CN1114407C - 螯合剂碘氯羟喹在制备用于治疗早老性痴呆的药物组合物中的用途 - Google Patents
螯合剂碘氯羟喹在制备用于治疗早老性痴呆的药物组合物中的用途 Download PDFInfo
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Abstract
本发明公开了螯合剂碘氯羟喹在制备用于治疗早老性痴呆的药物组合物中的用途。
Description
技术领域
本发明涉及螯合剂在制备用于治疗早老性痴呆的药物组合物中的用途。
背景技术早老性痴呆是主要在老年人中流行的一种慢性神经变性性疾病。
早老性痴呆的临床诊断是发现淀粉样蛋白沉淀在脑中出现并积累。淀粉样蛋白主要发现于神经元的末端区域，为形态学上非均质的沉淀，也称作老年斑。老年斑的形成与疾病的症状和体征的表现有关，包括遗忘症。当老年斑形成以后，在神经元体中产生神经纤维缠结，神经纤维缠结的形成与遗忘症以及痴呆的其他症状的恶化相关。
淀粉样蛋白沉淀的主要成分是多肽，本文中称之为Aβ(淀粉样蛋白-β)。Aβ通常是脑脊液的可溶性成分，它在其中的浓度约为3-5nM。Aβ可以有39-43个氨基酸，一般是40个氨基酸，处于成熟型并可从叫做淀粉样前体蛋白(APP)的细胞表面蛋白，作为蛋白水解分裂产物而得到(Kang等人，1987)。Aβ的正常功能目前尚未得知，但可能会形成跨细胞膜的阳离子选择性通道(Kawahara等人，1997)。
已表明合成的Aβ的沉淀反应是由多种环境因素引起的，包括低pH，高盐浓度，和金属例如锌、铜和汞的存在(Bush等人，1995)。据报道，Aβ本身专一并可饱和地与高亲和结合力的(KD＝107nM)锌以1∶1(锌∶Aβ)的摩尔比结合(Bush等人，1994a)。这种结合以锌的生理学浓度进行(Bush等人，1994b)。
有一种强有力的推测是，消除早老性痴呆患者体内的淀粉样蛋白沉淀将减轻早老性痴呆的症状。因此，已进行了多种尝试来制备清除淀粉样蛋白沉淀的药物。
WO 93/10459公开了通过给予锌结合剂而治疗早老性痴呆的方法。其中提到的优选化合物是植酸，去铁胺，枸橼酸钠，EDTA，1，2-二乙基-3-羟基-吡啶-4-酮，和1-羟乙基-3-羟基-2-甲基-吡啶-4-酮。
DE 3932338公开了螯合剂，如8-羟基-喹啉，在早老性痴呆的治疗中的应用。
US 5373021公开了双硫仑及其盐和类似物，它们可穿透血脑屏障。所公开的化合物可用于减少尤其是早老性痴呆导致的神经学损伤。
迄今所提出的用于治疗早老性痴呆的已知化合物具有多个缺点，这些缺点已妨碍了它们的广泛使用。例如，这些化合物中多数不能穿透血脑屏障，因此几乎不能到达淀粉样蛋白沉积的区域。双硫仑可穿透血脑屏障，但缺点是它也是醇阻碍物。
研究最深入的螯合剂是EDTA。然而，EDTA对锌和铜的螯合作用是非常弱的。另外，EDTA不能穿透血脑屏障并认为其有相当大的毒性。
发明内容本发明的目的是提供一种已知药物化合物制备用于治疗早老性痴呆的药物组合物的新用途，所述新化合物具有穿透血脑屏障的能力，可有效地与重金属结合成螯合物以防止淀粉样蛋白聚集，并可再溶解淀粉样蛋白沉淀。利用碘氯羟喹即可达到这一新用途目的。
本文中所用的术语“早老性痴呆的治疗”是指早老性痴呆在其发展的任何阶段的预防、控制和治疗。
碘氯羟喹的化学名称是5-氯-7-碘-8-羟基喹啉，它属于羟基喹啉类。碘氯羟喹的已知用途是作为局部抗感染剂。特别是，碘氯羟喹已用于治疗阿米巴病和传染性腹泻。碘氯羟喹在pH7-11的范围内几乎不溶于水。在此范围外可达到合适的浓度。
碘氯羟喹对Fe，Co，Ni和Zn的螯合能力是已知的(Kidani等人，1974，和Tateishi等人，1973)。利用质量分光光度测定法测得碘氯羟喹相对Co(II)，Ni(II)，Cu(II)和Zn(II)的配位数是2，而对Fe(III)的配位数是3。据说，碘氯羟喹的注射制剂穿过了血脑屏障，当以10-20mg/kg的剂量给药时，其在脑中的残留浓度在20μl/ml的数量级(Tateishi等人，1975，和Tamura，1975)。还发现碘氯羟喹的浓度在象海马这样直接受到早老性痴呆影响的脑部区域中是高的。
利用显微放射自显影技术，已表明碘氯羟喹能在猴子的海马中形成锌螯合物。该锌(II)螯合物主要发现于苔藓纤维的末端轴-树突触小结中。当将碘氯羟喹静脉注射到神经系统中时，未结合的碘氯羟喹有极其迅速的穿透能力，而几乎没有血脑屏障(Shiraki，1979)。
虽然已知碘氯羟喹有螯合及血脑屏障穿透能力，但并不能就此预言它也具有再溶解锌沉淀的Aβ的能力。按照本发明，碘氯羟喹制备用于治疗早老性痴呆的药物组合物的新用途正是基于这一意想不到的发现。
目前，人们相信碘氯羟喹和Aβ竞争性地螯合锌和其他重金属。碘氯羟喹被认为是最强有力的螯合剂，因此将主要俘获重金属离子。于是，由于碘氯羟喹将俘获锌离子，则已沉淀的锌-Aβ中的Aβ将再溶解到周围的液体中。碘氯羟喹与锌的配合物将穿透血脑屏障并从机体中清除。
