CN1436076A - 治疗心血管疾病的方法 - Google Patents
治疗心血管疾病的方法 Download PDFInfo
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- CN1436076A CN1436076A CN01811212A CN01811212A CN1436076A CN 1436076 A CN1436076 A CN 1436076A CN 01811212 A CN01811212 A CN 01811212A CN 01811212 A CN01811212 A CN 01811212A CN 1436076 A CN1436076 A CN 1436076A
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- Prior art keywords
- rapamycin
- medicament
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- ester
- hydroxyl
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Abstract
本发明提供一种治疗或抑制有需要的哺乳动物的心血管,脑血管,或外周血管疾病的方法,该方法包括给所述哺乳动物提供有效量的雷帕霉素。
Description
发明背景
本发明涉及雷帕霉素在治疗和抑制心血管疾病,脑血管疾病,及外周血管疾病中的用途。
现在,在美国,心血管疾病(CVD)的主要形式——冠状动脉疾病是死亡的主要原因,每年有超过550,000的人死于这种疾病。在美国,脑血管疾病是死亡的第三大原因。冠状动脉疾病和脑血管疾病的病因均归因于动脉粥样硬化。由于它的临床表现,动脉粥样硬化是每年发生的超过一百万的心脏病发作和大约400,000的中风的主要原因。除了与动脉粥样硬化有关的高发病率和死亡率外,据估计,在损失的薪金,损失的生产力和医疗保健费方面,动脉粥样硬化每年要花费美国超过$八百亿[Levy,R.,Am.Heart J.110:1116(1985)]。大量确实的证据已经证实了血胆固醇过多与早期动脉粥样硬化间的关系;血浆胆固醇水平越高,随后心脏病发作的危险就越大。[Steinberg,D.,JAMA 264:3047(1991);LipidResearch Clinics Program,JAMA 251:351(1984);Rifkind,B.,Am.J.Cardiol.54:30C(1984)]。然而,最新的资料证实动脉粥样硬化过程远比与血浆脂质水平的简单相互关系更复杂,且在血管壁内存在全身及局部因素,其在这种疾病的发展中起着重要的作用[Sulistiyani,Adelman,S.J.,Chandrasekaran,A.,Jayo,J.和St.Clair,R.W..Arteriosclerosis andThrombosis 15:837,(1995)]。
动脉粥样硬化是一种与多种病因有关的复杂疾病。研究显示,涉及它的主要因素,如日常饮食-导致的血脂过多和遗传缺损或脂蛋白代谢异常已经受到广泛关注。动脉粥样硬化局部病变的特征在于血管壁中脂质的积聚。随着脂质的积聚,还存在导致内皮机能障碍,平滑肌增殖,和基质沉积的血管壁损害。这些改变最终导致所谓“动脉粥样斑”的形成。随着这些动脉粥样斑的膨胀和成熟,它们的表面发生破裂,导致严重的血栓形成事件。基本上,此过程可在身体的所有血管中发生,从而导致许多严重的疾病种类,包括冠状动脉疾病,外周血管疾病,心肌梗塞形成和中风。
近来发现免疫系统的细胞在所有动脉粥样硬化过程中发挥着重要的作用,因而该过程被描述为血管壁的慢性炎性-纤维增生疾病。单核细胞和T-淋巴细胞与受损内皮的粘附及它们随后到内膜中的迁移是损害发展中第一及最重要的步骤。CD4+T-细胞与巨噬细胞在损害中的共同-定位,HLA Class II分子的充分表达及共同刺激的分子CD40及其配体(CD40L)显示细胞-介导的免疫性对动脉粥样硬化形成的作用。对各种动物模型进行的研究表明,T-和B-细胞,及单核细胞和巨噬细胞可促进损害的发展,且事实上,其对于动脉粥样硬化损害的发展非常重要。重要地是,局部血管壁的免疫作用通过参与动脉粥样斑的膨胀及破裂而继续。除了血管壁中的局部过程外,炎症反应的全身症状也与损害的发展有关。因此,C-反应性蛋白和血纤蛋白原的血浆水平及白细胞数肯定与心血管疾病的危险有关。
