CN1227011C - 治疗哮喘的药物及其用途 - Google Patents
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Abstract
公开了一种治疗主体中腺苷衰竭的方法。该方法包括给予所述主体以治疗腺苷衰竭有效量的亚叶酸或其药用盐。还公开了一种治疗哮喘的方法,其包括给予所述主体以治疗哮喘有效量的脱氢表雄甾酮、其类似物或其药用盐。
Description
本发明涉及通过服用亚叶酸或其药用盐治疗腺苷衰竭(adenosinedepletion)的方法。本发明还涉通过服用脱氢表雄甾酮、其类似物或其药用盐治疗哮喘的方法。
腺苷是一种嘌呤,它对中间代谢有贡献还参与各种哺乳动物组织生理活动的调节。腺苷参与许多局部调节机制,尤其是在中枢神经***(CNS)突触和外周神经***中的神经效应器接点上。中枢神经***中,腺苷抑制各种神经递质的释放,如乙酰胆碱、去甲肾上腺素、多巴胺、5-羟色胺、谷氨酸和GABA;抑制神经传递;降低神经元冲动导致脊柱痛觉缺失;还具有抗焦虑特性。见,A.Pelleg和R.Porter,药物治疗(Pharmacotherapy)10(2),157(1990);J.Daval等,生命科学(Life Sciences)49:1435(1991)。在心脏中,腺苷抑制起博点的活动,减慢AV传导,具有抗心律不齐和致心律不齐的作用,调节自律控制,及激发***素的合成和释放。见,K.Mullane和M.William,腺苷和腺苷受体289页(M.Willians编,Humana出版社,1990)。腺苷具有强血管扩张作用,能调节血管紧张性。见,A.Deuseen等,J.pflugers Arch.406:608(1986)。现今,腺苷在临床上用于治疗室性心动过速或其他心脏病。见,C.Chronister美国急诊医疗杂志(AmericanJournal of Critical Care)2(1):41-47(1993)。研究了一些腺苷类似物以用作抗惊厥、抗焦虑和神经保护药物。见,M.Higgins等,药学世界和科学(Pharmacy Warld&Science)16(2):62-68(1994)。
腺苷还被认为是支气管哮喘症状的主要决定因子。它诱导支气管收缩和气道平滑肌收缩。见,J.Thorne和K.Broadley美国呼吸和急诊医学杂志(American Journal of Respiratory&Critical Care Medicine)149(2,pt.1):392-399(1994);S.Ali等,药剂和作用(Agents&Actions)37(3-4):165-167(1992)。腺苷在哮喘症患者中引起支气管收缩,而在非哮喘患者中则不然。见,Bjorck等,美国呼吸疾病综述(American Review of Respiratory Disease)145(5):1087-1091(1992);S.Holgate等,纽约科学院年鉴(Annals oftheNew York Academy of Sciences)629:227-236(1991)。
从上易于看出:(i)腺苷衰竭能导致许多有害病症,而治疗腺苷衰竭的方法可以是一种极其有用的治疗方法;(ii)诱导腺苷衰竭的方法也可以用于治疗诸如哮喘的病症。
因而,本发明的第一方面是在需要治疗的主体中治疗腺苷衰竭的方法。该方法包括给予所述主体治疗腺苷衰竭有效量的亚叶酸或其药用盐。该方法适用于下列主体:患有类固醇诱发的腺苷衰竭的主体,患有焦虑症的主体,患有消耗性疾病的主体,或患有任何可归因于腺苷衰竭的其他疾病的主体,或提高腺苷水平将对治疗有利的情形。
本发明的第二方面是亚叶酸或其药用盐在制备用于治疗腺苷衰竭的药物中的用途。
本发明的第三方面是在需治疗主体中治疗哮喘的方法,包括给予主体治疗哮喘有效量的脱氢表雄甾酮、其类似物或其药用盐。
本发明的第四方面是脱氢表雄甾酮、其类似物或其药用盐在制备用于治疗哮喘的药物中的用途。
