权;欧洲专利497,512,1997年9月24日授权;美国专利5,300,506,1994年4月15日授权;欧洲专利申请711,769,1996年5月15日公开;世界专利申请WO94/2460,1994年2月3日公开;美国专利5,541,180,1996年7月30日授权;欧洲专利申请591,280,1994年4月13日公开;欧洲专利639,192,1996年5月15日授权;欧洲专利申请674,621,1995年10月4日公开;和欧洲专利486,666,1997年8月13日授权。上述专利和专利申请均全文引入本文作为参考。
下述参考文献涉及以上提到的用于本发明的优选实施方案的某些5HT1激动剂的药理学性质:Robert等,《头痛》(Cephalagia)18(6):406,1998年7月/8月;Marathe等,Biopharm.Drug Dispos.19(6):381-94,1998年9月;Saxena等,《欧洲药理学杂志》(Eur.J.Pharmacol.)351(3):329-39,1998年6月26日;Goldstein等,《头痛》(Cephalagia)18(6):410,1998年7月/8月;Buchan等,《头痛》(Cephalagia)18(6):410,1998年7月/8月;Block等,《头痛》(Cephalagia)18(6):409-10,1998年7月/8月;和Sheftell等,《头痛》(Cephalagia)18(6):403-4,1998年7月/8月;Perry等,《药物》(Drugs)(新西兰)55(6):889-922,1998年6月;Bomhof等,《头痛》(Cephalagia)(挪威)18(1):33-7,1998年1月;Klasson等,《头痛》(Headaches)(美国)37(10):640-5,1997年11月/12月;Goldstein等,《头痛》(Cephalagia)(挪威)16(7):497-502,1996年11月;Parsons等,《心血管药理学杂志》(J.Cardiovasc.Pharmacol.)(美国)32(2):220-4,1998年8月;和Schoenen J.,Curr.Opin.Neurol.10(3):237-43,1997年6月。这些参考文献均全文引入本文作为参考。
本文中所用的术语“治疗”是指阻止或逆转其进展或者缓解或预防术语“治疗”所涉及的疾病或病症或所述疾病或病症的一种或多种症状。本文所用的术语“处置”是指治疗疾病或病症的行为,而术语“治疗”如上所定义。
本发明涉及将甲氧氯普胺和5HT1受体激动剂作为同一药物组合物的一部分一起给药治疗偏头痛的方法,以及将这两种活性成分作为旨在获得联合治疗的有益效果的适宜给药方案的一部分分别给药治疗偏头痛的方法。适宜的给药方案、各药物的给药量以及活性成分给药的间隔取决于所用的5HT1激动剂、所用药物制剂的类型、所治疗患者的特点和偏头痛的严重程度。通常,在实施本发明的方法时,对于体重70kg的一般成年人,5HT1受体激动剂通常以约1至约400mg/天的量以单剂量或分开的剂量口服给药,而甲氧氯普胺则以约5至约125mg/天的量以单剂量或分开的剂量给药。根据头痛的严重程度和给药途径,甲氧氯普胺通常以约20至约80mg/天的量给药。可将甲氧氯普胺口服、鼻内、静脉内、以直肠栓剂的形式给药或者用“自溶(flash)”制剂(即,不用水就可以使药物在口腔内溶解)给药。
下表举例说明了在联合使用时某些特定的5HT1激动剂和甲氧氯普胺的优选剂量范围。
5H11激动剂 | 用药的剂量范围 | 甲氧氯普胺的剂量范围 |
伊利曲坦 | 20至80mg | 5至20mg |
利扎曲坦 | 5至10mg | 5至20mg |
舒马普坦 | 25至100mg | 5至20mg |
那拉曲坦 | 1至5mg | 5至20mg |
本发明的组合物和方法中所用的5HT1受体激动剂及其可药用盐可以单独给药或者与可药用的载体或稀释剂一起给药。可将它们以常规方式用一种或多种可药用载体进行配制。所述化合物可以口服、颊部、鼻内、胃肠外(例如静脉内、肌肉内或皮下)或直肠给药,或者以适于通过吸入或吹入给药的形式进行给药。
