CN100528164C - 用于增强认知保养的抑制素产品 - Google Patents
用于增强认知保养的抑制素产品 Download PDFInfo
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- CN100528164C CN100528164C CNB038073854A CN03807385A CN100528164C CN 100528164 C CN100528164 C CN 100528164C CN B038073854 A CNB038073854 A CN B038073854A CN 03807385 A CN03807385 A CN 03807385A CN 100528164 C CN100528164 C CN 100528164C
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- galanthamine
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Abstract
本发明涉及一种包括给药有效量的雪花胺(I)和抑制素(II)的治疗痴呆或记忆力障碍的方法。本发明进一步涉及含有雪花胺(I)作为第一种活性成分和抑制素(II)作为第二种活性成分的产品,其作为联合制剂同时地、单独地或按顺序地应用于患有早老性痴呆症或相关的痴呆疾病的病人的治疗中;本发明还涉及相关的药物组合物及其应用。
Description
发明领域
本发明涉及一种包括给药有效量的雪花胺(I)和抑制素(II)的治疗痴呆或记忆力障碍的方法。本发明进一步涉及含有雪花胺(I)作为第一种活性成分和抑制素(II)作为第二种活性成分的产品,其作为联合制剂同时地、单独地或按顺序地应用于患有早老性痴呆症疾病或相关的痴呆疾病的病人的治疗中;本发明还涉及相关的药物组合物及其应用。
发明背景
早老性痴呆症(AD)是一种以记忆力丧失和痴呆为特征的慢性神经变性病症。如在AD的情况中一样,非早老性痴呆症痴呆与记忆力丧失和痴呆相关。AD和非AD痴呆都通常伴随有行为的、精神病学的和/或包括精神病、抑郁症、焦虑和激动以及其他情绪改变和社会退缩在内的心理学的症状。实际上,痴呆的行为学的、精神病学的和/或心理学的症状可发生在60-90%的患有早老性痴呆症(AD)或其他痴呆疾病的病人中,并且由于其为照顾者压力的重要来源并且给照顾者带来焦虑综合症,因此它是至关重要的。
与痴呆或记忆力障碍相关的,更特别是与早老性痴呆症(AD)相关的行为学的、精神病学的和/或心理学的临床表现,可通过临床已接受的标度,例如简明精神病标度、早老性痴呆症评价标度-非认知的、通用综合症的相关评价、痴呆行为紊乱标度、神经精神病学列表、康奈尔痴呆抑郁标度、Cohen-Mansfield焦虑列表、老年病学抑郁标度、行为等级标度、痴呆的无行为能力评价、照顾者的时间和痴呆情绪评价标度。
在最初的照料医院和家庭护理中,对患有痴呆或记忆力障碍的病人的行为学的、精神病学的和/或心理学表现的治疗包括使用抗精神病药、抗抑郁药、抗焦虑药和抗癫痫剂/抗惊厥剂例如卡马西平和丙戊酸。
乙酰胆碱脂酶(AChE)是一种在胆碱能的(乙酰胆碱)神经传递中起关键作用的酶。在生理学上,乙酰胆碱水解为乙酸根和胆碱的水解作用用于使突触末端释放的乙酰胆碱分子失活,并因此终止由神经未梢的乙酰胆碱(ACh)释放引发的突触信号传导的发生。Ac hE抑制剂是抑制降解乙酰胆碱的酶的一类化合物。因此,通过抑制AchE,突触中的乙酰胆碱的保留时间延长,因此乙酰胆碱的活性增强。乙酰胆碱酯酶抑制剂包括雪花胺、卡巴拉汀多萘哌齐和他克林。
雪花胺,也被称为雪花胺anthamine或(4aS,6R,8aS)-4a,5,9,10,11,12-六氢-3-甲氧基-11-甲基-6H-苯并呋喃[3a,3,2-ef][2]苯并氮杂-6-醇是一种天然产生的有机物质,其可来源于普通雪花莲和许多石蒜科植物的球茎,同时也可通过合成的方法制备。最近,雪花胺成为用于与早老性痴呆症相关的神经学的和行为症状的综合治疗的临床评价的主体,并且在许多世界市场上正获得或等待获得市场批准,其商品名为REMINYL。
