CN1252715A - 用于预防局部缺血心脏病的制剂 - Google Patents
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- CN1252715A CN1252715A CN98804402A CN98804402A CN1252715A CN 1252715 A CN1252715 A CN 1252715A CN 98804402 A CN98804402 A CN 98804402A CN 98804402 A CN98804402 A CN 98804402A CN 1252715 A CN1252715 A CN 1252715A
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Abstract
本发明涉及一种用于预防次级并发症,局部缺血心脏病的制剂,其包括一种具下式的作为活性成分的化合物:本制剂可以通过抑制动脉硬化患者的动脉壁斑(内膜增厚)的破坏来预防各种次级局部缺血心脏病。
Description
本发明涉及通过抑制动脉壁斑(plaque)(内膜增厚)的破裂,来预防患有动脉硬化患者的各种继发性局部缺血心脏病。
动脉硬化是局部缺血的一种主要损伤。在动脉硬化的初级阶段,根据动脉部位的不同,可以观察到损伤的组成有所不同,由冠状动脉平滑肌细胞引起的弥散性内膜增厚甚至可以发生在十几岁的年龄。随着年龄的增加,增厚逐渐发展,最终发展成为斑,其是一种发生于动脉腔内并占据相当面积的动脉粥样硬化损伤。美国心脏协会根据斑成分的变化将斑分为六个类型,并规定脂质蓄积是斑形成和发展的首要和主要机制(Stary,H.C.,Circulation,92,pp.1335-1374(1995))。
最近有人阐述,急性冠状综合症(例如不稳定的心绞痛或急性心肌梗塞)的发作与由于斑成分的不稳定所导致的斑破裂有密切关系,而不是由于严重的血管狭窄(Falk,E.等人,Circulation,92,pp.657-671(1995))。
据说,根据斑的成分,将斑分为难破裂型(稳定型斑)和另一种易破裂类型(不稳定型斑)。稳定型斑主要由细胞外的基质成分,例如纤维和细胞成分(如平滑肌细胞)组成,并具有一个相当厚的纤维性的覆盖层,其将小规模的脂质沉积(如果有的话,是在内膜的深部)覆盖起来。
另一方面,不稳定型斑主要是由脂质成分(例如胆甾醇酯)组成,其中可见大噬菌体或炎症细胞的浸润,并且其中有非常薄和脆弱的纤维性的覆盖层覆盖着血管的腔侧(Falk,E.等人,Circulation,92,pp.657-671(1995))。通过不稳定型斑的破裂其将损伤到斑的深部,由此,动脉粥样化的糊状物将与血管接触,诱发血栓,并且在动脉粥样化的中心血栓形成迅速发展,其导致了血管闭合以及随后的心脏病事件的发生(Fuster,V.等人,N.Eng.J.Med,326,pp.242-250以及310-318(1992))。
不仅是在冠状动脉,由动脉硬化的斑破裂引起的血栓部分以栓子的形式转移上游的好血管处,在那里形成血栓,其与局部缺血疾病(例如暂时性局部缺血侵害,脑梗塞或外周动脉血栓)的发作密切相关。
基于以上问题,本发明采用用于动脉硬化的兔子或仓鼠模型进行了筛选,并找到了有效的化合物,在此基础上完成了本发明。
更具体地,本发明直接涉及一种基于对斑稳定作用的预防局部缺血心脏病的制剂,其包含由下式代表的化合物作为活性成分。
