CN1604780A - 在前痴呆状态中使用罗苏伐他汀 - Google Patents
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Abstract
本发明提供了一种预防患者中痴呆的方法，包括向有发展成痴呆危险的患者给予有效量的罗苏伐他汀或其药学可接受的盐。
Description
发明背景
罗苏伐他汀(此处定义为包括其药学可接受的盐，诸如，美国专利号5,260,440的实施例1和实施例7中分别所记载的钠盐或钙盐)。罗苏伐他汀钙盐的化学名为双[(E)-7-[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰基)氨基]嘧啶-5-基]-(3R，5S)-3，5-二羟基庚-6-烯酸]钙盐，是本文所述的本发明优选的化合物。美国专利号5,260,440在本文中引入作为参考。罗苏伐他汀是一种可抑制3-羟基-3-甲基-戊二酰辅酶A(HMG-CoA)还原酶的他汀。罗苏伐他汀可用于治疗诸如血胆固醇过多、高脂蛋白血症和动脉粥样硬化等疾病。
最近的研究得出，使用他汀类可以显著降低老年人发生痴呆的危险。Zornberg等人，DA.Statins and the Risk of Dmentia Lancet356：1627-1631(November 11，2000)。作者认为，他们所发现的是一种联系而不是偶然的联系。人们发现，使用洛伐他汀治疗血胆固醇过多可以在注意力和精神运动速度的神经心理测试中产生较小的递减结果，Am J.Med.2000：108：538-547(2000)。其它的研究发现，在用他汀类治疗后，没有发现其对人的认知能力产生任何作用，同上在542页。因此之前从未有罗苏伐他汀在预防痴呆中的用途的记载。
发明概述
本文提供了一种预防患者中痴呆的方法，包括向有发展成痴呆危险的患者给予有效量的罗苏伐他汀，和罗苏伐他汀或其药学可接受的盐在制备用于向有发展成痴呆危险的患者给药的药物中的用途。
发明详述
就本发明的目的而言，痴呆还包括阿耳茨海默症(AD)、血管性痴呆以及混合症状。痴呆的早期阶段在某种程度上被阐述及定义。例如，研究所使用的一组患有发展成痴呆危险的人，这些患者均患有轻度的认知缺损(MCI)。MCI指的是患者虽然患有记忆损伤但是没有到达痴呆的临床标准的一种临床状态。Petersen，等人，Practice parameter：Early detection of demetia：Mild cognitive impairment(anevidence-based review)，Neurology，56：1133-1142(2001)。用以下几条标准来确定MCI：1)存在主观性的记忆缺失，优选通过问卷填表证实；2)由词汇表测试所表现的行为来评估保存的广泛性智力功能(preserved general intellectual functioning)；3)通过认知测试来证明记忆缺损的存在；4)日常生活活动不受影响；以及5)没有发生痴呆。
另一组患有发展成痴呆危险的人是那些伴随有与年龄有关的记忆衰退(从CD)的处于前-痴呆(pre-demented)状态的人，AACD通常定义为，与年龄匹配对照组相比，在任一认知功能性上发生多种f-标准偏差的下降。K.Ritchie等人，Classification criteria for mildcognitive impairment：A population-based validation study，Neurology 56：37-42(2001)。Ritchie等人，争驳，AACD具有较高的对于痴呆发作的预言性确实性，Id在40页。
进一步的前痴呆状态可以通过以下标准的检查确定：1)主观上的认知缺陷疾病：涉及-由患者或代理人报告的实质上的认知缺损，其可包括一种或多种认知域，不一定必须包括记忆；2)客观性的认知缺损：由一系列的神经心理测验建立，优选那些可进行至少2年的测验，且所述测验必需包括记忆、注意力、可视空间能力(visuospatialabilities)以及执行功能；3)整体的认知刻度：总体的退化刻度(Global Deterioration Scale(GDS))的分值为3；以及4)按照DSM-III-R标准不属于痴呆。
Graham等人描述了另一种前-痴呆状况，Prevalence andseverity of cognitive impairment with and without dementia inan elderly population，Lancet 349：1793-6(1997)。