由于碘氯羟喹是相当强的螯合剂，它也可以与酶或辅基的金属离子结合成螯合物。因此，可将其理想地用于将痕量金属离子或辅基补充到用碘氯羟喹治疗的病人体内，特别是在建立长期碘氯羟喹治疗时使用。
维生素B12含有钴。早先在日本患者中进行的亚急性脊髓视神经病(SMON)的研究中，以比推荐剂量更高的量长期给予这些患者碘氯羟喹，结果显示了长期碘氯羟喹治疗和维生素B12缺乏之间的联系。在本申请中，通过体外和体内研究证明了碘氯羟喹和B12之间的相互作用。因此，为了防止B12不足，在碘氯羟喹给药的同时或之后给予维生素B12将是有益的。
碘氯羟喹可以任何合适的量，以任何合适的盖仑制剂形式，并按照任何给药方案给药。
根据患者的病情，优选的每日给药量是10mg-750mg碘氯羟喹。一般的日剂量是100mg。另外，也可以每日分三次给予10mg-250mg，优选100mg碘氯羟喹。日剂量高至750mg，持续给药两周，将不会有任何神经毒性或其他副作用的危险。
为了预防早老性痴呆的症状和体征的发生，或者为了延迟该疾病发展过程中的症状和体征，碘氯羟喹可以长期，即多至10年，以10mg-100mg的日剂量给药。
实际的给药量将由监管医师根据多种因素来决定，例如所治疗患者的年龄、病情、病史等。本文中显示的结果表明碘氯羟喹的给药量存在一个“窗口”，在此范围内可达到最佳溶解效果。这样的窗口可由医师利用常规试验来测定。
如果碘氯羟喹将长期给药，则它优选周期性给药。在第一期中，碘氯羟喹可以给药例如1到3周，接着是清除期，它可用来修复碘氯羟喹的任何不希望的副作用。清除期可持续1到4周。在清除期期间，优选给予B12和其他辅基和/或痕量金属。清除期过后再重复第一期。长期的周期性治疗不仅将再溶解锌-Aβ聚集物，而且可预防性抑制锌-Aβ聚集物的形成。
碘氯羟喹的周期性给药还可降低药物的潜在毒性，这意味着这种治疗可扩展到疾病的整个发展期。
本发明还涉及碘氯羟喹在制备用于治疗早老性痴呆的药物组合物中的用途。
其中所述药物组合物用于以每日1到3次给药，碘氯羟喹的每日剂量为10-250mg。包含碘氯羟喹的药物组合物可以被配制成用于口服、胃肠外或经皮给药的形式。
包含碘氯羟喹的药物组合物可以是任何用于肠内和肠胃外给药的合适的盖仑制剂，目的在于将足够浓度的碘氯羟喹释放到脑中。如果希望碘氯羟喹迅速在脑中达到高浓度，则优选以静脉注射方式给药。由于口服给予药物组合物是更方便的，因此如果迅速在脑内达到高浓度不是那么重要的话，则可采用口服给药方式。该药物组合物也可经皮给药。
包含碘氯羟喹的药物组合物还可包含其他活性成分。尤其是，该组合物可含有痕量金属或辅基，如维生素B12，和/或其他任何可并行地用于治疗早老性痴呆的治疗剂，以改善或减轻早老性痴呆的症状和体征，或延迟早老性痴呆的任何症状或体征的发生。另一方面，其他活性成分也可作为分别的药物组合物与包含碘氯羟喹的药物组合物一起给药。
本发明还涉及包含碘氯羟喹和维生素B12的药物组合物，其中所述药物组合物用于以每日1到3次给药，其中碘氯羟喹的每日剂量是10-750mg，维生素B12的每日剂量是为了防止维生素B12不足所用的常规剂量。
按照本发明，碘氯羟喹的新用途包括：
1)用于已诊断为患有任何临床阶段的早老性痴呆的病人的治疗，
2)用于预防伴有早期或前驱症状和体征的患者发病，和/或
3)延迟早老性痴呆的症状或体征的发生或发展或加重或恶化。
附图说明
对附图的简要说明：图1描绘了碘氯羟喹对β啶粉样蛋白的溶解作用。具体实施方式
下面将利用实施例来阐述本发明。
实施例
实施例1
边搅拌边将5.3g碘氯羟喹悬浮于200ml正癸烷中。让未溶解的物质沉降。排除癸烷后将干燥的未溶解碘氯羟喹称重，结果显示癸烷中仅溶解了2％的碘氯羟喹。将100ml(淡黄色)上清液与100ml PBS(磷酸盐缓冲盐水)pH7.4一起搅拌并使相分离。合并PBS(下层相)并过滤以除去随着用有机溶剂萃取而在相分界面形成的残余物。假定有2％的碘氯羟喹溶解于正癸烷中，并假定癸烷/碘氯羟喹的1∶1混合物与PBS的分配系数是1/1750，则碘氯羟喹在PBS中的浓度为800nM。
取得脑试样，已确定该试样的组织病理学诊断为早老性痴呆。一式两份分别用最终PBS/碘氯羟喹提取物为100％，10％和1％以及只有PBS的3ml碘氯羟喹/PBS溶液将0.5g额叶新皮质的试样匀化。
将此匀浆以150,000×g的速度离心30分钟，合并上清液并保存于冰上(级分“S”)。将沉淀进行同样的匀化和离心操作，并再次合并所得上清液(级分“P”)。
每种上清液各1ml用200μl冰冷的10％TCA(三氯醋酸)处理以沉淀包括Aβ的总蛋白。所得沉淀用100％乙醇洗涤一次并再悬浮于100μlTBS(tris 20mM，NaCl 150mM pH7.4)中。
将7.5μl样品(S或P)与等体积的含有4％SDS(十二烷基硫酸钠)的tris-tricine样品缓冲液一起煮沸5分钟，并加载到Novex预制的10-20％tris-tricine凝胶上，接着Western转移到硝化纤维素上。利用mAbWO2检测Aβ的信号(由Aβ的残余物5-16产生)并利用ECL(电化学发光)显示出来。检测系统的灵敏度为5-10pg。