亚叶酸是叶酸代谢的中间产物,由叶酸在体内转化成的活性形式,抗坏血酸是这种转化过程的必需因子。亚叶酸已用作叶酸拮抗剂(如氨甲蝶呤)的解毒药,这些拮抗剂能阻断叶酸向亚叶酸的转化。另外亚叶酸已用作抗贫血剂(对抗叶酸缺乏)。见,默克索引(the Merck Index),专题No.4141(第11版,1989)。迄今还没有人报道或暗示亚叶酸在患腺苷衰竭病人中的应用,或在提高脑或其他器官中腺苷水平的治疗方法中的应用。
本发明公开的腺苷衰竭治疗方法可用于治疗类固醇诱发的腺苷衰竭;刺激腺苷合成从而治疗或控制焦虑症(如治疗经前综合症);加快体重增长或治疗消耗性疾病、或经给予亚叶酸治疗其他腺苷相关疾病。因此,“腺苷衰竭”这一术语意在包含以下两种情形:即主体中腺苷水平比原腺苷水平低的情形;和腺苷水平与原始水平基本相同,但由于病人的其他条件或变化使得达到比原水平较高的腺苷水平将对治疗有利的情形。本方法优选用于腺苷水平低于原始水平的病人中。本发明主要涉及人体的治疗,但也可用于其他哺动物如狗和猫作为兽医目的的治疗。
亚叶酸和其药用盐(以下有时称为“活性化合物”)是已知的,可以按已知的方法步骤制备。见,默克索引,专题No.4141(第11版,1989);美国专利No.2,741,608。
药用盐应该同时是药理上和药物上可接受的。这种药理上和药物上可接受的盐可以是亚叶酸羧基的碱金属或碱土金属盐,如钠盐、钾盐或钙盐。亚叶酸钙盐是优选的药用盐。
优选以药物组合物的形式给予主体活性化合物。用于本发明的药物组合物包括那些适于吸入、口服、表皮使用(包括颊、舌下、皮肤和眼内)、非胃肠给药(包括皮下、真皮内、肌肉内、静脉内和关节内)和透皮给药的那些。该组合物可以方便地呈剂量单位形式,可以按本领域熟知的任何方法制备。
适于口服的组合物可以是分立的单位,如胶囊,扁囊剂、锭剂或片剂,每个单位含有预定量的活性化合物,呈粉末或颗粒、水性或非水性液体中的溶液或悬液、水包油或油包水乳液。这种组合物可用任何适宜的制药方法制备,包括使活性化合物与适当载体结合的步骤。一般本发明的组合物是这样制备的,将活性化合物与液体或研细的固体载体或两者均匀地紧密地混合,然后需要时将形成的混合物成形。例如,将含有活性成分有或无一种或多种辅助成分的粉末或颗粒压片或模制可制备片剂。呈自由流动形式,如粉末或颗粒的化合物选择性地与粘合剂、润滑剂、惰性稀释剂、和/或表面活性剂/分散剂混合,在适当的机器中压制可制得压片。粉化的化合物用惰性粘合剂湿润,在适当机器中模制可制得模制片剂。
口服组合物可包含或不包含本领域已知的肠衣,后者防止该组合物在胃中崩解,而使得在小肠中释放药物。
适于颊(舌下)给药的组合物包括在调味基质(通常为蔗糖和***胶或黄嗜胶)中含活性化合物的锭剂;和在惰性基质如明胶和甘油或蔗糖和***胶中含活性化合物的软锭剂。
适于胃肠外给药的组合物包括活性化合物的灭菌水性或非水性注射液,该制剂优选与目的受体的血液等渗。这些制剂可以含有抗氧化剂、缓冲剂、制菌剂和使组合物与目的受体血液等渗的溶质。水性和非水性灭菌悬液可以含有悬浮剂和增稠剂。这些组合物可以存在于单位剂量或多剂量容器中,例如封口安瓿和小瓶中;也可以在冷冻干燥条件下保存,使用前只需加入无菌液态载体,例如盐水或注射用水。当即注射的溶液和悬液可以从以上描述的各种无菌粉末、颗粒和片剂制得。
适于表皮(优选皮肤)使用的组合物采取软膏、霜剂、洗剂、糊剂、凝胶、喷雾剂、气溶胶或油剂形式。可以使用的载体包括凡士林、羊毛脂、聚乙二醇、醇类、透皮增效剂,或其中两种或多种的混合物。
适于透皮给药的组合物可采取独立的补片形式,它适于长时间与受体表皮保持紧密接触。适于透皮给药的组合物还可以通过离子电渗法输送(见,如《药物研究》(Pharmaceutical Research)3,318(1986)),一般采取活性化合物的缓冲(非必需)水溶液形式。
剂量随着主体的年龄、体重和状况而变化。可以用低于最佳剂量的小剂量开始治疗,然后加大剂量直至达到该条件下的最佳效果。一般,剂量可为1,5,10或20mg/kg体重,到100,200,500或1000mg/kg体重。目前,优选剂量为5到500mg/kg,更优选10-200mg/kg,最优选20-100mg/kg。一般,活性化合物优选以能产生有效结果而不引起不应有的伤害或有害副作用的浓度下给药,可以按单一剂量单位给药,或者需要时以一天内适当的次数给予适当的亚剂量单位。