已知的雪花胺的药理学包括抑制AchE的能力。对于一种AChE-抑制剂例如雪花胺的治疗评价是基于如下的事实:在AD病人的大脑中,由于细胞死亡或突触变性造成释放一些Ach作为突触信号传导信使(神经递质)的神经元发生机能障碍或无机能。在这种病理环境中,AchE抑制剂通过延长时间从而使得可利用由剩余的功能突触末端释放的Ach分子来激活突触后的神经元膜中的Ach受体,从而增强了ACh-介导的突触活性。雪花胺是一种可逆的胆碱脂酶抑制剂。雪花胺与酶、乙酰胆碱脂酶竞争性地相互作用,并相对于丁酰胆碱脂酶来说,显示出对乙酰具有10至50倍的选择性。
近来,发现了雪花胺的新的药理学特性,其表明雪花胺可通过独立于其抑制AchE的能力的机制,例如尼古丁受体的变构调节来增强Ach的活性。雪花胺同样被报道具有改善AD的行为学的和精神病学的症状的效果。
雪花胺已被用于许多必须接受终身治疗的慢性疾病的治疗中。已显示,雪花胺在关节炎症、疲劳综合症、狂燥症、精神分裂症、记忆力机能障碍、包括早老性痴呆症(US 4663318)、酒精中毒、尼古丁依赖、注意力障碍(WO 99/21561)的治疗方面具有效果。时差抑制素抑制3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)还原酶、胆固醇生物合成中的限速酶,同时可用于预防和治疗血胆甾醇过多、高脂血症、动脉粥样硬化及其类似的病症。
在胆固醇和β-淀粉蛋白-一种在患有早老性痴呆症的病人脑部收集得到的蛋白的产生间存在一种假设的关系;抑制素可减少β-淀粉蛋白的产生。提示性的调查结果有:
-服用抑制素(HMG辅酶-A还原酶抑制剂)的病人具有一较低的发生早老性痴呆症和痴呆的可能性
-胆固醇增加了兔子和小鼠脑部的β-淀粉蛋白肽的产生
-抑制素降低了培养物和活的动物(几内亚猪)脑部的脑神经元中的β-淀粉蛋白肽的产生
-当采用以安慰剂作为对照、用40或60mg的洛伐抑制素进行随机的临床实验治疗时,具有高水平的低密度脂蛋白胆固醇的病人显示出血清β-淀粉蛋白的下降。
发明简述
本发明涉及一种包括给药有效量的雪花胺(I)和抑制素(II)的治疗痴呆或记忆力障碍的方法。典型地,所述的痴呆为早老性痴呆症(AD)导致的痴呆。在5到6个月的雪花胺的随机临床实验中,对于抑制素对早老性痴呆症病人中的认知保养的效果以及共给药抑制素和雪花胺的安全性进行了研究。抑制素和雪花胺的联合施用与单独采用雪花胺获得的效果相比,证明加强了认知的效果。
抑制素(II)选自:辛伐抑制素(simvastatin)、普伐抑制素(pravastatin)、洛伐抑制素(lovastatin)、氟伐抑制素(fluvastatin)、阿脱伐抑制素(atorvastatin)或罗伐抑制素(rosuvastatin),或任意一种种上述物质的有治疗活性的酸加成盐形式。所述的盐包括其中活性成分(II)能与合适的酸形成盐盐的形式,酸的例子有无机酸比如氢卤酸,例如盐酸或氢溴酸;硫酸、硝酸、磷酸及其类似的酸;或有机酸,例如,举例来说,乙酸、丙酸、羟乙酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己氨磺酸、水杨酸、对氨基水杨酸、扑酸及其类似的酸。雪花胺可方便的以(1∶1)氢溴酸盐的方式使用。
优选地,抑制素(II)的量等于或小于采用所述抑制素(II)进行单一治疗所批准的量。
最优选的是其中每个剂量形式中的作为主药雪花胺(I)为8,16或24mg的产品。
本发明还涉及含有作为第一活性成分的雪花胺(I)和作为第二活性成分的抑制素(II)的产品,其作为联合制剂用于同时地,单独地或顺序地应用于患有痴呆或记忆力障碍的病人的治疗中。