为了验证TCA对Aβ的沉淀，将1μg合成Aβ1-40加入1ml含有10％BSA的PBS中，并按上述过程处理该溶液。在沉淀的颗粒状物中检测到了Aβ的信号，而在上清液中没有检测到。
结果显示于图1中。
从图1可推断出，碘氯羟喹可有效地促进所测试浓度下的Aβ的溶解。另外，发现最佳浓度是10％，这表明Aβ的聚集形式之一，可推测为二聚物，比其他形式更易溶于PBS。
图1中仅显示了一个试样的数据，另19个试样的数据均表明了相同的趋向，即：碘氯羟喹可有效地促进Aβ的溶解。
实施例2
在该实施例中对比碘氯羟喹和EDTA的螯合能力。
将10ng合成Aβ样品置于微量滴定槽中，通过加入25μM ZnCl使其聚集。然后通过过滤将该聚集物转移到0.2μm尼龙膜上。这些聚集物分别用200μl单独的TBS、含有2μM EDTA的TBS、和含有2μM碘氯羟喹的TBS洗涤。将该膜固定，用抗-Aβ单克隆抗体6E10探测，并显色以用来接触ECL-膜。测量ECL-膜的透光度，并以100％单独的TBS为基准计算相对信号强度。EDTA的相对信号强度是66％，而碘氯羟喹的相对信号强度是49％。
结果表明，对于锌沉淀的Aβ来说，碘氯羟喹是更好的螯合剂。
实施例3
在该实施例中证明碘氯羟喹的再溶解作用。
制备Aβ在pH7.4的TBS中的2.5μM溶液。95％的Aβ保持溶解状态。加入30μM锌使溶解的Aβ沉淀，仅有43％仍保留在溶液中。随后向锌沉淀的Aβ中加入120μM碘氯羟喹，则使溶解的Aβ增加到70％。
结果表明碘氯羟喹可再溶解锌沉淀的Aβ。
实施例4
在该实施例中利用NMR谱研究体外碘氯羟喹对维生素B12的影响。
由于碘氯羟喹在pH7-11的范围内几乎不溶于水，因此该研究在pH13条件下进行。制备三管样品。第一管含有0.5ml 1mg碘氯羟喹，第二管含有0.5ml 1.4mg氰钴胺(B12)，第三管含有0.5ml 0.5mg碘氯羟喹+0.7mg氰钴胺(摩尔比3∶1)。
用DRX 400MHz分光光度计在20℃记录1H NMR谱。第三管样品的谱与第一和第二管样品的谱对比的结果显示，氰钴胺的某些共振谱发生了位移，对碘氯羟喹的两个共振谱也观察到了相同的结果。结果提示了碘氯羟喹和氰钴胺之间的相互作用。
实施例5
在该实施例中研究碘氯羟喹在体内对维生素B12的影响。
六周龄的雄性小鼠用碘氯羟喹预先处理三天(50mg/kg/天)。将这些小鼠分为两组，对照组和用[57Co]-氰钴胺注射的组。注射48小时后将这些动物处死，解剖出脑、肝和肾并用γ-计数器计数，结果表示为千cpm/g组织(净重)±SEM。下表1中列出了各组的放射性值：
表1
| 治疗 | 脑 | 肝 | 肾 |
| 对照 | 9.4±0.9 | 97±8 | 895±207 |
| [57Co]B12 | 8.4±1.5 | 85±21 | 252±61 |
结果比较显示，在脑和肝中的放射性累积量没有明显变化。在肾中维生素B12的量出现减少。由此可以得出：碘氯羟喹对小鼠某些器官中的B12浓度有影响。
参考文献
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Claims (7)
1.碘氯羟喹在制备用于治疗早老性痴呆的药物组合物中的用途。
2.按照权利要求1的用途，其中所述药物组合物用于以每日1到3次给药，碘氯羟喹的每日剂量为10-250mg。
3.按照权利要求1或2所述的用途，其中包含碘氯羟喹的药物组合物被配制成用于口服给药的形式。
4.按照权利要求1或2所述的用途，其中的药物组合物配制成用于胃肠外给药的形式。
5.按照权利要求1或2所述的用途，其中的药物组合物配制成经皮给药的形式。
6.包含碘氯羟喹和维生素B12的药物组合物，其中所述药物组合物用于以每日1到3次给药，其中碘氯羟喹的每日剂量是10-750mg，维生素B12的每日剂量是为了防止维生素B12不足所用的常规剂量。
7.按照权利要求6的药物组合物，其中碘氯羟喹的每日剂量是10-250mg。
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| NO (1) | NO990595L (zh) |
| NZ (1) | NZ334124A (zh) |
| PL (1) | PL188838B1 (zh) |
| PT (1) | PT959888E (zh) |
| RU (1) | RU2193406C2 (zh) |
| SI (1) | SI0959888T1 (zh) |
| SK (1) | SK283117B6 (zh) |
| TR (1) | TR199900293T2 (zh) |
| WO (1) | WO1998006403A1 (zh) |