由式(I)代表的本发明化合物(这里称为本发明化合物)在用于动脉硬化的仓鼠模型中,在不低于血胆甾醇水平的的低剂量下可以抑制动脉壁上脂质的沉积。此模型中的脂质沉积据说是初级的损伤,其中的单细胞衍生大噬菌体可以储藏胆甾醇酯,形成泡沫状的细胞,后者可以沉积在血管中(Mark C.Kowala等人,动脉硬化和血栓形成,13,pp.435-444(1993))。
一般认为,本发明化合物的ACAT抑制作用主要归于本发明化合物通过大噬菌体抑制胆甾醇,然而,在前述的单细胞向细胞壁的粘附以及大噬菌体形成的步骤中,通常认为还有另一种作用机制,例如抑制白三烯合成和促进前列环素的生成。从这个作用可以明显地看到,本发明化合物从早期即可以抑制血管壁上脂质的沉积,它是斑改善最明显和最初的作用机制。
在本发明中采用的负荷胆甾醇兔子的动脉硬化治疗模型中,在动脉粥样化的生长期,使普通的颈动脉发生病理改变,其中的随着富含脂质成分(主要由大噬菌体组成)的不稳定型斑的发展,内膜逐渐增厚。本发明化合物抑制此时期的斑生长,并显示出抑制内膜增厚的活性。
这个阶段的主动脉弓处于完整斑阶段,其中的内膜增厚已经接近结束。从病理上来看,大噬菌体和许多平滑肌细胞混合在一起,细胞内外富集了脂质成分,并形成了不完整斑的纤维性覆盖物。
尽管本发明化合物没有显示出消弱内膜增厚程度的作用,但其降低了斑中的脂质成分,并反向地促进了纤维性成分的生成,并加速了血管腔侧由平滑肌细胞和弹性蛋白的弹性纤维组成的纤维覆盖物的构成。
简而言之,本发明化合物促进了斑的稳定化。在本发明化合物不低于血胆甾醇水平的剂量下,人们已经证实了这些作用的进展。
通过持续给予患有遗传高血脂的WHHL兔子本发明化合物,已经对上述化合物对各种动脉硬化损伤的作用进行了研究,上述兔子模型是用于家族性高血脂的动物模型,在发展为后期复合损伤的老年期损伤之前,从年轻期起,经过一个较长的时期,其可以发展为青少年性的局部缺血心脏病。在进行尸体解剖时发现,20个月的老年WHHL兔子的主动脉的损伤形成了复合损伤,其中的胶原蛋白和弹性蛋白与平滑肌细胞和大噬菌体混合在一起,并观察到有许多胆甾醇、结晶和钙的沉积以及损伤的内膜和脆弱的介面。
本发明化合物显示出降低动脉壁上胆甾醇含量的作用,进一步地,修饰损伤部位的的成分,加固和稳定血管的构筑。因此抑制了胆甾醇结晶在斑中的沉积。
其进一步促进内膜弹性蛋白的生成,抑制胶原蛋白的生成,尤其是增加斑皮质部分中弹性蛋白/胶原蛋白的比例。我们认为这代表其可以诱导内膜纤维成分变化为用于构筑血管介面的正常类型。
而且,本发明化合物显示出促进介面弹性蛋白的生成并压缩内皮细胞的作用。由于模型是陈旧性损伤,可以使脆弱的介面和损伤的内皮有所发展,故本发明化合物有可能通过加固血管的构筑,起到改进整个血管损伤的作用。
这些结果显示,本发明化合物在不引起血胆甾醇水平变化的剂量下,对多种血管损伤起到了直接的作用。
通常认为本发明化合物的ACAT抑制活性与降低斑中的脂质成分有密切的关系,在考虑其对纤维性成分生成的促进作用时,本发明化合物对平滑肌细胞还有另外一种作用机制。
由于正常介面的收缩型平滑肌细胞中的弹性蛋白占主导地位,故认为本发明化合物可以通过直接或间接的作用诱导收缩型平滑肌细胞转变为内膜,并且可以促进血管壁的器官加固,这些均导致了血管整体功能的改善。
本发明化合物是一个众所周知的化合物,其公开于日本专利申请40898/1994(相应的美国专利5,475,130)。
作为活性成分的本发明化合物的剂量可以根据情况变化。在口服给药的情况下,成人的每日剂量通常在0.5-120mg/人,可以一天一次给药,也可以每天分成几次给药。