雷帕霉素是一种由吸水链霉菌产生的大环三烯抗生素,其具有抗真菌活性,特别是可在体外和体内抗白色假丝酵母[C.Vezina等,J.Antibiot.28,721(1975);S.N.Sehgal等,J.Antibiot.28,727(1975);H.A.Baker等,J.Antibiot.31,539(1978);美国专利US3,929,992;和美国专利US3,993,749]。此外,单独(US4,885,171)或与溶链菌联合(US4,401,653)使用时,雷帕霉素还具有抗肿瘤活性。
雷帕霉素的免疫抑制作用已经在FASEB 3,3411(1989)中公开。环孢菌素A和FK-506,及其它大环分子,作为免疫抑制剂也是有效的,并可用于预防移植排斥[FASEB 3,3411(1989);FASEB 3,5256(1989);R.Y.Calne等,Lancet 1183(1978);和美国专利US 5,100,899]。R.Martel等[Can.J.Physiol.Pharmacol.55,48(1977)]公开了雷帕霉素在实验性变态反应性脑脊髓炎模型,即一种多发性硬化模型中是有效的;在佐剂性关节炎模型,即一种类风湿性关节炎模型中是有效的;并可有效抑制IgE-样抗体的形成。
雷帕霉素还可用于预防或治疗全身性红斑狼疮[美国专利US5,078,999],肺部炎症[美国专利US5,080,899],胰岛素依赖性糖尿病[美国专利US5,321,009],皮肤病,如牛皮癣[美国专利US5,286,730],肠疾病[美国专利US5,286,731],平滑肌细胞增殖及血管损伤后的内膜增厚[美国专利US5,288,711和美国专利US5,516,781],成人T-细胞白血病/淋巴组织瘤[欧洲专利申请EP525,960A1],眼睛炎症[美国专利US5,387,589],恶性肿瘤[美国专利US5,206,018],心脏炎性疾病[美国专利US5,496,832],和贫血[美国专利US5,561,138]。
发明描述
本发明提供一种治疗或抑制有需要的哺乳动物的心血管疾病或外周血管疾病的方法,该方法包括给所述哺乳动物提供有效量的雷帕霉素。如此处所定义,术语“雷帕霉素”定义了一类免疫抑制化合物,其含有碱性的雷帕霉素核心(如下所示)。本发明的雷帕霉素包括作为雷帕霉素核心的衍生物而被化学或生物改性,同时仍保留有免疫抑制性的化合物。因此,术语“雷帕霉素”包括雷帕霉素的酯,醚,肟,腙,和羟胺,及雷帕霉素核心上的官能团已经通过还原或氧化而被改性的雷帕霉素。术语“雷帕霉素”还包括雷帕霉素药学上可接受的盐,其能够利用所含的酸性或碱性部分形成这种盐。
雷帕霉素
优选雷帕霉素的酯和醚是雷帕霉素核心42-位和/或31-位羟基的酯和醚,雷帕霉素核心(27-酮化学还原之后的)27-位羟基的酯和醚,及雷帕霉素核心(42-羟基氧化后的)42-位酮和27-位酮的肟,腙,和羟胺。
雷帕霉素优选的42-和/或31-酯和醚在下列专利中公开,其全部引入此处作为参考:雷帕霉素的烷基酯(美国专利US4,316,885);氨烷基酯(美国专利US4,650,803);氟化酯(美国专利US5,100,883);酰胺酯(美国专利US5,118,677);氨基甲酸酯(美国专利US5,118,678);甲硅烷基醚(美国专利US5,120,842);氨基酯(美国专利US5,130,307);缩醛(美国专利US5,51,413);氨基二酯(美国专利US5,162,333);磺酸酯和硫酸酯(美国专利US5,177,203);酯(美国专利US5,221,670);烷氧基酯(美国专利US5,233,036);O-芳基,-烷基,-烯基,和-炔基醚(美国专利US5,258,389);碳酸酯(美国专利US5,260,300);芳基羰基和烷氧羰基氨基甲酸酯(美国专利US5,262,423);氨基甲酸酯(美国专利US5,302,584);羟基酯(美国专利US5,362,718);受阻酯(美国专利US5,385,908);杂环酯(美国专利US5,385,909);偕-二取代的酯(美国专利US5,385,910);氨基链烷酸酯(美国专利US5,389,639);磷酰基氨基甲酸酯(美国专利US5,391,730);氨基甲酸酯(美国专利US5,411,967);氨基甲酸酯(美国专利US5,434,260);脒基氨基甲酸酯(美国专利US5,463,048);氨基甲酸酯(美国专利US5,480,988);氨基甲酸酯(美国专利US5,480,989);氨基甲酸酯(美国专利US5,489,680);受阻的N-氧化酯(美国专利US5,491,231);生物素酯(美国专利US5,504,091);O-烷基醚(美国专利US5,665,772);和PEG酯(美国专利US5,780,462)。这些酯和醚的制备在上面所列的专利中公开。