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| US7045531B1 (en) | 1997-03-11 | 2006-05-16 | The General Hospital Corporation | Composition comprising a metal chelator and a method of treating amyloidosis by administering the metal chelator |
| EA002526B1 (ru) * | 1997-08-21 | 2002-06-27 | П.Н.Геролиматос С.А. | Применение фанхинона для лечения болезни альцгеймера |
| JP2001521002A (ja) * | 1997-10-24 | 2001-11-06 | コーネル リサーチ ファンデーション インク． | 脳の代謝機能不全のための栄養補充剤 |
| US5994323A (en) * | 1997-12-31 | 1999-11-30 | P.N. Gerolymatos S.A. | Pharmaceutical compositions comprising clioquinol in combination with vitamin B12 and therapeutic and prophylactic uses thereof |
| US20020025944A1 (en) * | 2000-04-28 | 2002-02-28 | Bush Ashley I. | Use of clioquinol for the therapy of Alzheimer's disease |
| US6323218B1 (en) * | 1998-03-11 | 2001-11-27 | The General Hospital Corporation | Agents for use in the treatment of Alzheimer's disease |
| US6638711B1 (en) | 1999-04-29 | 2003-10-28 | The General Hospital Corporation | Methods for identifying an agent that inhibits oxygen-dependent hydrogen peroxide formation activity but does not inhibit superoxide-dependent hydrogen peroxide formation |
| US20050112543A1 (en) * | 1998-03-11 | 2005-05-26 | The General Hospital Corporation | Method of screening for drugs useful in treating Alzheimer's disease |
| CA2358487C (en) * | 1999-01-07 | 2008-11-18 | P.N. Gerolymatos S.A. | Use of phanquinone for the treatment or prevention of memory impairment |
| US6692234B2 (en) | 1999-03-22 | 2004-02-17 | Water Management Systems | Pump system with vacuum source |
| EP1256582A1 (en) * | 2000-02-09 | 2002-11-13 | Hokuriku Seiyaku Co., Ltd. | 1h-imidazopyridine derivatives |
| FR2818551B1 (fr) * | 2000-12-22 | 2007-06-01 | Claude Marc Pierre Hannoun | Utilisation de chelateurs pour le traitement des maladies a prions |
| US6803379B2 (en) * | 2002-06-04 | 2004-10-12 | Jose A. Fernandez-Pol | Pharmacological agents and methods of treatment that inactivate pathogenic prokaryotic and eukaryotic cells and viruses by attacking highly conserved domains in structural metalloprotein and metalloenzyme targets |