本发下式明中的预防剂可以制成固体形式后给药,例如片剂、丸剂、胶囊、粒剂、干糖浆等。
在制备固体制剂时,可以使用各种添加剂,例如赋形剂,崩解剂,粘合剂,润滑剂或包衣基质,并可以采用振荡粒化方法,流化床粒化方法或破裂粒化方法。
赋形剂包括甘露醇,木糖醇,山梨醇,葡萄糖,蔗糖,乳糖,结晶纤维素,结晶纤维素羧甲基纤维素钠,磷酸氢钙,小麦淀粉,水稻淀粉,玉米淀粉,土豆淀粉,羧甲基淀粉钠,糊精,脂肪酸甘油三酯。
崩解剂包括低取代的羟丙基纤维素,羟甲基纤维素,羧甲基纤维素钠,淀粉,结晶纤维素,羟丙基淀粉等。
粘合剂包括甲基纤维素,羟丙基纤维素,羟丙基甲基纤维素,聚乙烯基吡咯烷酮,明胶,阿拉伯胶,乙基纤维素,聚乙烯基醇,出芽短梗孢糖,琼脂,黄耆胶等。
润滑剂包括硬脂酸,硬脂酸镁,硬脂酸钙,滑石,硬化的油,蔗糖脂肪酸酯等。
抗氧化剂包括二丁基羟基甲苯(BHT),焦性没食子酸丙酯,丁基羟基茴香醚(BHA),α-生育酚,柠檬酸等。
包衣剂包括羟丙基甲基纤维素,羟丙基纤维素,甲基纤维素,乙基纤维素,邻苯二甲酸羟丙基甲基纤维素,乙酸琥珀酸羟丙基甲基纤维素,羧甲基乙基纤维素等。
增色剂包括焦油色,氧化钛等。
矫正剂包括柠檬酸,己二酸,抗坏血酸,甲醇等。
表面活性剂包括聚氧乙烯硬化蓖麻油,单硬脂酸甘油酯,单硬脂酸脱水山梨醇酯,单棕榈酸脱水山梨醇酯,聚山梨酸酯,十二烷基硫酸钠,聚乙二醇,蔗糖脂肪酸酯等。
增塑剂包括柠檬酸三乙酯,三醋精,鲸蜡醇等。
基于斑稳定活性的本发明预防局部心脏病制剂可以任意适合给药的剂型经口服或非肠道途径使用。这些剂型的实例有注射液,溶液,乳化剂,栓剂等。
本发明化合物可以抑制大噬菌体的粘附、浸润以及泡沫化,这些是斑不稳定化的初级损伤,并可以在斑的生长期抑制内膜增厚。
本发明化合物进一步可以从斑的成分中消除脂质,促进纤维生成,其导致了斑的稳定化,通过这种斑稳定作用可以预防斑的破裂。因此,其可以提供一种有用的药物,它能够预防由随后的血栓性(血管)闭合引起的局部缺血心脏病的发作。
下列实验实施例和实施例将更加充分地解释本发明。实验实施例1[在负荷高脂肪的仓鼠动脉硬化治疗模型中的抗动脉硬化活性][实验操作]
用5只6周大的雄性金仓鼠作为实验动物(可以从Nihon SLCK.K.得到)。用下列高脂肪的饲料喂养仓鼠10周,以准备动脉硬化模型。
在此期间,给药组在给予饲料的同时持续给予本发明化合物。
收集血液后,切下主动脉弓,在显微镜下将外膜完全剥离。将组织固定于10%的中性缓冲福尔马林溶液中,用Oil Red O溶液进行脂肪染色,并将其附于载玻片上的甘油-明胶溶液中,制备组织标本。
借助图象分析系统(Adobe Photoshop,Unitimage for theApple Macintosh)对脂肪染色部位的面积(μm2)和动脉面积(mm2)进行了测定,并计算两个值的比例,以确定动脉壁上的脂质沉积程度。
使用自动分析仪(Hitachi 7150型),按照酶方法(AutoseraCHO-2,Daiichi Kagaku Yakuhin K.K.)测定总血胆甾醇水平。
将药物与高脂肪的饲料进行混合,药物的浓度为0.003%和0.03%,由摄入的饲料量以及体重来计算剂量。
高脂肪饲料的组成:用于大鼠MF的饲料(可从Oriental KoboK.K.获得),其含有10%的椰子油以及0.05%的胆甾醇。(结果)
结果列于表1。表1[在负荷高脂肪的仓鼠身体上动脉硬化治疗模型中的抗动脉硬化活性]
总血胆甾醇 动脉壁上的脂质沉积程度 抑制
mk/kg mg/dl μm2/mm2 (%)