用于口服给药的药物组合物可以是,例如通过常规方法用可药用赋形剂例如粘合剂(例如预胶化的玉米淀粉、聚乙烯吡咯烷酮或羟丙甲基纤维素);填料(例如乳糖、微晶纤维素或磷酸钙)、润滑剂(例如硬脂酸镁、滑石或二氧化硅);崩解剂(例如马铃薯淀粉或淀粉乙醇酸钠)或湿润剂(例如十二烷基硫酸钠)制备的片剂或胶囊的形式。可将片剂通过本领域公知的方法进行包衣。用于口服给药的液体制剂可以是例如溶液剂、糖浆或混悬剂,或者是用于在使用前用水或其它适宜的溶媒配制的干燥产品的形式。所述液体制剂可以通过常规方法用可药用添加剂例如助悬剂(例如山梨醇糖浆、甲基纤维素或氢化的食用脂肪);乳化剂(例如卵磷脂或阿拉伯胶);非水溶媒(例如杏仁油、油状的酯或乙醇)和防腐剂(例如对羟基苯甲酸甲酯或丙酯或山梨酸)制备。
用于颊部给药的组合物可以是以常规方式配制的片剂或锭剂的形式。
本发明的5HT1激动剂及其盐可以配制成用于通过注射、包括使用常规的导管插入技术或输注进行给药的形式。用于注射的制剂可以是单位剂量的形式,例如在安瓿中,或是在添加有防腐剂的多剂量容器中。组合物可以是在油或含水溶媒中的混悬液、溶液或乳液的形式,并且可以含有助悬剂、稳定剂和/或分散剂等配制用的试剂。
或者,活性成分可以是用于在使用前用适宜的溶媒例如无菌无热源的水重新配制的粉末形式。
本发明的5HT1激动剂及其盐还可以配制成直肠用组合物,例如含有常规的栓剂基质如可可脂或其它甘油酯的栓剂或保留灌肠剂。
对于鼻内给药或吸入给药,通常将本发明的活性化合物以溶液或混悬液的形式从泵喷雾容器通过患者的挤压或泵压进行输送,或者以气雾剂喷雾的形式从加压容器或使用适宜抛射剂的雾化器输送,所述抛射剂可以是,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它适宜的气体。对于加压的气雾剂,可以通过提供一个阀门来确定剂量单位,以输送计量的量。加压容器或雾化器可以含有活性化合物的溶液或混悬液。用于吸入器或吹入器的胶囊和药筒(由例如明胶制备)可以含有本发明化合物和适宜的粉末基质如乳糖或淀粉的混合物。
用于在一般成年人中治疗偏头痛的气雾剂制剂优选能够在每一计量的剂量或一“喷”气雾剂中含有20μg至1000μg本发明的化合物。气雾剂总的每日剂量通常在约100μg至10mg之间。可以每天给药数次,例如2、3、4或8次,每次1、2或3剂。
化合物或盐的5-HT1受体激动剂活性可以在关于5-HT1A受体所描述的用大鼠皮层作为受体源用[3H]8-OH-DPAT作为放射性配体(D.Hoyer等,《欧洲药理学杂志》(Europ.J.Pharmacol.),1985;118:13)以及关于5-HT1D受体所描述的用牛尾(bovine caudate)作为受体源用[3H]5-HT作为放射性配体(R.E.Heuring和S.J.Peroutka,《神经科学杂志》(J.Neuroscience),1987;7:894)的体外受体结合试验中进行测定。
化合物在5-HT1D结合位点的体外活性可以按照下述方法进行测定。将牛尾组织制成匀浆并悬浮在20体积含有50mM Tris-HCl(三[羟基甲基]氨基甲烷盐酸盐)的pH7.7的缓冲液中。然后将匀浆以45,000G离心10分钟。弃除上清液,将得到的沉积物重新悬浮在约20体积pH7.7的50mM Tris-HCl缓冲液中。将该悬浮液于37℃预保温15分钟,然后将悬浮液再次以45,000G离心10分钟并弃除上清液。将得到的沉积物(约1克)重新悬浮在150ml含有0.01%抗坏血酸(最终的pH为7.7)和10mM帕吉林和4mM氯化钙(CaCl2)的15mMTris-HCl缓冲液中。在使用前将悬浮液在冰上放置至少30分钟。
然后将抑制剂、对照或载体按照下述方法进行保温。向50ml 20%二甲亚砜(DMSO)/80%蒸馏水溶液中加入200ml氚代5-羟色胺(2nM)在含有0.01%抗坏血酸和10mM帕吉林及4mM氯化钙(CaCl2)并且加有100nM 8-羟基-DPAT(二丙基氨基四氢萘)和100nM美舒麦角的50mMTris-HCl缓冲液中(pH7.7)中的溶液。向该混合物中加入750ml牛尾组织并将形成的悬浮液旋涡振荡以确保形成均匀的悬浮液。然后将悬浮液在25℃的振动水浴中保温30分钟。保温结束后,将悬浮液用玻璃纤维滤纸(例如Whatman GF/B-滤纸)过滤。然后将沉积物用4ml 50mM pH7.7的Tris-HCl缓冲液洗涤3次。然后将沉积物置于含有5ml闪烁液体(水溶胶2)的闪烁计数瓶内并放置过夜。可以计算化合物各剂量的抑制百分比。然后可以从抑制百分比的值计算IC50值。