其中RA和RB分别选自在上述美国专利任何一个中公开的氢和酯或醚形成基团。
雷帕霉素优选的27-酯和醚在美国专利US5,256,790中公开,其引入此处作为参考。这些酯和醚的制备在上述专利中公开。
雷帕霉素优选的肟,腙,和羟胺在美国专利US5,373,014,US5,378,836,US5,023,264和US5,563,145中公开,其引入此处作为参考。这些肟,腙,和羟胺的制备在上面所列的专利中公开。42-氧代雷帕霉素的制备在美国专利US5,023,263中公开,其引入此处作为参考。
特别优选的雷帕霉素包括雷帕霉素[美国专利US3,929,992],雷帕霉素3-羟基-2-(羟甲基)-2-甲基丙酸42-酯[美国专利US5,362,718];和42-O-(2-羟基)乙基雷帕霉素[美国专利US5,665,772]。
应用时,当所述雷帕霉素含有适宜的碱性部分时,可从有机酸和无机酸形成药学上可接受的盐,例如乙酸,丙酸,乳酸,柠檬酸,酒石酸,丁二酸,反丁烯二酸,顺丁烯二酸,丙二酸,苦杏仁酸,苹果酸,邻苯二甲酸,盐酸,氢溴酸,磷酸,硝酸,硫酸,甲磺酸,萘磺酸,苯磺酸,甲苯磺酸,樟脑磺酸,及类似已知可接受的酸。当所述雷帕霉素含有适宜的酸性部分时,还可从有机碱和无机碱形成盐,如碱金属盐(例如,钠,锂,或钾),碱土金属盐,铵盐,各烷基中含1-6个碳原子的烷基铵盐或各烷基中含1-6个碳原子的二烷基铵盐,及各烷基中含1-6个碳原子的三烷基铵盐。
相对于提供本发明保护的化合物或物质,本发明所用术语“提供”是指直接给予这种化合物或物质,或给予可在体内形成有效量化合物或物质的前体药物,衍生物或类似物。
本发明雷帕霉素治疗或抑制心血管疾病或外周血管疾病的能力是使用ApoE敲除(EKO)小鼠,它是一种很好接受的人动脉粥样硬化动物模型,在标准药理学试验过程中加以证实的。在此试验过程中,使用雷帕霉素作为本发明雷帕霉素的典型实施例。下面简单概括了所用过程及所得结果。
在鞋盒式笼子中饲养4-6周大的雄性EKO小鼠,这些小鼠可随意接触到食物和水。根据重量将动物随机分成5组(N=12-15小鼠/组),在研究的第一周喂以Purina Rodent Chow。并在此时期及研究剩余的12周内,每隔2天给予动物0,1,2,4或8mg/kg雷帕霉素,使用2%吐温-80,1%羧甲基纤维素作为赋形剂和对照组。在研究的第2周至第13周,把动物的食物换成以酪蛋白为基础的Western Diet。在研究的最后,处死动物,获得血浆样品,并首先用盐水灌注,然后用10%福尔马林灌注心脏。使用酶方法,用分别源于Boehringer Mannheim和Wako Biochemicals的市售试剂盒,及Boehringer Mannheim Hitachii 911分析器(BoehringerMannheim Diagnostic Laboratory Systems,Indianapolis,IN)测定总胆固醇和甘油三酯。使用FPLC大小分级进行血浆脂蛋白的分离和量化。简单地说,将50-100ml血清过滤,并注射到两个串联的Superose 6柱(Amersham Pharmacia Biotech,UK,Ltd)中,用1mM EDTA钠和0.15MNaCl以恒定的流速洗脱。使用Millennium软件(Waters TechnologiesCorporation)求代表VLDL,LDL和HDL的各曲线面积的积分,并通过将总胆固醇值乘以各峰面积的相对百分比而量化脂蛋白部分。小心地分离主动脉,处理前,在福尔马林固定剂中保留48-72小时。通过油红O染色法确定动脉粥样硬化的损害。使血管褪色,然后使用Nikon SMU800显微镜成像,该显微镜配有与作为像捕获软件的IMAQ ConfigurationUtility(National Instrument)相连的Sony 3CCD电视摄像系统。使用RobertColl(Coleman Technologies)设计的阈值应用软件包沿着主动脉弓量化损害。利用程序的阈值功能,在血管,特别是包含在从右总颈动脉的近侧边缘到左锁骨下动脉的远侧边缘的主动脉弓内的部分上进行自动损害评估。主动脉粥样硬化的数据以在此严格定义的腔区域内所包含损害的百分比表示。对照组与治疗组间的统计学显著性差异是使用Dunnett’s Test在1%显著性水平测定的(p<0.01)。下表概括了在动脉粥样硬化的标准药理学试验过程中得到的结果。
表1.雷帕霉素对ApoE缺损小鼠中的主动脉粥样硬化和血浆脂质的作用 | ||||||
