CN1750838A - 含有贵金属微粒的药品 - Google Patents
含有贵金属微粒的药品 Download PDFInfo
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- CN1750838A CN1750838A CNA200480004537XA CN200480004537A CN1750838A CN 1750838 A CN1750838 A CN 1750838A CN A200480004537X A CNA200480004537X A CN A200480004537XA CN 200480004537 A CN200480004537 A CN 200480004537A CN 1750838 A CN1750838 A CN 1750838A
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- noble metal
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- platinum
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Abstract
本发明公开了一种预防及/或治疗选自肌肉萎缩性侧索硬化症和阿耳茨海默病等神经变性疾病、类风湿性关节炎等风湿性疾病、心肌梗塞等缺血性心脏病、应激性溃疡、皮炎、动脉硬化及高血脂的药品,作为有效成分,含有铂等贵金属或含贵金属合金微粒(例如铂胶体)的药品。
Description
技术领域
本发明涉及含贵金属微粒,预防及/或治疗肌肉萎缩性侧索硬化症等神经变性疾病、风湿性疾病、局部缺血性心脏病、应激性溃疡、皮炎、动脉硬化及高血脂的药品。
背景技术
肌肉萎缩性侧索硬化症(Amyotrophic lateral sclerosis:下面在本发明的说明书中有时简略为“ALS”)是从大脑皮层到脊髓的上位运动神经元及从脊髓到肌肉的下位运动神经元,选择性紊乱的进行性神经变性疾病。ALS的发病率高,在日本也有许多患者。临床特征是肌肉萎缩和肌力下降,病情一旦发展,因肌力下降,会发生语言障碍、吞咽障碍、呼吸障碍等。病势进展比较迅速,若不用人工呼吸器等,许多人维持2~4年就会死亡。但是由于ALS没有根治的办法,因此,关于这种疾病,包括对患者的护理,成为社会性的大问题。ALS从其发病的形态上分为独发性和家族性两种。大家知道家族性的ALS有显性和隐性遗传性。近年来,作为显性遗传性ALS1型的起源基因,被鉴定出活性氧的代谢酶Cu/Zn Superoxide Dismutase(铜·锌超氧化歧化酶;SOD1)。ALS的大多数是独发性的,遗传性的不到20%。由于ALS1占全部ALS中的比例为2%以下,所以在弄清ALS发病的分子机构和治疗法的开发方面期待着发现SOD1基因之外的ALS起源基因。然而作为采取隐性遗传形式的ALS2型的起源基因,又被分离、鉴定出ALS2CR6基因。而在关于ALS等神经变性疾病中,活性氧发生的机理方面,因变种等变异的蛋白凝集,而引起活性氧发生的学说是有权威的(Current Topic in Medical Chemistry 1:507-517,2001)。
对于ALS尚未确立包括药物治疗在内的根本治疗法。药物中使ALS延缓发展的药剂,被采用的是利鲁唑(リルテツク),除此之外还采用了肌肉驰缓剂、镇痛剂、镇定药、安眠药、维生素B剂等,但全都只不过是针对症状的药物疗法。
风湿病是以因结缔组织炎症、变性或代谢紊乱造成的种种异常为特征的疾病,是关节、肌肉、骨骼、韧带等运动器官受损,伴有疼痛和僵硬的疾病。典型的风湿病是类风湿性关节炎,由于全身的结缔组织变化引起胶原病的全身性红斑狼疮(SLE)和自体免疫疾病也包含在风湿病之内。