化合物或盐与5-HT1A受体结合的能力可以按照下述方法进行测定。将大鼠的大脑皮层组织形成匀浆并分成每份1克的样品,然后用10体积0.32M的蔗糖溶液稀释。将悬浮液以900G离心10分钟,分出上清液并以70,000G再次离心15分钟。弃除上清液,将沉积物重新悬浮在10体积15mM的Tris-HCl(pH7.5)中。将上清液于37℃保温15分钟。预保温结束后,将上清液以70,000G离心15分钟并弃除上清液。将得到的组织沉积物重新悬浮在含有4mM氯化钙和0.01%抗坏血酸的50mMTris-HCl缓冲液(pH7.7)中。将组织于-70℃下存放直至准备进行实验。在临用前将组织解冻,用10mm帕吉林稀释并放置在冰上。
然后将组织按照下述方法进行保温。准备各种剂量的50微升对照、抑制剂或载体(1%DMSO最终浓度)。向该溶液中加入200ml 1.5nM氚代DPAT在含有4mM氯化钙、0.01%抗坏血酸和帕吉林的50mM Tris-HCl缓冲液(pH7.7)中的溶液。然后向该溶液中加入750ml组织并将形成的悬浮液旋涡振荡以确保均匀。然后将悬浮液在37℃的振动水浴中保温30分钟。然后将溶液过滤,用4ml含有154mM氯化钠的10mMpH7.5的Tris-HCl缓冲液洗涤2次。计算化合物、对照或载体各剂量的抑制百分比。可以从抑制百分比的值计算IC50值。
化合物在5-HT1A和5-HT1D受体的激动剂和拮抗剂活性可以按照如下方法用单一饱和浓度进行测定。将雄性Hartley豚鼠杀头并从海马分离出5-HT1A受体,而5-HT1D受体则通过于350mM在Mcllwain组织切片机上切片并从适当的切片上切下黑质得到。将各组织用手动玻璃-特氟隆匀浆器在含有1mM EGTA的5mM HEPES缓冲液(pH7.5)中形成匀浆,然后以35,000xg于4℃离心10分钟。将沉积物重新悬浮在含有1mM EGTA的100mM HEPES缓冲液(pH7.5)中达到每管20mg(海马)或5mg(黑质)蛋白的最终蛋白浓度。加入如下试剂以使各管内的反应混合物含有2.0mM MgCl2,0.5mM ATP,1.0mM cAMP,0.5mM IBMX,10mM磷酸肌酸,0.31mg/mL肌酸磷酸激酶,100mM GTP和0.5-1微居[32P]-ATP(30Ci/mmol:NEG-003-New England Nuclear)。通过于30℃下向硅氧烷化处理的微量离心管中加入组织(一式三份)开始保温15分钟。向各管中加入20mL组织,10mL药物或缓冲液(最终浓度的10倍),10mL 32nM激动剂或缓冲液(最终浓度的10倍),20mL毛喉素(3mM最终浓度)和40mL上述反应混合物。通过加入100mL 2%SDS,1.3mMcAMP,含有40,000dpm[3H]-cAMP(30Ci/mmol:NET-275-NewEngland Nuclear)的45mM ATP溶液终止保温以检测从柱子中回收的cAMP。用Salomon等,《分析生物化学》(Analytical Biochemistry),1974,58,541-548中描述的方法完成[32P]-ATP和[32P]-cAMP的分离。通过液体闪烁计数对放射性进行定量。用10mM(R)-8-OH-DPAT定义5-HT1A受体的最大抑制,用320nM5-HT定义5-HT1D受体的最大抑制。然后计算试验化合物相对于(R)-8-OH-DPAT对5-HT1A受体的抑制作用或5-HT对5-HT1D受体的抑制作用的抑制百分比。相对32nM激动剂的作用计算由激动剂引起的对抑制毛喉素刺激的腺苷酸环化酶活性的逆转。
可以按照如下方法在豚鼠中测试化合物拮抗5-HT1D激动剂-诱导的体温降低的体内活性。
用来自Charles River的雄性Hartley豚鼠(到达时的体重为250-275克,试验时的体重为300-600克)进行实验。在实验前将豚鼠在常规的实验室条件下以7a.m.至7p.m.的光照程序饲养至少7天。直到试验时,食物和水均可以自由获取。