给药剂量 | 甘油三酯(mg/dl) | 总胆固醇(mg/dl) | VLDL-C(mg/dl) | LDL-C(mg/dl) | HDL-C(mg/dl) | 主动脉粥样硬化(%包含损害) |
对照组 | 104±13 | 1186±47 | 807±48 | 371±13 | 7±3 | 39.5±2.6 |
1mg/kg+ | 132±16 | 1434±35 | 903±34 | 508±18* | 23±6 | 21.6±3.1* |
2mg/kg+ | 143±20 | 1311±80 | 763±64 | 517±18* | 31±5* | 14.9±3.1* |
4mg/kg+ | 136±12 | 1281±58 | 749±58 | 494±10* | 38±5* | 16.4±2.8* |
8mg/kg+ | 134±9 | 1167±75 | 644±58 | 475±21* | 49±3* | 12.03±2.3* |
数据为平均值±S.E.
+雷帕霉素的给药剂量
*与对照组显著不同(p<0.01)。
表I中的结果表明,与对照组的EKO小鼠相比,用雷帕霉素治疗可显著(p<0.01)增加HDL-胆固醇和LDL-胆固醇的水平,而不显著影响甘油三酯,总胆固醇,和VLDL-胆固醇的水平。表I还显示出在用雷帕霉素治疗过的小鼠中出现动脉粥样硬化水平的显著性及戏剧性降低。当证实对照组动物存在39.6%主动脉弓的平均损害时,用1mg/kg雷帕霉素治疗的动物中的动脉粥样硬化仅为21.6%,而其在2,4,和8mg/kg的给药剂量时,分别进一步降低至14%,16%和12%。这代表了在很好接受的人动脉粥样硬化模型中,主动脉粥样硬化戏剧性地减少了3倍。
在上述标准药理学试验过程中所获得的结果的基础上,雷帕霉素可用于治疗或抑制心血管疾病和外周血管疾病。更特别是,本发明的雷帕霉素可用于治疗或抑制冠状动脉疾病,脑血管疾病,动脉硬化,动脉粥样硬化,非动脉粥样硬化性动脉硬化,或源于细胞事件的血管壁损害,其中所述细胞事件可导致免疫介导的血管损害。本发明的雷帕霉素还可用于抑制中风或多梗死性痴呆。
根据本发明,预期雷帕霉素可作为单独的活性成分提供本发明所保护的心血管,脑血管或外周血管益处,或雷帕霉素可与其它药剂联合给药提供有益的心血管,脑血管或外周血管作用。这种药剂通常是已知种类的化合物,包括ACE抑制剂,如喹那普利,哌道普利,雷米普利,卡托普利,群多普利,福森普利,赖诺普利,莫昔普利,和依那普利;血管紧张素II受体拮抗剂,如坎地沙坦,厄贝沙坦,氯沙坦,缬沙坦,和替米沙坦;fibric酸衍生物,如氯贝特,和吉非贝齐;HMG Co-A还原酶抑制剂,如西立伐他汀,氟伐他汀,阿托伐他汀,洛伐他汀,普伐他汀,辛伐他汀;β肾上腺素能阻断剂,如索他洛尔,噻吗洛尔,艾司洛尔,卡替洛尔,普萘洛尔,倍他洛尔,喷布洛尔,纳多洛尔,醋丁洛尔,阿替洛尔,美托洛尔,和比索洛尔;钙通道阻断剂,如硝苯地平,维拉帕米,尼卡地平,地尔硫卓,尼莫地平,氨氯地平,非洛地平,尼索地平,和苄普地尔;抗氧化剂;抗凝剂如,华法令,达肝素,肝素,依诺肝素,和达那肝素;及用于激素替代疗法的含雌激素的药剂,如共轭雌激素,乙炔雌二醇,17-β-雌二醇,雌二醇,和硫酸哌嗪雌酮。
因此,本发明还提供一种产品,其含有雷帕霉素和一种或多种选自ACE抑制剂,血管紧张素II受体拮抗剂,fibric酸衍生物,HMG Co-A还原酶抑制剂,β肾上腺素能阻断剂,钙通道阻断剂,抗氧化剂;抗凝剂,和用于激素替代疗法中的含雌激素的药剂的药剂,它们可作为联合制剂同时,分开或顺序给药,用于治疗或抑制哺乳动物的心血管,或外周血管疾病。
应当理解,雷帕霉素的有效剂量可根据所用的特定化合物,给药方式,所治疗病症的情况及其严重程度,和与所治疗个体有关的各种身体因素而变化。根据本发明,当以大约5μg-0.75mg/kg体重的每日口服剂量给予雷帕霉素时,可获得令人满意的结果。计划的每日剂量根据给药途径而变化。
当雷帕霉素被用作联合给药的组合物的一部分时,组合物各组分的剂量是在预定的治疗时期内给予的。组合物的组分可同时给予;或作为含两种组分的单一给药形式给予;或作为单独的剂量单位给予;所述组合物的组分还可在治疗期间,在不同时间给予,或其中一个作为另一个的预处理给予。这种给药可以任何方式给予,用于将此处的活性化合物直接给予接受者的血流,包括口服,经由植入物,非肠道(包括静脉内,腹膜内和皮下注射),直肠,鼻内,阴道,和透皮。为了达到公开的目的,透皮给药包括通过身体表面和身体通道内层,包括上皮和粘膜组织的所有给药。这种给药可使用本发明的化合物,或其药学上可接受的盐,以洗剂,乳膏,泡沫,药膏,混悬液,溶液,和栓剂(直肠和阴道)进行。