| AU2002950217A0 (en) | 2002-07-16 | 2002-09-12 | Prana Biotechnology Limited | 8- Hydroxy Quinoline Derivatives |
| ES2440217T3 (es) * | 2002-10-04 | 2014-01-28 | Prana Biotechnology Limited | Compuestos neurológicamente activos |
| US20080063599A1 (en) * | 2002-11-18 | 2008-03-13 | Jorge Setoain Quinquer | Compounds Which Can Be Used To Diagnose And Monitor Diseases Associated With The Formation Of Amyloid Protein Fibrils |
| WO2004087160A1 (en) * | 2003-04-03 | 2004-10-14 | Prana Biotechnology Ltd | Treatment of neurological conditions |
| AU2004290464A1 (en) * | 2003-11-19 | 2005-06-02 | Acrux Dds Pty Ltd | Method and composition for treatment or prophylaxis of amyloidosis disorders |
| US20060194723A1 (en) * | 2005-02-28 | 2006-08-31 | Rabinoff Michael D | Novel medication treatment and delivery strategies for Alzheimer's Disease, other disorders with memory impairment, and possible treatment strategies for memory improvement |
| US8865763B2 (en) | 2005-10-14 | 2014-10-21 | Alltech, Inc. | Methods and compositions for altering cell function |
| US8871715B2 (en) | 2005-10-14 | 2014-10-28 | Alltech, Inc. | Use of selenium compounds, especially selenium yeasts for altering cognitive function |
| CN102764279B (zh) * | 2005-10-14 | 2015-04-01 | 全面技术公司 | 改变细胞功能的方法和组合物 |
| PT2289909E (pt) * | 2005-11-30 | 2015-02-10 | Abbvie Inc | Método de rastreio, processo de purificação de globulómeros a-beta não difundíveis, anticorpos selectivos contra os referidos globulómeros a-beta não difundíveis e processo para o fabrico dos referidos anticorpos |
| ZA200809493B (en) * | 2006-04-14 | 2010-08-25 | Prana Biotechnology Ltd | Method of treatment of age-related macular degeneration (AMD) |
| NZ607881A (en) * | 2006-07-14 | 2014-11-28 | Genentech Inc | Humanized antibody against amyloid beta |
| CA2657681C (en) * | 2006-07-14 | 2019-03-19 | Ac Immune S.A. | Humanized antibodies against beta amyloid protein |
| US8613923B2 (en) | 2007-06-12 | 2013-12-24 | Ac Immune S.A. | Monoclonal antibody |
| US8048420B2 (en) | 2007-06-12 | 2011-11-01 | Ac Immune S.A. | Monoclonal antibody |
| PT2238166E (pt) | 2007-10-05 | 2014-02-11 | Genentech Inc | Utilização do anticorpo anti-amilóide beta em doenças oculares |