对于类风湿性关节炎(RA)没有根治的办法,凭经验进行对症治疗。治疗方法除了药物治疗之外,进行基础治疗(休养、患者教育及理疗等)、手术治疗等。但治疗原则是药物治疗。作为药物治疗,为了抑制因RA引起的滑膜炎,减轻疼痛而广泛应用阿斯匹林、消炎痛、双氯芬酸等非甾体性消炎药(NSAID)。但在重病例中也有使用强的松龙等甾体剂的情形。另外,为了改正RA的免疫异常而延缓骨骼损伤的进程,经常使用抗风湿药。抗风湿药,例如使用金制剂(金苹果酸钠和金诺芬等)和甲氨喋呤等免疫抑制剂。
由于心脏的冠状动脉粥样硬化等引起血管狭窄或闭塞,因冠状动脉血流减少引起心功能失调,叫作由心肌缺血状态导致的缺血性心脏病。具有代表性的缺血性心脏病是心绞痛及心肌梗塞。心肌梗塞是因血栓造成持续缺血而引起心肌坏死,有时甚至至死。比较轻的一时性的心绞痛则在发作时发生剧烈的胸痛。
心绞痛的药物治疗使用亚硝酸异戊酯、硝酸甘油、硝酸异山梨醇等亚硝酸剂、β阻断剂、钙拮抗剂、潘生丁等冠状动脉舒张剂。对于心肌梗塞,急性期使用末梢血管扩张剂、尿激酶等血栓溶解剂、肝素钠等血液凝固阻止剂、阿斯匹林和噻氯匹定等抗血小板剂等。但是特别在心肌梗塞的急性期尚未提供能有效抑制心肌坏死的药剂。
另外,就应激性溃疡、皮炎、动脉硬化及高血脂病,也进行了应用种种药品的尝试,但是几乎不能提供可以有满意治疗效果的药品,而期待着开发新的药品。
另一方面,大家知道铂胶体分解活性氧的一种过氧化氢(特开平10-68008号公报,0040段)。可是,在此公报中并没有表明铂胶体在治疗及/或预防ALS等神经变性疾病、风湿性疾病、缺血性心脏病、应激性溃疡、皮炎、动脉硬化或高血脂方面的有效性。
发明内容
本发明的目的是提供一种预防及/或治疗ALS和阿耳茨海默病(早老性痴呆)等神经变性疾病、类风湿性关节炎等风湿性疾病、心肌梗塞等缺血性心脏病、应激性溃疡、皮炎、动脉硬化及高血脂的药品。本发明者们锐意研究的结果,发现给与铂胶体等金属胶体可以预防及/或治疗上述各种疾病。本发明是在上述想法的基础上完成的。
也就是说,本发明提供预防及/或治疗选自神经变性疾病、风湿性疾病、缺血性心脏病、应激性溃疡、皮炎、动脉硬化及高血脂病的药品,含有贵金属或贵金属的合金微粒作为有效成分。
由上述发明优选,提供神经变性疾病例如肌肉萎缩性侧索硬化症、阿耳茨海默病或帕金森氏病的上述药品;以及神经变性疾病例如肌肉萎缩性侧索硬化症的上述药品;风湿性疾病例如类风湿性关节炎的上述药品;缺血性心脏病例如急性期的心肌梗塞的上述药品;应激性溃疡例如应激性胃溃疡或应激性十二指肠溃疡的上述药品。
另外,由上述发明更优选,提供贵金属为选自钌、铑、钯及铂的一种或两种以上的上述药品;贵金属为铂的上述药品;贵金属微粒平均粒径为10nm以下铂胶体的上述药品。
从另一观点,是提供预防及/或治疗选自神经变性疾病、风湿性疾病、缺血性心脏病、应激性溃疡、皮炎、动脉硬化及高血脂病的方法,提供对包括人类在内的哺乳类动物给与贵金属微粒的方法。而且,本发明还提供为了制造上述药品而使用的贵金属微粒。
附图说明
图1表示对患有肌肉萎缩性侧索硬化症的试验用小鼠,给与本发明的药品,用红外线传感器测定小鼠运动量的结果示意图。○表示正常小鼠的结果;■表示本发明的药品给与组(0.5μg/kg)的结果;●表示非给药组(病态小鼠)的结果。
图2为本发明的药品对例4中的浮肿率显示效果的示意图。○表示对照组(生理盐水给与组)的结果;●表示本发明的药品给与组(5μmol/kg/day)的结果。
图3为本发明的药品对例4中的骨骼损伤显示效果的示意图。
图4为表示例7中用UVA(20J/cm2)照射第10天的小鼠耳廓状态的照片。左边表示阳性对照结果,右边表示涂敷本发明药品小鼠的结果。
具体实施方式