含本发明活性化合物的口服制剂可含有任何通常所用的口服形式,包括片剂,胶囊剂,口腔形式,锭剂,糖锭或口服液体,混悬液或溶液。胶囊剂可含有活性化合物与惰性填料和/或稀释剂,如药学上可接受的淀粉(例如玉米,马铃薯或木薯淀粉),糖,人造食品甜味剂,粉状纤维素,如结晶纤维素和微晶纤维素,面粉,明胶,树胶的混合物。有益的片剂是通过常规的压片法,湿制粒法或干制粒法,并使用药学上可接受的稀释剂,粘合剂,润滑剂,崩解剂,表面改性剂(包括表面活性剂),悬浮剂或稳定剂制造的,包括,但不限制于,硬脂酸镁,硬脂酸,滑石粉,十二烷基硫酸钠,微晶纤维素,羧甲基纤维素钙,聚乙烯吡咯烷酮,明胶,海藻酸,阿拉伯树胶,黄原胶,柠檬酸钠,复合硅酸盐,碳酸钙,甘氨酸,糊精,蔗糖,山梨醇,磷酸二钙,硫酸钙,乳糖,高岭土,甘露糖醇,氯化钠,滑石粉,干淀粉和糖粉。优选的表面改性剂包括非离子和阴离子表面改性剂。表面改性剂的代表性例子包括,但不限制于,泊咯沙姆188,苯扎氯铵,硬脂酸钙,十六醇十八醇混合物,聚西托醇乳化蜡,脱水山梨糖醇酯,胶态二氧化硅,磷酸盐,十二烷基硫酸钠,硅酸铝镁,和三乙醇胺。更优选将泊咯沙姆188作为表面改性剂。此处的口服制剂可利用标准延迟或时间释放制剂来改变活性化合物的吸收。雷帕霉素优选的口服制剂在美国专利US 5,559,121;US5,536,729;US5,989,591;和US5,985,325中公开,其引入此处作为参考。
在某些情况下,希望能以气雾剂的形式将所述化合物直接给予导气管。
本发明的化合物还可非肠道或腹膜内给药。作为自由基或药学上可接受的盐,这些活性化合物的溶液或混悬液可通过在水中与表面活性剂如羟丙基纤维素适当混合而制备。分散液还可在丙三醇,液体聚乙二醇及其在油中的混合物中制备。在普通的贮藏和使用条件下,这些制剂还可含有防腐剂,从而防止微生物的生长。
适于注射的药物形式包括无菌水溶液或分散液及用于临时制备无菌可注射溶液或分散液的无菌粉末。在所有情况下,所述形式必须是无菌的且在一定程度必须是可流动的,从而具有方便注射的能力。在制造和贮藏条件下,它必须是稳定的,且必须使它防腐,从而防止微生物,如细菌和真菌的污染。所述载体可以是含水,乙醇,多元醇(例如,丙三醇,丙二醇和液体聚乙二醇),及其适宜混合物,和植物油的溶剂或分散介质。用于给予雷帕霉素的优选非肠道制剂在美国专利US 5,530,006;US5,516,770;和US5,616,588中公开,其引入此处作为参考。
栓剂可由传统材料,包括椰子油及甘油制成,其可在加入或不加入蜡剂的情况下改变栓剂的熔点。还可使用水溶性栓剂基质,如各种分子量的聚乙二醇。
Claims (32)
1.一种治疗或抑制有需要的哺乳动物的心血管,脑血管,或外周血管疾病的方法,该方法包括给所述哺乳动物提供有效量的雷帕霉素。
2.根据权利要求1所述的方法,其中所述雷帕霉素是雷帕霉素。
3.根据权利要求1所述的方法,其中所述雷帕霉素是雷帕霉素的酯,醚,肟,腙,或羟胺。
4.根据权利要求3所述的方法,其中所述雷帕霉素是雷帕霉素的42-酯或42-醚。
5.根据权利要求4所述的方法,其中所述雷帕霉素是雷帕霉素3-羟基-2-(羟甲基)-2-甲基丙酸42-酯。
6.根据权利要求4所述的方法,其中所述雷帕霉素是42-O-(2-羟基)乙基雷帕霉素。
7.根据权利要求1-6任何一项所述的方法,其中所述雷帕霉素可与选自ACE抑制剂,血管紧张素II受体拮抗剂,fibric酸衍生物,HMG Co-A还原酶抑制剂,β肾上腺素能阻断剂,钙通道阻断剂,抗氧化剂;抗凝剂,或用于激素替代疗法中的含雌激素的药剂的一种或多种联合提供。
8.一种治疗或抑制有需要的哺乳动物的冠状动脉疾病,脑血管疾病,动脉硬化,动脉粥样硬化,非动脉粥样硬化性动脉硬化,或源于细胞事件的血管壁损害的方法,其中所述细胞事件可导致免疫介导的血管损害,该方法包括给所述哺乳动物提供有效量的雷帕霉素。
9.根据权利要求8所述的方法,其中所述雷帕霉素是雷帕霉素。
10.根据权利要求8所述的方法,其中所述雷帕霉素是雷帕霉素的酯,醚,肟,腙,或羟胺。
11.根据权利要求10所述的方法,其中所述雷帕霉素是雷帕霉素的42-酯或42-醚。
12.根据权利要求11所述的方法,其中所述雷帕霉素是雷帕霉素3-羟基-2-(羟甲基)-2-甲基丙酸42-酯。
13.根据权利要求11所述的方法,其中所述雷帕霉素是42-O-(2-羟基)乙基雷帕霉素。
14.根据权利要求8-13任何一项所述的方法,其中所述雷帕霉素可与选自ACE抑制剂,血管紧张素II受体拮抗剂,fibric酸衍生物,HMG Co-A还原酶抑制剂,β肾上腺素能阻断剂,钙通道阻断剂,抗氧化剂;抗凝剂,或用于激素替代疗法中的含雌激素的药剂的一种或多种联合提供。