前痴呆状态也可通过采用血管性认知缺损的测定来进行评估，如Wentzel等人，Progression of impairnent in patients withvascula cognitive impairment without demetia，Neurology 2001；57：714-6(2001)。在此研究中，发现46％的参与者的患有由血管性CIND发展而来的痴呆。
在实施本发明的过程中，临床医生会例如使用上述方法中的一种来确定患者是否有发展成痴呆的危险。在本发明的另一个方面，吻合了例如上述定义的前痴呆病况标准的患者，作为适于给予有效量的罗苏伐他汀的患者的一个特定的例子。有效量的罗苏伐他汀是指足以在症状上缓解患者认知性症状的量。这可以例如通过示例来表示，即认知性症状的发展或恶化降低，或者患有认知性症状形式的患者情况变得更糟(发展成痴呆)的危险降低。
医生可采用熟知的方法来优化罗苏伐他汀的使用以预防痴呆。例如，熟练的医生可使用临床研究作为一种手段以使药物的效力最大化。相应地，罗苏伐他汀的治疗效果可以通过对患有前痴呆病症的患者进行传统的临床对照试验来证实。罗苏伐他汀在所述患者上的治疗性效果可以通过认知性症状的症状缓解来显示，即，认知性症状的发展或恶化降低，或者患有认知性症状形式的患者情况变得更糟(发展成痴呆或痴呆的程度恶化)的危险降低。
罗苏伐他汀可使用已知方法口服或非肠道给药。如果是口服给药，罗苏伐他汀可以片剂、粉末、胶囊、颗粒、水性或油性混悬液或诸如糖浆或酏剂的液体形式提供。如果是非肠道给药，其可典型的以水性或油性混悬液的形式给药。可使用传统的方法配制罗苏伐他汀或其药学可接受的盐，例如，可使用赋型剂、粘合剂、润滑剂、水性或油性助溶剂、乳化剂和助悬剂。也可进一步的使用防腐剂和稳定剂。优选的制剂示例性的记载在PCT申请号WO 01/54668之中，此文在此处引入作为参考。剂量可根据给药途径、年龄、重量、病况和患者疾病的种类来改变，但是典型的为0.5-200mg/天。如果口服剂型形式的使用剂量为1-100mg/天，则优选使用的剂量为1-80mg/天。如果是非肠道给药，剂量可以是0.5-50mg/天。剂量可以单次或分离的剂量给予。罗苏伐他汀典型的给药方案患者是口服，一日一次，每次服用1-80mg。
在小鼠身上进行的试验证实，皮下给药2或20mg/kg罗苏伐他汀(钙盐)14天，可增加eNOS的表达和活性，且能减少由中脑动脉闭塞(MCAO)引起的脑缺血而后继性产生的梗塞体积。该研究通常根据M.Endres等人阐述的方法进行，Stroke protection by 3-hydroxy-3-methylglutaryl(HMG)-CoA reductase inhibitors mediated byendothelial nitric oxide synthase，，Proc.Natl.Acad.Sci.USA，95：8880-8885(1998)。在很多病例中，已知痴呆是中风的蓄积性神经变异作用的结果。这些可以是主要的中风也可以是亚临床类型的中风，并都引起异源的痴呆症，通常称为血管性痴呆(VAD)。在该研究中，罗苏伐他汀保护小鼠大脑预防脑局部缺血。罗苏伐他汀可预防痴呆的机制即是通过保护大脑预防脑局部缺血。
不希望被任何理论所束缚，人们相信，有几种机理使得罗苏伐他汀可预防痴呆。内皮氧化一氮合酶(eNOS)由动脉脉管系统的内皮细胞所表达。eNOS通过将氨基酸精氨酸转化成瓜氨酸而释放氧化一氮(NO)。NO使得紧埃着内皮细胞的血管平滑肌舒张，由此是一种有效的血管舒张剂。大脑血管的扩张使得脑内血流增加，保护了大脑不产生局部缺血症状。
淀粉样蛋白前体(APP)以及早老因子-1(PS-1)的基因突变导致脑内肽类淀粉状蛋白-β(Aβ)水平升高，从而导致了家族性阿耳茨海默痴呆(fAD)。在这些基因上没有变异的阿耳茨海默患者的大脑具有主要由Aβ构成的纤维状的小半鞘翅(plaques)，就如同fAD患者的大脑一样。由此，认为大脑内Ab水平的升高可引起Aβ向小半鞘翅的沉积(淀粉样变性)和阿耳茨海默痴呆(AD)。大多数痴呆患者显示具有淀粉样变性和脑局部缺血的证据。事实上，诊断患有可能为AD的患者，死时伴随有淀粉状小半鞘翅和较少的血管性局部缺血(小的“腔隙”梗死)的迹象，比其他具有相同数量的淀粉状小半鞘翅的患者的认知功能更为糟糕。由此，通过采用上述机理以防止脑局部缺血，罗苏伐他汀可同时预防VAD、AD和混合型AD/VAD。