对照 -- 406.0±44.9 665.1±159.2 -本发明化合物 1.5 372.0±35.5 217.5±40.5* 67.3本发明化合物 1.5 231.2±4.9* 46.2±8.6** 93.1
平均值±S.E.(n=5)
*p<0.05,**p<0.01vs.对照
(对照组动脉壁上脂质沉积程度—给药组实验实施例2[在负荷胆甾醇的兔子身体上动脉硬化治疗模型中的抗动脉硬化活性][实验操作]
将预先喂给1%富集胆甾醇饲料的10只兔子(5个月大,NZW属,雄性;可从Kitayama RABES K.K.得到)作为实验动物,使之成为动脉硬化模型。
患有动脉硬化的一组兔子用兔子用RC-4正常饲料(可从OrientalKobo K.K.获得)喂养3个月,将其作为对照组,在此期间同时口服给予给药组本发明化合物,剂量为一次,每次3mg/kg/天。
收集血样后,切除普通的颈动脉和主动脉,将其中的某一部分固定于10%中性缓冲福尔马林溶液中,制备动脉组织的切片。采用ElasticVan Gieson(EVG)染色制备弹性蛋白的弹性纤维染色标本,采用Oil RedO染色制备脂肪染色的标本,采用抗人类α-肌动蛋白抗体1A4染色制备平滑肌染色标本。
用5分制的标准,以弹性蛋白阳性以及脂质染色阳性的强度,对内膜弹性蛋白纤维生成的程度和介面脂质沉积程度进行了评价(级别;0:没有变化,1:最小,2:温和,3:中等,4:严重)。借助图象分析系统对内膜的面积(I)和介面的面积(M)进行了测定(AdobePhotoshop,Unitimage for the Apple Macintosh),并计算两个值的比例(I/M)。
用弹性蛋白阳性面积与给出的内膜表面面积之比计算内膜表面纤维覆盖物中的弹性蛋白的密度。α-肌动蛋白阳性面积与处于相似部位的内膜表面面积之比被定义为平滑肌的密度。用氯仿∶甲醇(2∶1)溶液从切除的主动脉部分提取胆甾醇,并按照酶方法(CholesterolCII-Test WAKO,Free Cholesterol C-TEST WAKO,Wako Pure ChemicalIndustries Ltd.)进行分析。
使用自动分析仪(Hitachi 7150型),按照酶方法(AutoseraCHO-2,Daiichi Kagaku Yakuhin K.K.)测定总血胆甾醇水平。
结果列于表2,3,4和5。表2[在负荷胆甾醇的兔子动脉硬化治疗模型中的抗动脉硬化活性]
总血胆甾醇 通常颈动脉中内 抑制
膜增厚的程度
mk/kg mg/dl I/M (%)对照 -- 165.3±43.9 1.02±0.33 --本发明化合物 3 113.4±38.6 0.45±0.18 55.9I/M=内膜面积/介面面积表3[在负荷胆甾醇的兔子动脉硬化治疗模型中的抗动脉硬化活性]
动脉壁上的 动脉壁上的 动脉壁上的
总血胆甾醇 游离胆甾醇 胆甾醇酯 抑制(%)
mk/kg mg/g mg/g mg/g
对照 -- 417.0±35.0 128.2±11.8 288.8±24.3 -本发明化合物 3 338.2±29.9 119.1±12.2 219.1±18.4* 24.1*p<0.05表4[在负荷胆甾醇的兔子身体上动脉硬化治疗模型中的抗动脉硬化活性]
介面脂质 内膜弹性
mk/kg 沉积程度 抑制(%) 蛋白纤生成 促进(%)
对照 -- 2.3±0.3 -- 0.8±0.2 --本发明化合物 3 1.2±0.1* 47.8 1.7±0.2** 112.5
平均值±S.E.