15.一种抑制有需要的哺乳动物的中风或多梗死性痴呆的方法,该方法包括给所述哺乳动物提供有效量的雷帕霉素。
16.根据权利要求15所述的方法,其中所述雷帕霉素是雷帕霉素。
17.根据权利要求15所述的方法,其中所述雷帕霉素是雷帕霉素的酯,醚,肟,腙,或羟胺。
18.根据权利要求17所述的方法,其中所述雷帕霉素是雷帕霉素的42-酯或42-醚。
19.根据权利要求18所述的方法,其中所述雷帕霉素是雷帕霉素3-羟基-2-(羟甲基)-2-甲基丙酸42-酯。
20.根据权利要求18所述的方法,其中所述雷帕霉素是42-O-(2-羟基)乙基雷帕霉素。
21.根据权利要求15-20任何一项所述的方法,其中所述雷帕霉素可与选自ACE抑制剂,血管紧张素II受体拮抗剂,fibric酸衍生物,HMGCo-A还原酶抑制剂,β肾上腺素能阻断剂,钙通道阻断剂,抗氧化剂;抗凝剂,或用于激素替代疗法中的含雌激素的药剂的一种或多种联合提供。
22.雷帕霉素在制备治疗或抑制哺乳动物心血管,脑血管,或外周血管疾病的药剂中的用途。
23.雷帕霉素在制备治疗或抑制哺乳动物冠状动脉疾病,脑血管疾病,动脉硬化,动脉粥样硬化,非动脉粥样硬化性动脉硬化,或源于细胞事件的血管壁损害的药剂中的用途,其中所述细胞事件可导致免疫介导的血管损害。
24.雷帕霉素在制备抑制哺乳动物中风或多梗死性痴呆的药剂中的用途。
25.一种产品,其含有雷帕霉素和一种或多种选自ACE抑制剂,血管紧张素II受体拮抗剂,fibric酸衍生物,HMG Co-A还原酶抑制剂,β肾上腺素能阻断剂,钙通道阻断剂,抗氧化剂;抗凝剂;或用于激素替代疗法中的含雌激素的药剂的药剂,它们可作为联合制剂同时,分开或顺序给药,用于治疗或抑制哺乳动物的心血管,脑血管,或外周血管疾病。
26.一种产品,其含有雷帕霉素和一种或多种选自ACE抑制剂,血管紧张素II受体拮抗剂,fibric酸衍生物,HMG Co-A还原酶抑制剂,β肾上腺素能阻断剂,钙通道阻断剂,抗氧化剂;抗凝剂,或用于激素替代疗法中的含雌激素的药剂的药剂,它们可作为联合制剂同时,分开或顺序给药,用于治疗或抑制哺乳动物的冠状动脉疾病,脑血管疾病,动脉硬化,动脉粥样硬化,非动脉粥样硬化性动脉硬化,或源于细胞事件的血管壁损害,其中所述细胞事件可导致免疫介导的血管损害。
27.一种产品,其含有雷帕霉素和一种或多种选自ACE抑制剂,血管紧张素II受体拮抗剂,fibric酸衍生物,HMG Co-A还原酶抑制剂,β肾上腺素能阻断剂,钙通道阻断剂,抗氧化剂;抗凝剂,或用于激素替代疗法中的含雌激素的药剂的药剂,它们可作为联合制剂同时,分开或顺序给药,用于抑制哺乳动物的中风或多梗死性痴呆。
28.根据权利要求25-27任何一项所述的产品,其中所述雷帕霉素是雷帕霉素。
29.根据权利要求25-27任何一项所述的产品,其中所述雷帕霉素是雷帕霉素的酯,醚,肟,腙,或羟胺。
30.根据权利要求25-27任何一项所述的产品,其中所述雷帕霉素是雷帕霉素的42-酯或42-醚。
31.根据权利要求25-27任何一项所述的产品,其中所述雷帕霉素是雷帕霉素3-羟基-2-(羟甲基)-2-甲基丙酸42-酯。
32.根据权利要求25-27任何一项所述的产品,其中所述雷帕霉素是42-O-(2-羟基)乙基雷帕霉素。
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US21211700P | 2000-06-16 | 2000-06-16 | |
US60/212,117 | 2000-06-16 |
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JP (1) | JP2003535899A (zh) |
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CN (1) | CN1436076A (zh) |
AR (1) | AR028959A1 (zh) |
AU (2) | AU6844601A (zh) |
BR (1) | BR0111601A (zh) |
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NO (1) | NO20026008L (zh) |
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CN100384416C (zh) * | 2006-03-20 | 2008-04-30 | 杨军 | 一种用于治疗心血管疾病的药物组合物 |