本发明也同样地涉及包括一种载体和作为第一活性成分的雪花胺(I)以及作为第二活性成的抑制素(II)的药物组合物,优选地,每一成分以在患有痴呆或记忆力障碍的病人中产生疗效的量存在。本发明还涉及一种制备上述药物组合物的方法。
此外,本发明还涉及抑制素(II)在制备用于增强在患有痴呆或记忆力障碍的病人中的雪花胺(I)的疗效的药物中的应用。
发明详述
如本文中所述,术语“痴呆”包括智力退化和其他精神病变,不考虑损害日常活动的病因,并且是由以前成功行为发生缺陷的结果。痴呆的恰当的例子包括但不限于,早老性痴呆症导致的痴呆、血管相关的痴呆、与多处梗塞相关的痴呆、脑外伤导致的痴呆、弥漫性脑损伤导致的痴呆、拳击痴呆、亨廷顿舞蹈症导致的痴呆、酒精中毒导致的痴呆、弥漫性白质病变导致的痴呆、与帕金森氏症相关的痴呆、Lewy体病变导致的痴呆、皮克症导致的痴呆、多系统退化导致的痴呆、进行性核上麻痹导致的痴呆、与关岛(Guam)的ALS-帕金森氏痴呆复合体相关的痴呆、前叶痴呆和皮层基底退化导致的痴呆。
如本文中采用的,术语“记忆力障碍”将包括记忆力丧失、精神恶化、精神承受力变小和认知丧失。
如本文中采用的“治疗有效量”是指由研究者、兽医、医生或其他临床医师所追求的在包括减轻接受治疗的障碍和疾病的症状的组织系统、动物或人体中引起生物学或药物学应答的活性化合物或药物制剂的量。更特别地,在本发明的直接涉及的包括给药雪花胺和一种或多种抑制素的联合治疗中,“治疗有效量”是指共同给药的药物的组合量,从而使联合效果能引起所要的生物学或药物学应答。例如,雪花胺和辛伐抑制素的治疗有效量为当同时或按顺序服用时具有联合的效果即治疗效果时的雪花胺的量和辛伐抑制素的量。此外,本领域的熟练技术人员将会认识到,在采用治疗有效量来共同治疗的情况中,如上述例子中所示,单独的雪花胺的量和/或辛伐抑制素的量可以是或不是治疗有效的。
如本文中使用的,术语“组合物”是指包括给特定量的特定成分的产品,以及由特定量的特定成分直接或间接地形成的任何产品。
根据本发明所述的方法,组合物中的单独的组分可以通过任何合适的方式同时地、按顺序地、单独地或以单独的药物制剂的形式进行给药。当雪花胺和抑制素以分开的剂量形式给药时,每一化合物每天给药的剂量数目可以相同或不同。雪花胺和抑制素可通过相同或不同的给药途径进行给药。给药的适当方法的例子包括但不仅限于口服的、静脉内的(iv)、肌肉内的(im)、皮下的(sc)、透皮的和直肠的给药方式。也可以将化合物直接给药至神经系统,其包括但不仅限于大脑内的、心室内的、大脑心室内的、鞘内的、脑池内的、脊柱内的给药途径和/或通过带或不带泵送装置的经由颅内的或脊柱内的针和/或导管给药的外周脊柱给药途径。可根据同时的或交替的方案,在治疗过程中的相同或不同的时间,将雪花胺和抑制素以分多次给药的剂型或单次给药的剂型并行的方式进行给药。因此,应当理解本发明可包括所有的这种同时的或交替治疗的方案,并且对术语“给药”作相应的解释。
优选的进行给药的剂量和剂量方案可由本领域熟练技术人员来确定,并根据给药方式、制剂的强度和疾病情况的发展而变化。此外,与接受治疗的特定病人相关的因素,包括病人的性别、年龄、体重、日常饮食、身体活动、给药时间和伴随的疾病,将对剂量和/或给药方案产生进行调整的需要。
实施例
本目标是在5个月和6个月的雪花胺的随机临床实验期间评价抑制素对患有早老性痴呆症的病人的认知保养的效果。
研究设计
-数据是从受限于每天采用24mg雪花胺或安慰剂治疗的病人的3组双盲的、安慰剂作为对照的临床实验中综合而来的。
-根据雪花胺的等级和任意的抑制素的使用来对病人进行分类。
功效结果
-通过末次观察前推法(LOCF)使用标准的11项(ADAS-cog/11),对早老性痴呆症评价标度-认知亚标度中的变化进行了评价
-进行病人亚组间的比较以控制相关的混淆因子。
安全性结果
-计算了包括反胃、腹泻、厌食和呕吐,以及这些胃肠症状中的任意一种的,通常与乙酰胆碱脂酶抑制剂相关连的不良副作用发生率,并比较了采用含有抑制素的雪花胺和单独采用雪花胺的相对风险。