本发明还公开了一种治疗哮喘(尤其是非类固醇依赖性哮喘)的方法,包括给予需要该治疗的主体以抑制或控制哮喘有效量的脱氢表雄甾酮(DHEA)、其类似物或其药用盐。可用于实施该方法的DHEA和其类似物的例子由下式代表:
其中:
虚线代表双键存在或不存在;
R为氢或卤原子;
R1为氢或SO2OM,其中M为氢、M为钠、M为硫苷脂基团:
M为磷脂基团:
其中R2和R3相同或不同,各自为1-14个碳原子的直链或支链烷基,或葡糖苷酸基团:
式I5-位的氢原子呈α或β构型或该化合物包括两种构型的混合物。上述式(I)化合物的例子包括:
DHEA,其中R和R1各为氢,存在双键;
16-α-溴表雄甾酮,其中R为溴,R1为氢,双键存在;
16-α-氟表雄甾酮,其中R为氟,R1为氢,双键存在;
本胆烷醇酮,其中R和R1各为氢,双键不存在;
二氢表雄甾酮硫酸酯,其中R为氢,R1为SO2M,M为如上定义的硫苷脂基团,双键不存在。式I化合物中,优选R为卤原子(如溴、氯或氟),R1为氢,双键存在。更优选式I化合物为16-α-氟表雄甾酮。
按照对本领域技术人员显而易见的已知方法或其变异方法制备式I化合物。见,美国专利4,956,355,英国专利2,240,472,欧洲专利申请429,187,PCT专利申请91/04 030;也见,M.Abou-Gharbia等药物科学杂志(J.Pharm.Sci)70,1154-1157(1981),默克索引,专题No.7710(第11版,1989)。
用于治疗哮喘的化合物如上所述可以是化合物本身或呈药用盐形式(两者都称为“活性化合物”),活性化合物盐可以按上述方法***给药,或如下所述给予主体的肺中。一般,活性化合物的给药剂量为1-3600mg/kg,更优选约5-1800mg/kg,最优选约20-100mg/kg。活性化合物可一天给药一次或几次。
可用适当的方法将本发明活性化合物投药至主体的肺中,但优选产生含可吸入颗粒的气溶胶,该可吸收颗粒含活性化合物,主体吸入这种颗粒(即吸入给药)。可吸收颗粒可以是液态或固态。
实施本发明的含活性化合物颗粒应包括具有可吸入大小的颗粒,即,颗粒大小足够小,当吸入时能通过口腔和喉进入支气管和肺泡中。一般,约0.5-10μm大小(更优选小于约5μm大小)的颗粒是可吸入的。气溶胶中的非可吸入颗粒将沉积在咽部并被吞咽,最好将气溶胶中非可吸入颗粒的量减至最少。对于鼻内给药,优选10-500μm的颗径以保证在鼻腔中的保留。
用于制备气溶胶的活性化合物液态药物组合物,通过将活性化合物与适当的载体如无菌无热源水混合而制得。含可吸入的粉碎活性化合物干颗粒的固体组合物,通过将干燥活性化合物用研钵研磨制得,然后将此粉碎组合物通过400目的筛子以破坏或分出大的附聚物。含活性化合物的这种固体颗粒组合物可任选地含有助于形成气溶胶的分散剂。适合的分散剂为乳糖,其可与活性化合物以适当比例混合(如1比1的重量比)。
利用诸如喷雾器的任何适当方式可产生含活性化合物的液粒气溶胶。见,如美国专利4,501,729。喷雾器是有市售的设备,它将活性成分的溶液或悬液转变为治疗用气溶胶,这是通过在压缩气体(一般为空气或氧气)的加速下通过一窄的文丘里喷孔或借助于超声震动实现的。适用于喷雾器的组合物是由液体载体中的活性成分组成的,其中活性成分最多可占组合物的40%w/w,但优选低于20%w/w,载体一般为水或稀醇水溶液,优选通过加入例如氯化钠使其与体液等渗。可加可不加的添加剂包括防腐剂(如果组合物没有无菌制备)如羟基苯甲酸甲酯,抗氧化剂,调味剂,挥发油,缓冲剂和表面活性剂。
类似地,含活性化合物的固体颗粒气溶胶可用任何固体颗粒药物气溶胶发生器制得。向主体投送固体颗粒药物的气溶胶发生器能产生可吸入性颗粒,以适于人体给药的速度产生含预定剂量药物的气溶胶。这种气溶胶发生器的例子包括计量吸入器和吹入器。
在上述哮喘治疗方法中,泛醌可与DHEA或其类似物联合给药。此处“联合给药”意指DHEA或DHEA类似物与泛醌(a)同时给药(优选将两种药物配制在共同的药物载体中),或(b)在同一治疗方案过程中的不同时间点分别给药。在后一情形中,两种化合物的给药时间要足够接近主体肺(和心脏)中泛醌-泛醌耗竭的时间,从而对抗给予DHEA或其类似物可能对肺(和心脏)功能造成的任何损害。此处“泛醌”指具有基于2,3-二甲氧基-5-甲基苯醌核的结构具有可变类贴酸链(含1-12个单不饱和反式类异戊二烯单元)的一类化合物。这种化合物在本领域中称为“辅酶Qn”,其中n等于1-12。这些化合物可以是下式代表的化合物:
其中n=1-10。在本发明的方法中,优选泛醌化合物是其中n=6-10的上式化合物(即辅酶Q6-10),最优选其中n=10(即辅酶Q10)。
当泛醌用药用载体与DHEA、其类似物或其盐分开配制时(例如,当DHEA、其类似物或其盐投入主体肺中,而泛醌***给药),可用如上所述的任何技术来配制泛醌。
一般,泛醌的给药量应该是在主体肺和心脏中抵消由DHEA、其类似物或其盐引起的泛醌耗竭的有效量,该剂量随主体状况和给药途径而变化,优选泛醌给药量为每天共约1-1200mg/kg体重,更优选约30-600mg/kg,最优选约50到150mg/kg。每天给药一次或数次。
现提供下列实施例以更全面地说明本发明;而不构成对本发明的限制。下列实施例中,DHEA指脱氢表雄甾酮,s表示秒,mg表示毫克,kg表示千克,KW表示千瓦,MHz表示兆赫,nmol表示纳摩尔。
实施例1和2
亚叶酸和DHEA对体内腺苷水平的影响
用管饲法每天一次给予年青成年雄性Fischer 344大鼠(120克)羧甲基纤维素中的脱氢表雄甾酮(DHEA)(300mg/kg)或甲基睾酮(40mg/kg)共14天。每天腹膜内给予亚叶酸(50mg/kg)计14天。第15天,在脑颅部用微波脉冲(1.33kw,2450MHz,6.5s)处死动物,这样就即刻将所有脑蛋白变性,防止腺苷进一步代谢。从动物中取出心脏,在死亡后10秒内于液氮中迅速冷冻。整体取出肝和肺,死亡后30秒内迅速冷冻。然后切下脑组织。提取组织腺苷,衍生化为1,N6-亚乙烯基腺苷,并按Clark和Dar的方法(神经科学方法杂志(J.ofNeuroscience Methods)25:243(1988)),用分光荧光法检测用高效液相色谱法(HPLC)分析。这些实验的结果列在表1中。结果用平均值±SEM表示,与对照组相比,χP<0.05,与DHEA或甲基睾酮处理组相比,φP<0.05。
表1,DHEA、δ-1-甲基睾酮和亚叶酸对大鼠各组织中腺苷水平的影响。
处理 | 细胞内腺苷(nmol/mg蛋白) | |||
心脏 | 肝 | 肺 | 脑 | |
对照 | 10.6±0.6(n=12) | 14.5±1.0(n=12) | 3.1±0.2(n=6) | 0.5±0.04(n=12) |
DHEA(300mg/kg) | 6.7±0.5(n=12)ψ | 16.4±1.4(n=12) | 2.3±0.3(n=6)ψ | 0.19±0.01(n=12)ψ |
甲基睾酮(40mg/kg) | 8.3±1.0(n=6)ψ | 16.5±0.9(n=6) | N.D. | 0.42±0.06(n=6) |
甲基睾酮(120mg/kg) | 6.0±0.4(n=6)ψ | 5.1±0.5(n=6)ψ | N.D. | 0.32+0.03(n=6)ψ |
亚叶酸(50mg/kg) | 12.4±2.1(n=5) | 16.4±2.4(n=5) | N.D. | 0.72±0.09(n=5)ψ |
DHEA(300mg/kg)+亚叶酸(50mg/kg) | 11.1±0.6(n=5)φ | 18.8±1.5(n=5)φ | N.D. | 0.55±0.09(n=5)φ |
甲基睾酮(120mg/kg)+亚叶酸(50mg/kg) | 9.1±0.4(n=6)φ | N.D. | N.D. | 0.60±0.06(n=6)φ |
这些试验的结果显示用DHEA或甲基睾酮处理两周的大鼠在多种器官中表现腺苷衰竭。这种衰竭在脑(用DHEA衰竭60%,用高剂量甲基睾酮衰竭34%)和心脏(用DHEA衰竭37%,用高剂量甲基睾酮衰竭22%)尤为显著。同时给予亚叶酸则完全消除了类固醇介导的腺苷衰竭。单独给予亚叶酸则使所有研究器官中腺苷水平提高。
以上实施例用于说明本发明而非限制本发明。本发明由以下权利要求定义,这些权利要求的等价物包括在本发明中。
Claims (20)