CN100435755C (zh) * | 2004-07-27 | 2008-11-26 | 微创医疗器械(上海)有限公司 | 药物洗脱支架 |
CN105997940A (zh) * | 2016-05-11 | 2016-10-12 | 中国人民解放军第三军医大学 | 炎症微环境响应性纳米药物、其制备方法及应用 |
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US6641611B2 (en) | 2001-11-26 | 2003-11-04 | Swaminathan Jayaraman | Therapeutic coating for an intravascular implant |
US20040137066A1 (en) * | 2001-11-26 | 2004-07-15 | Swaminathan Jayaraman | Rationally designed therapeutic intravascular implant coating |
CA2472341C (en) | 2002-02-01 | 2011-06-21 | Ariad Gene Therapeutics, Inc. | Phosphorus-containing compounds & uses thereof |
US20030176455A1 (en) * | 2002-03-13 | 2003-09-18 | Wyeth | Method of inhibiting cell death |
SI1553940T1 (sl) * | 2002-07-30 | 2008-08-31 | Wyeth Corp | Parenteralne farmacevtske oblike, ki vsebujejo rapamicin-hidroksiester |
EP1635830B1 (en) * | 2002-09-17 | 2008-11-05 | Wyeth | Granulate formulation of the rapamycin ester cci-779 |
WO2004060283A2 (en) | 2002-12-16 | 2004-07-22 | Nitromed, Inc. | Nitrosated and nitrosylated rapamycin compounds, compositions and methods of use |
AR042938A1 (es) | 2003-02-06 | 2005-07-06 | Wyeth Corp | Uso del cci-779 en el tratamiento de la fibrosis hepatica |
US7728033B2 (en) | 2003-05-05 | 2010-06-01 | Clinigene International Private Limited | Mycophenolate mofetil in diabetic nephropathy |
US7220755B2 (en) | 2003-11-12 | 2007-05-22 | Biosensors International Group, Ltd. | 42-O-alkoxyalkyl rapamycin derivatives and compositions comprising same |
DE102004019845A1 (de) * | 2004-03-29 | 2005-10-20 | Krka Tovarna Zdravil D D | Verfahren zur Herstellung einer festen pharmazeutischen Zusammensetzung |
US20050232965A1 (en) * | 2004-04-15 | 2005-10-20 | Robert Falotico | Local administration of a combination of rapamycin and 17 beta-estradiol for the treatment of vulnerable plaque |
AU2005249794A1 (en) * | 2004-06-04 | 2005-12-15 | Teva Pharmaceutical Industries, Ltd. | Pharmaceutical composition containing irbesartan |