-计算了包括背部疼痛、腿部痉挛、骨骼痛、肌肉萎缩、肌肉乏力和肌痛,以及这些肌肉骨骼症状中的任意一种的,通常与抑制素相关连的不良事件的发生率,并比较了采用含有抑制素的雪花胺和单独采用抑制素的相对风险。
-计算了包括腹痛或头痛的通常与乙酰胆碱脂酶抑制剂或抑制素相关连的不良事件发生率,并比较了采用含有抑制素的雪花胺和单独采用雪花胺以及单独采用抑制素的相对风险。
限制
作为伴随治疗,使用抑制素的模式在剂量、类型和持续时间方面多种多样。本研究对于抑制素的效果的测试不是十分强有力。
结果
药物治疗组的特征
将每一治疗组的基线统计和病人特征总结于表1中。
表1.药物治疗组的特征
平均值(SD) | 平均值(SD) | 平均值(SD) | 平均值(SD) | ||
以年数表示的年龄<sup>2</sup>ADAS-Cog基线总胆固醇<sup>3</sup>MMSE基线<sup>4</sup> | 72.4(8.4)26.8(11.3)218.0(47.2)18.2(4.1) | 74.0(7.8)25.7(8.9)219.3(38.1)18.4(3.8) | 75.7(7.9)26.5(10.1)228.3(43.6)18.7(3.8) | 75.2(8.2)26.8(10.6)224.6(43.8)18.7(4.0) | 0.0450.8520.1770.784 |
百分比 | 百分比 | 百分比 | 百分比 | ||
AD严重程度,%轻微的<sup>4</sup> | 61.9% | 66.0% | 64.8% | 64.9% | 0.98 |
除非特别注明,所有值均为平均值(SD)。
1P-值是基于连续变量的方差分析和绝对变量的卡方检验
2成对比较差异显著性(P≤0.05):抑制素+雪花胺与只有单独的雪花胺相比;抑制素+雪花胺与两者都没有相比。
3由于丢失了数据N=1311。
4微型智力状态测试(MMSE):轻微的(MMSE≥18)作为与中等的对比(MMSE<18)。
服用抑制素的病人的比例为6.9%(n=92)。
抑制素亚组具有较低比例的女性(p=0.06)
抑制素+雪花胺组比非抑制素组年轻3岁(p=0.05)
各个组在基线水平的认知分数和总胆固醇方面相似。
按组划分的抑制素类型的分布示于表2中。
表2:在采用抑制素治疗的雪花胺的临床实验病人中的抑制素类型的分布(n=92)
1采用24mg/天的雪花胺和抑制素作为伴随药物来治疗的病人
2采用安慰剂和抑制素作为伴随治疗剂来治疗的病人
3基于卡方检验的P-值
4在采用2种抑制素治疗的10位病人中,仅对采用的第一种抑制素进行编码。
采用按照抑制素分组的在分布方面没有显著性差异(p=0.135)的5种不同的抑制素(辛伐抑制素、普伐抑制素、洛伐抑制素、氟伐抑制素、阿脱伐抑制素)来治疗病人。
辛伐抑制素具有最高的使用频率(在抑制素+雪花胺组中为38.1%,在仅采用抑制素的组中为34%)。
在仅采用抑制素的组中,导致血清中低密度脂蛋白胆固醇最大程度地减少的抑制素(辛伐抑制素和阿脱伐抑制素)在更高比例的病人中施用(在抑制素+雪花胺组中为40.5%,在仅采用抑制素的组中为52%)。
在两组抑制素治疗组中能透过中枢神经系统的抑制素(辛伐抑制素和洛伐抑制素)在相似比例的病人中施用(在抑制素+雪花胺组中为59.5%,在仅采用抑制素的组中为58%)。
采用抑制素和雪花胺治疗的效果(意向治疗分析)
在仅采用雪花胺(-0.88,SE 0.25)和采用抑制素+雪花胺(-2.85,SE 0.91)的组中认知状况得到改善。
在仅采用安慰剂(2.24,SE 0.24)和仅采用抑制素(1.98,SE0.85)的组中认知状况发生减退。
仅采用雪花胺的效果非常显著(p<0.001),抑制素的效果不显著(p=0.083),并且抑制素和雪花胺的相互作用不显著(p=0.183)。
在未经多重比较校正的情况下,在成对比较中,抑制素+雪花胺的效果似乎优于仅采用雪花胺的组(p=.037)。
这些结果基于作为研究对照的ANOVA和采用MMSE的AD严重程度;当将分析限制到所观察到的案例数据时,也发现了类似的结果(表3)。