| ES2332687B1 (es) * | 2008-03-13 | 2011-01-10 | Proyecto De Biomedicina Cima, S.L. | Nuevos usos de 4pba y sus sales farmaceuticamente aceptables. |
| JP6081356B2 (ja) | 2010-07-30 | 2017-02-15 | エーシー イミューン エス．エー． | 安全で機能的なヒト化抗βアミロイド抗体 |
| FR2966827B1 (fr) | 2010-10-27 | 2014-08-22 | Kimonella Ventures Ltd | Compose peptidique utile pour l'inhibition de la formation de plaques amyloides |
| AU2013385618B2 (en) * | 2013-04-02 | 2017-01-05 | Annji Pharmaceutical Co., Ltd. | Multifunctional quinoline derivatives as anti-neurodegenerative agents |
| US11844774B2 (en) | 2014-04-24 | 2023-12-19 | Omoidesouzou Co., Ltd. | Amyloid fiber formation limiter or inhibitor |
| KR20160057500A (ko) * | 2014-11-05 | 2016-05-24 | 아카데미아 시니카 | 클리오퀴놀을 포함하는 자폐증 스펙트럼 장애의 치료용 약학적 조성물 |
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| US3174899A (en) * | 1960-12-30 | 1965-03-23 | Ciba Geigy Corp | Composition for the management of post antibiotic enteritis |
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| GB9010039D0 (en) * | 1990-05-03 | 1990-06-27 | Reckitt & Colmann Prod Ltd | Medicament preparation |
| GB9108080D0 (en) * | 1991-04-15 | 1991-06-05 | Smithkline Beecham Plc | Pharmaceutical composition |
| JP3277211B2 (ja) * | 1991-11-12 | 2002-04-22 | プラナ・バイオテクノロジー・リミテッド | アルツハイマー病の試験方法と治療方法 |
| US5607691A (en) * | 1992-06-12 | 1997-03-04 | Affymax Technologies N.V. | Compositions and methods for enhanced drug delivery |
| WO1995019178A1 (en) * | 1994-01-13 | 1995-07-20 | Research Foundation For Mental Hygiene, Inc. | Methods and compositions for treatment and diagnosis of alzheimer disease and other disorders |
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| US5505958A (en) * | 1994-10-31 | 1996-04-09 | Algos Pharmaceutical Corporation | Transdermal drug delivery device and method for its manufacture |
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| US5373021A (en) * | 1991-11-04 | 1994-12-13 | Cypros Pharmaceutical Corporation | Use of disulfiram for Neuronal Protection |
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