EP1656941A1 (en) * | 2004-11-09 | 2006-05-17 | Clinigene International Private Limited | Compositions for the treatment of diabetic nephropathy |
GB0503936D0 (en) | 2005-02-25 | 2005-04-06 | San Raffaele Centro Fond | Method |
US20080175887A1 (en) * | 2006-11-20 | 2008-07-24 | Lixiao Wang | Treatment of Asthma and Chronic Obstructive Pulmonary Disease With Anti-proliferate and Anti-inflammatory Drugs |
US9283211B1 (en) | 2009-11-11 | 2016-03-15 | Rapamycin Holdings, Llc | Oral rapamycin preparation and use for stomatitis |
JP5746749B2 (ja) | 2010-03-15 | 2015-07-08 | エクソンモービル・ケミカル・パテンツ・インク | アルコールの製造方法 |
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GB9606452D0 (en) * | 1996-03-27 | 1996-06-05 | Sandoz Ltd | Organic compounds |
NZ501652A (en) * | 1997-06-13 | 2001-09-28 | American Home Prod | Tablet comprising a core and sugar overcoat comprising rapamycin, sugars and binders |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN100435755C (zh) * | 2004-07-27 | 2008-11-26 | 微创医疗器械(上海)有限公司 | 药物洗脱支架 |
CN100384416C (zh) * | 2006-03-20 | 2008-04-30 | 杨军 | 一种用于治疗心血管疾病的药物组合物 |
CN105997940A (zh) * | 2016-05-11 | 2016-10-12 | 中国人民解放军第三军医大学 | 炎症微环境响应性纳米药物、其制备方法及应用 |
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BR0111601A (pt) | 2003-07-01 |
EP1292302A2 (en) | 2003-03-19 |
NO20026008D0 (no) | 2002-12-13 |
AU2001268446B2 (en) | 2005-08-11 |
HUP0301244A3 (en) | 2005-01-28 |
WO2001097809A2 (en) | 2001-12-27 |
IL153405A0 (en) | 2003-07-06 |
CZ20024115A3 (cs) | 2003-06-18 |
AR028959A1 (es) | 2003-05-28 |
WO2001097809A3 (en) | 2002-05-10 |
CA2412636A1 (en) | 2001-12-27 |
ZA200300418B (en) | 2004-04-15 |
AU6844601A (en) | 2002-01-02 |
KR20030010710A (ko) | 2003-02-05 |
US20020013335A1 (en) | 2002-01-31 |
MXPA02012410A (es) | 2003-04-25 |
NZ523114A (en) | 2004-07-30 |
NO20026008L (no) | 2002-12-13 |
JP2003535899A (ja) | 2003-12-02 |
HUP0301244A2 (hu) | 2003-08-28 |
PL365455A1 (en) | 2005-01-10 |
EA200300027A1 (ru) | 2003-06-26 |
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