另一种罗苏伐他汀预防痴呆的机理是降低大脑Aβ水平。罗苏伐他汀可减少大脑Aβ水平的机理是，通过增加Aβ从大脑中去除。细胞表面受体LRP-1(LDL受体相关的蛋白-1)显示可介导束缚在LRP-1配体载脂蛋白E(ApoE)和β-2巨球蛋白(口2M)上的Aβ的转移。LRP-1表达减少相关的多形现象与AD风险的升高有关。与LRP-1配体ApoE等位的等位基因ApoE4的遗传特性也与AD风险的升高相关。进一步的证据表明，LRP-1在大脑脉管系统的内皮细胞中表达，依靠LRP-1的功能，通过在内皮细胞层之间的转移，Aβ正常的被挤出大脑。由此，LRP-1/ApoE可表示为一种从大脑中除去Aβ的重要的途径。LRP-1基因，如同与之非常相关的LDLR基因，含有一种称为效应元(SRE1)的DNA序列。该基因序列导致了对与胆固醇相关的固醇的细胞内水平敏感的基因的转录。当细胞固醇水平下降，含有SRE基因的转录便增加。事实上，给予胆固醇降低剂量的他汀类后，肝脏LRP-1 mRNA水平显示有所增加。罗苏伐他汀减少了胆固醇的生物合成。通过减少胆固醇的生物合成，罗苏伐他汀可降低内皮细胞固醇水平，由此可增加LRP-1基因的转录。LRP-1细胞表面受体所得的增加性的表达可增加配体-介导的Aβ从大脑中的挤出。他汀类进一步的可知可增加ApoE的表达。ApoE增加的表达可进一步的增加ApoE/LRP-1介导的Aβ从大脑中的挤出。由此，罗苏伐他汀可预防痴呆的另一个机理是通过增加LRP-1/ApoE依赖型的Aβ从大脑中的挤出来实现的。
罗苏伐他汀显示优于其它的辅酶A(HMG-CoA)还原酶抑制剂的在降低患者胆固醇上的特性，且特别的意想不到的在其预防痴呆的能力上。由此，令人惊讶且意想不到的是，罗苏伐他汀可提供一种预防患有发展成痴呆危险的患者，诸如显示具有观察到的前痴呆状况的患者，发生痴呆的方法。
Claims (2)
1.一种预防患者中痴呆的方法，包括向有发展成痴呆危险的患者给予有效量的罗苏伐他汀或其药学可接受的盐。
2.罗苏伐他汀或其药学可接受的盐在制备用于对有发展成痴呆危险的患者给药的药物中的应用。
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| GB0322552D0 (en) | 2003-09-26 | 2003-10-29 | Astrazeneca Uk Ltd | Therapeutic treatment |
| US7777034B2 (en) | 2003-11-24 | 2010-08-17 | Teva Pharmaceutical Industries Ltd. | Crystalline ammonium salts of rosuvastatin |
| ES2364143T3 (es) | 2003-12-02 | 2011-08-25 | Teva Pharmaceutical Industries Ltd. | Estandar de referencia para caracterización de rosuvastatina. |
| CA2573857A1 (en) | 2004-07-13 | 2006-02-16 | Teva Pharmaceutical Industries Ltd. | A process for the preparation of rosuvastatin involving a tempo-mediated oxidation step |
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| EP1446123A1 (en) | 2004-08-18 |
| BR0213434A (pt) | 2004-11-09 |
| HUP0401798A3 (en) | 2005-06-28 |
| SE0103509D0 (sv) | 2001-10-19 |
| ZA200402844B (en) | 2005-01-24 |
| MXPA04003631A (es) | 2004-07-30 |
| US20060229321A1 (en) | 2006-10-12 |
| RU2004112422A (ru) | 2005-04-10 |
| IS7218A (is) | 2004-04-13 |
| KR20040058201A (ko) | 2004-07-03 |
| IL161380A0 (en) | 2004-09-27 |
| CA2463597A1 (en) | 2003-04-24 |
| JP2005505605A (ja) | 2005-02-24 |
| WO2003032995A8 (en) | 2004-06-03 |
| CO5580773A2 (es) | 2005-11-30 |
| HUP0401798A2 (hu) | 2005-01-28 |
| PL369573A1 (en) | 2005-05-02 |
| NO20041840L (no) | 2004-05-05 |
| WO2003032995A1 (en) | 2003-04-24 |
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