级别;0:没有变化,1:最小,2:温和,3:中等,4:严重
内膜表面的 内膜表面的
mk/kg 纤维蛋白密度 促进率(%) 平滑肌密度 促进率(%)
对照 --- 110±21 --- 518±41 ---本发明化合物 3 151±30 37 614±35 18.5*p<0.1vs.对照实施实例3 [在遗传高血脂的WHHL兔子上的抗动脉硬化活性][实验操作]
在18个月内,持续给予两个月大的患有遗传高血脂的WHHL兔子(可从Kitayama RABES K.K.得到)本发明化合物,然后进行尸体解剖。
将主动脉的其中一部分固定于10%中性缓冲福尔马林溶液中,然后将其包埋或冷冻包埋在石蜡中,制备动脉组织的切片。切片用Hematoxylin和Eosin(HE)、Elastic Van Gieson(EVG)、Azan-Mallory以及Oil Red O进行染色。在显微镜的观察下评价阳性率,用5分制(级别;0:没有变化,1:最小,2:温和,3:中等,4:严重)来衡量动脉硬化损伤中的组分变化。用氯仿∶甲醇(2∶1)的溶液提取主动脉另一部分中的胆甾醇,并按照酶方法(Cholesterol CII-TestWAKO,Wako Pure Chemical Industries Ltd.)对动脉壁中的总胆水平甾醇进行分析。
使用自动分析仪(Hitachi 7150型),按照酶方法(AutoseraCHO-2,Daiichi Kagaku K.K.),对尸体解剖时的总血胆甾醇水平值进行测定。
将药物与兔子用RC-4饲料(可从Oriental Kobo K.K.获得)进行混合,药物的浓度为0.005%和0.05%。每天在上午9:00和11:30时喂给兔子制成的饲料,给料量严格控制在20g/kg体重。(结果)
结果列于表6和7。表6[在遗传高血脂的WHHL兔子上的抗动脉硬化活性]
总血胆甾醇 动脉壁上的总胆甾醇 抑制(%)
mk/kg mg/dl mg/g
对照 --- 514±33 39.8±54 --本发明化合物 1 462±13 29.3±4.8 26.4本发明化合物 10 438±20 32.2±2.6 19.1
平均值±S.E.表7[在遗传高血脂的WHHL兔子上的抗动脉硬化活性]
主动脉硬化中的斑成分 胆甾醇党积
mg/kg 内膜胆甾醇沉积 内膜弹性蛋白 内膜胶原蛋白
对照 --- 3.6±0.1 1.3±0.2 3.9±0.1本发明化合物 1 2.6±0.2* 1.5±0.2 3.0±0.2**本发明化合物 10 2.2±0.1*** 1.8±0.2 3.0±0.1***
mg/kg 内膜表面弹性蛋白/胶原蛋白 介质弹性蛋白
对照 --- 0.64±0.07 0.26±0.07本发明化合物 1 1.26±0.24** 0.93±0.20*本发明化合物 10 2.01±0.36*** 1.59±0.09**
平均值±S.E.