1.式I化合物或其药用盐在制备用于治疗哮喘的药物中的用途:
其中:
虚线代表双键存在或不存在;
R为氢或卤原子;
R1为氢或SO2OM,其中M为氢、钠或硫苷脂基团:
或M为磷脂基团:
其中R2和R3相同或不同,各自为1-14个碳原子的直链或支链烷基,或葡糖苷酸基团:
2.根据权利要求1的用途,其中R为卤原子,R1为氢,并在所述结构式I的虚线处存在双键。
3.根据权利要求1的用途,其中所述式I化合物选自脱氢表雄甾酮、16-α-溴表雄甾酮、16-α-氟表雄甾酮、本胆烷醇酮、脱氢表雄甾酮硫酸酯和其药用盐。
4.根据权利要求1的用途,其中所述式I化合物是16-α-氟表甾酮或其药用盐。
5.根据权利要求1的用途,其中所述药物是***给药的药物组合物。
6.根据权利要求1的用途,其中所述药物是吸入给药的药物组合物。
7.根据权利要求1的用途,所制备的药物中还包括泛醌。
8.根据权利要求1的用途,其中所述哮喘是非类固醇依赖性哮喘。
9.一种药物组合物,其含有能抑制或控制哮喘的有效量的脱氢表雄甾酮或药学上或兽医学上可接受的盐;其中脱氢表雄甾酮如下述化学式所示:
其中虚线代表双键存在或不存在;R为氢或卤原子;R1为氢或SO2OM,
其中M选自H、Na、或如下式的硫苷脂基团
或如下式的磷脂基团,
其中R2和R3相同或不同,为直链或支链C1-C14烷基或下式的葡糖苷酸基团:
其中所述药物组合物为可吹入尺寸的颗粒,所述可吹入尺寸的颗粒为0.5~10μm的用于吸入的颗粒,或10μm~500μm的用于鼻内给药的颗粒。
10.权利要求9的药物组合物,其中所述药物组合物为液体或固体。
11.权利要求9的药物组合物,其为吸入制剂。
12.权利要求9的药物组合物,其中所述可吹入尺寸的颗粒为小于5μm大小的颗粒。
13.权利要求9的药物组合物,其中所述药物组合物为鼻内给药制剂。
14.权利要求9的药物组合物,其进一步包含泛醌。
16.权利要求15的用途,其中所述药物组合物为液体或固体。
17.权利要求15的用途,其为吸入制剂。
18.权利要求17的用途,其中所述可吹入尺寸的颗粒为小于5μm大小的颗粒。
19.权利要求15的用途,其中所述药物组合物为鼻内给药制剂。
20.权利要求15的用途,所制备的药物中进一步包含泛醌。
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1995
- 1995-02-24 US US08/393,863 patent/US5660835A/en not_active Expired - Lifetime
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1996
- 1996-02-15 WO PCT/US1996/001933 patent/WO1996025935A1/en not_active Application Discontinuation
- 1996-02-15 CA CA002213339A patent/CA2213339C/en not_active Expired - Fee Related
- 1996-02-15 JP JP52572896A patent/JP3725158B2/ja not_active Expired - Fee Related
- 1996-02-15 KR KR1019970705842A patent/KR100368803B1/ko not_active IP Right Cessation
- 1996-02-15 KR KR10-2000-7003343A patent/KR100374393B1/ko not_active IP Right Cessation
- 1996-02-15 CN CNB961920963A patent/CN1227011C/zh not_active Expired - Fee Related
- 1996-02-15 SG SG9803281A patent/SG79237A1/en unknown
- 1996-02-15 AU AU48677/96A patent/AU699917C/en not_active Ceased