可将本发明化合物以溶液的形式以1ml/kg的体积给药。所用载体随化合物的溶解度而改变。试验化合物通常在5-HT1D激动剂例如[3-(1-甲基吡咯烷-2-基甲基)-1H-吲哚-5-基]-3-硝基吡啶-3-基)-胺(该化合物可以按照1993年6月10日公开的PCT公开说明书WO93/11106中的描述制备,其给药剂量为5.6mg/kg,皮下)给药前60分钟口服(p.o.)给药或0分钟前皮下(s.c.)给药。在第一次读取体温之前,将各豚鼠置于含有木屑和金属网格底的透明塑料鞋盒内并使其适应环境30分钟。在每次读取体温后将动物放回原来的鞋盒内。在每次测定体温之前,用一只手将动物抓牢30秒钟的时间。使用带有小型动物探针的数字温度计进行体温测量。探针由带有环氧末端的半柔性尼龙制成。将温度探针插入直肠内6cm并在此停留30秒钟直至获得稳定的读数。然后记录温度。
在口服筛选实验中,在-90分钟测定“给药前”的基础体温读数,将试验化合物在-60分钟时给予并在-30分钟再次测定一次体温。然后在0分钟给予5-HT1D激动剂并在30、60、120和240分钟后测定体温。
在皮下筛选实验中,在-30分钟测定给药前的基础体温读数。将试验化合物和5-HT1D激动剂同时给药并在30、60、120和240分钟后测定体温。
将数据用双向方差分析用Newman-Keuls post hoc分析中的重复测定进行分析。
5-HT1激动剂活性可以通过关于5-HT1A受体所描述的用大鼠皮层作为受体源用[3H]-8-OH-DPAT作为放射性配体[D.Hoyer等,《欧洲药理学杂志》(Eur.J.Pharm.),118:13(1985)]以及关于5-HT1D受体所描述的用牛尾作为受体源用[3H]血清素作为放射性配体[R.E.Heuring和S.J.Peroutka,《神经科学杂志》(J.Neuroscience),7,894(1987)]的体外受体结合试验进行测定。对于所测试的活性化合物,在两种试验中均显示出1mM或以下的IC50。
可以通过测试化合物和盐模拟舒马普坦收缩狗离体隐静脉条的程度来评估所述化合物和盐作为抗偏头痛剂的效果(P.P.A.Humphrey等,《英国药理学杂志》(Br.J.Pharmacol.)1988;94:1128)。该效果可以被美赛西平(一种已知的血清素拮抗剂)阻断。已知舒马普坦可用于治疗偏头痛并可以在麻醉的狗中引起颈动脉血管阻力的选择性增加。Fenwick等人(《英国药理学杂志》(British Journal ofPharmacology),1989;96:83)认为这是其效力的基础。
Claims (11)
1.用于治疗偏头痛的药物组合物,含有甲氧氯普胺;5HT1受体激动剂,其中不包括唑米曲坦;和可药用载体。
2.权利要求1的药物组合物,其中的5HT1受体激动剂选自伊利曲坦、利扎曲坦、舒马普坦和那拉曲坦。
3.用于治疗偏头痛的药物组合物,含有伊利曲坦、甲氧氯普胺和可药用载体。
4.在哺乳动物中治疗偏头痛的方法,该方法包括,向所述哺乳动物施用抗偏头痛有效量的权利要求1的药物组合物。
5.在哺乳动物中治疗偏头痛的方法,该方法包括,向所述哺乳动物施用抗偏头痛有效量的权利要求2的药物组合物。
6.在哺乳动物中治疗偏头痛的方法,该方法包括,向所述哺乳动物施用可以使两种活性成分的组合在偏头痛的治疗中有效之量的甲氧氯普胺和5HT1受体激动剂,其中不包括唑米曲坦。
7.权利要求6的方法,其中的5HT1受体激动剂选自伊利曲坦、利扎曲坦、舒马普坦和那拉曲坦。
8.权利要求6的方法,其中的5HT1受体激动剂按照可以使分别给药的活性成分的组合在偏头痛的治疗中有效的给药方案分别给药。
9.权利要求6的方法,其中的5HT1受体激动剂以约1mg至约400mg/天的量给药,甲氧氯普胺以约5mg至约125mg/kg/天的量给药。
10.权利要求6的方法,其中的5HT1受体激动剂或其可药用盐通过口服给药,甲氧氯普胺通过静脉内给药。
11.提高伊利曲坦在哺乳动物中治疗偏头痛的药动学的方法,该方法包括,将伊利曲坦与甲氧氯普胺一起使用。
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