级别;0:没有变化,1:最小,2:温和,3:中等,4:严重
*p<0.05,**p<0.01,***p<0.001vs.对照实施例1
将50g本发明化合物溶于945g中等链长的脂肪酸甘油三酯和5g聚山梨酯80中,制备用于包囊的溶液。实施例2
将100g本发明化合物溶于895g中等链长的脂肪酸甘油三酯和5g聚山梨酯80中,制备用于包囊的溶液。实施例3
将10g本发明化合物溶于985g大豆油和5g聚山梨酯80中,制备用于包囊的溶液。实施例4
将50g本发明化合物溶于945g中等链长的脂肪酸甘油三酯和5g聚山梨酯中。用20g硅酸钙和40g磷酸氢钙的预混合物吸收10g生成的溶液,然后加入29g甘露醇制备粉末状混合物。再加入1g硬脂酸镁制备粉末。实施例5
将50g本发明化合物溶于945g中等链长的脂肪酸甘油三酯和5g聚山梨酯中。用20g硅酸钙和40g磷酸氢钙的预混合物吸收10g生成的溶液,然后加入24g乳糖制备粉末状混合物。再加入1g硬脂酸镁和5g滑石,使混合物均匀混合,填充到胶囊中制备胶囊。实施例6
将50g本发明化合物溶于945g中等链长的脂肪酸甘油三酯和5g聚山梨酯中。用20g硅酸钙和40g磷酸氢钙的预混合物吸收10g生成的溶液,然后加入24g结晶纤维素和10g交联羧甲纤维素制备粉末状混合物。再加入1g硬脂酸镁和5g滑石,使混合物均匀混合,用压片机进行压片。实施例7配方(每个胶囊)
本发明化合物 30mg
油酸 268.65mg
聚山梨酯80 1.35mg
总量 300mg
将本发明化合物溶于油酸和聚山梨酯80中,制备用于包囊的溶液。
Claims (1)
1、基于斑稳定化活性来预防局部缺血心脏病的制剂,其含有一种具下式的作为活性成分的化合物:
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JP8265097 | 1997-04-01 | ||
JP82650/1997 | 1997-04-01 |
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CN98804402A Pending CN1252715A (zh) | 1997-04-01 | 1998-03-31 | 用于预防局部缺血心脏病的制剂 |
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EP (1) | EP0983764A4 (zh) |
KR (1) | KR20010005845A (zh) |
CN (1) | CN1252715A (zh) |
AU (1) | AU721698B2 (zh) |
CA (1) | CA2285367A1 (zh) |
WO (1) | WO1998043627A1 (zh) |
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WO1992007825A1 (en) * | 1990-11-05 | 1992-05-14 | Taisho Pharmaceutical Co., Ltd. | Phenol derivative |
WO1992009572A1 (fr) * | 1990-11-26 | 1992-06-11 | Taisho Pharmaceutical Co., Ltd. | Derive d'anilide |
WO1993013086A1 (en) * | 1991-12-25 | 1993-07-08 | Taisho Pharmaceutical Co., Ltd. | Anilide derivative |
CN1252714A (zh) * | 1997-04-01 | 2000-05-10 | 大正制药株式会社 | 用于预防再狭窄的制剂 |
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1998
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- 1998-03-31 EP EP98911142A patent/EP0983764A4/en not_active Withdrawn
- 1998-03-31 CN CN98804402A patent/CN1252715A/zh active Pending
- 1998-03-31 AU AU65212/98A patent/AU721698B2/en not_active Ceased
- 1998-03-31 KR KR1019997008919A patent/KR20010005845A/ko not_active Application Discontinuation
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EP0983764A4 (en) | 2002-07-03 |
AU6521298A (en) | 1998-10-22 |
WO1998043627A1 (fr) | 1998-10-08 |
EP0983764A1 (en) | 2000-03-08 |
CA2285367A1 (en) | 1998-10-08 |
KR20010005845A (ko) | 2001-01-15 |
AU721698B2 (en) | 2000-07-13 |
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