表3:如联合实验数据中ADAS-Cog的变化所反应的抑制素治疗效果
1最小平方平均值(LS)和标准误差(SE)
2根据含有抑制素(Y/N)、药物(雪花胺/PBO)、研究、基于MMSE的AD严重程度术语的四因素方差分析以及抑制素*药物
3也作为研究(p=0.037)和AD严重程度(p<.001)的对照
4也作为研究(p=0.065)和AD严重程度(p<.001)的对照
结论
虽然当其单独施用或与雪花胺联合施用时,抑制素的使用并未造成显著的改善,但是在5个月和6个月的临床实验中,雪花胺改善了患有早老性痴呆症的病人中的认知功能。然而,抑制素和雪花胺的联合使用与仅采用雪花胺治疗相比,的确增加了认知效果。该结果进一步表明:当与雪花胺联合对老年人给药时,高的抑制素剂量不是获得阳性结果所必须的。由于治疗组数目较小,不良事件数据不具有决定性。相对于仅采用抑制素或雪花胺的治疗来说,抑制素和雪花胺的组合可增加腹泻、腹部疼痛和肌肉或骨骼疼痛的风险。
Claims (14)
1.一种含有作为第一活性成分的雪花胺和作为第二活性成分的抑制素的产品,其作为联合制剂用于同时地、单独地或按顺序地应用于患有痴呆或记忆力障碍的病人的治疗中,其中抑制素选自:辛伐抑制素、普伐抑制素、洛伐抑制素、氟伐抑制素、阿脱伐抑制素或罗伐抑制素,或任意一种上述物质的有治疗活性的酸加成盐形式。
2.权利要求1的产品,其中雪花胺以雪花胺氢溴酸盐形式存在。
3.权利要求1的产品,其中抑制素的量等于或小于采用所述的抑制素进行单一治疗所批准的量。
4.权利要求1的产品,其中作为主药的雪花胺的量为每个剂量形式8、16或24mg。
5.一种包括载体和作为第一活性成分的雪花胺以及作为第二活性成分的抑制素的药物组合物,其中抑制素选自:辛伐抑制素、普伐抑制素、洛伐抑制素、氟伐抑制素、阿脱伐抑制素或罗伐抑制素,或任意一种上述物质的有治疗活性的酸加成盐形式。
6.权利要求5的组合物,包括载体和作为第一活性成分的雪花胺以及作为第二活性成分的抑制素,其中每一活性成分均以在患有痴呆或记忆力障碍的病人中产生治疗效果的量存在。
7.权利要求5的组合物,其中雪花胺以雪花胺氢溴酸盐形式存在。
8.权利要求5的组合物,其中抑制素的量等于或小于采用所述抑制素进行单一治疗所批准的量。
9.权利要求5的组合物,其中作为主药的雪花胺的量为每个剂量形式8、16或24mg。
10.抑制素在制备用于增强雪花胺在患有痴呆或记忆力障碍的病人中的治疗效果的药物中的应用,其中抑制素选自:辛伐抑制素、普伐抑制素、洛伐抑制素、氟伐抑制素、阿脱伐抑制素或罗伐抑制素,或任意一种上述物质的有治疗活性的酸加成盐形式。
11.权利要求10的应用,其中雪花胺以雪花胺氢溴酸盐形式存在。
12.权利要求10的应用,其中抑制素的量等于或小于采用所述抑制素进行单一治疗所批准的量。
13.权利要求10的应用,其中作为主药的雪花胺的量为每个剂量形式8、16或24mg。
14.一种制备如权利要求5到9中任意一项所限定的药物组合物的方法,其包括将雪花胺、抑制素和药学上可接受的载体混合的步骤,其中抑制素选自:辛伐抑制素、普伐抑制素、洛伐抑制素、氟伐抑制素、阿脱伐抑制素或罗伐抑制素,或任意一种上述物质的有治疗活性的酸加成盐形式。
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Non-Patent Citations (2)
Title |
---|
Statins and the risk of dementia. H. JICK ET AL.The LANCET,Vol.356 No.9242. 2000 |
Statins and the risk of dementia. H. JICK ET AL.The LANCET,Vol.356 No.9242. 2000 * |
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