- 1996-02-15 EP EP05004694A patent/EP1555025A3/en not_active Withdrawn
- 1996-02-15 NZ NZ302592A patent/NZ302592A/en not_active IP Right Cessation
- 1996-02-15 EP EP96904622A patent/EP0810863A4/en not_active Withdrawn
-
1997
- 1997-05-22 US US08/861,962 patent/US6087351A/en not_active Expired - Fee Related
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2000
- 2000-01-20 US US09/488,236 patent/US6670349B1/en not_active Expired - Fee Related
-
2003
- 2003-04-09 US US10/410,955 patent/US20040034029A1/en not_active Abandoned
-
2005
- 2005-06-02 JP JP2005162494A patent/JP2005306880A/ja active Pending
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2008
- 2008-08-21 US US12/196,223 patent/US20090053143A1/en not_active Abandoned
- 2008-08-21 US US12/196,233 patent/US20090054385A1/en not_active Abandoned
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MX9706404A (es) | 1998-08-30 |
US6087351A (en) | 2000-07-11 |
CA2213339C (en) | 2005-06-21 |
SG79237A1 (en) | 2001-03-20 |
AU699917B2 (en) | 1998-12-17 |
EP0810863A4 (en) | 2002-10-23 |
JPH11501620A (ja) | 1999-02-09 |
EP1555025A2 (en) | 2005-07-20 |
KR19980702443A (ko) | 1998-07-15 |
AU699917C (en) | 2001-08-16 |
NZ302592A (en) | 2001-09-28 |
US5660835A (en) | 1997-08-26 |
AU4867796A (en) | 1996-09-11 |
KR100374393B1 (ko) | 2003-03-04 |
KR100368803B1 (ko) | 2003-05-16 |
CN1175903A (zh) | 1998-03-11 |
JP3725158B2 (ja) | 2005-12-07 |
US20090053143A1 (en) | 2009-02-26 |
EP1555025A3 (en) | 2005-08-03 |
US20090054385A1 (en) | 2009-02-26 |
US6670349B1 (en) | 2003-12-30 |
US20040034029A1 (en) | 2004-02-19 |
WO1996025935A1 (en) | 1996-08-29 |
CA2213339A1 (en) | 1996-08-29 |
JP2005306880A (ja) | 2005-11-04 |
EP0810863A1 (en) | 1997-12-10 |
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