本发明的药品是预防及/或治疗选自神经变性疾病、风湿性疾病、缺血性心脏病、应激性溃疡、皮炎、动脉硬化及高血脂病的药品,其特征是含有效成分贵金属微粒。贵金属种类没有特别限制,可以使用金、钌、铑、钯、锇、铱或铂的任何种类。但优选钌、铑、钯或铂。贵金属微粒可以包含两种以上的贵金属。还可以使用至少含一种贵金属的合金微粒,或者含有一种或两种以上的贵金属微粒与贵金属之外的一种或两种以上的金属微粒的混合物。例如也可以使用金和铂构成的合金。其中优选的是铂或含铂的合金。特别优选的是铂。
贵金属微粒,优选可以形成比表面积大、表面反应性优良的胶体状态的微粒。微粒的粒径没有特别的限制,可使用平均粒径为50nm以下的微粒,优选平均粒径为20nm以下的,更优选平均粒径为10nm以下的,特别优选平均粒径为1~6nm左右的微粒。还可以使用更细小的微粒。
熟悉的贵金属微粒制造方法有许多种(例如特公昭57-43125号公报、特公昭59-120249号公报,以及特开平9-225317号公报;特开平10-176207号公报、特开2001-79382号公报、特开2001-122723号公报等),从事该行业者可以参照这些方法,容易地制造微粒。贵金属微粒制造方法,可以利用,例如称为沉淀法或金属盐还原反应法的化学方法;或者称为燃烧法的物理方法等。作为本发明药品的有效成分,使用哪种方法制造的微粒都可以,但是从制造的便利性和质量方面考虑,优选使用金属盐还原反应方法制造的微粒。
金属盐还原反应方法中,例如可以调制水溶性或有机溶媒可溶性贵金属盐溶液,或者贵金属络合物的水溶液或有机溶媒溶液,在此溶液中加入水溶性高分子后,把溶液的pH调节到9~11,在非活性气氛下,经加热回流而还原,获得金属微粒。贵金属的水溶性或有机溶媒可溶性盐的种类,没有特别限定,例如可以使用醋酸盐、氯化物、硫酸盐、硝酸盐、磺酸盐或磷酸盐等,也可以用它们的络合物。
金属盐还原反应方法中使用的水溶性高分子的种类,没有特别限制,例如可以使用聚乙烯吡喀烷酮、聚乙烯醇、聚丙烯酸、环糊精、氨基果胶、甲基纤维素等,也可以把它们两种以上搭配使用。可以优选使用聚乙烯吡喀烷酮,还可以更优选使用聚(1-乙烯基-2-吡咯烷酮)。另外,还可以取代水溶性高分子,或与水溶性高分子同时使用各种表面活性剂,如阴离子性、非离子性或脂溶性等表面活性剂。当还原使用醇的情况下,使用乙醇、n-丙醇、n-丁醇、n-戊醇、或者乙二醇等。不过,贵金属微粒的制造方法不限定于上述说明的方法。
本发明的药品可以用于预防及/或治疗选自神经变性疾病、风湿性疾病、缺血性心脏病、应激性溃疡、皮炎、动脉硬化及高血脂的疾病。
作为神经变性疾病,例如可以用肌肉萎缩性侧索硬化病、阿耳茨海默病、帕金森氏病等作示例,但并不限定于这些。本发明药品优选应用对象是肌肉萎缩性侧索硬化病。
作为风湿性疾病,例如可以用类风湿性关节炎、幼年性风湿性关节炎、红斑狼疮(盘状狼疮、全身性红斑狼疮、与用药有关的狼疮等)、硬皮症、弥漫性筋膜炎、多发性肌炎、坏死性脉管炎及其它血管病、斯耶格伦氏综合症(干燥综合症)、重叠综合症等弥漫性结缔组织异常、伴有脊髓炎的关节炎、变性关节病(骨关节病、变形性关节病)、伴有感染病原体的关节炎、伴有风湿病症状的代谢性及内分泌性疾病、肿瘤(肿疡)、神经·血管异常、骨及软骨病、关节外疾病、有关节症状的各种疾病等作为示例(Decker J.L.等,Arth.Rheum.,26(8),1983),但并不限定于这些。本发明药品优选的应用对象是类风湿性关节炎。
在本说明书中使用的缺血性心脏病术语,至少包含心绞痛及心肌梗塞,分别包含各种病型。例如心绞痛中有劳力性心绞痛及自发性心绞痛(海老原等编,“心绞痛与β阻断剂-临床药理与临床应用-”,临床医学研究教会,1989)、也有分类为劳力性心绞痛和不稳定心绞痛的情形(American HealthAssociation)。心肌梗塞一般是引起冠状动脉大分支闭塞,在其供血的范围产生广范围的坏死。缺血性心脏病也有分类为劳力性心绞痛、心肌梗塞(包括急性及陈旧性)、中间型、及无痛性缺血性心脏病(包括无症状性及慢性心肌损伤)的情形(安部等编,“心绞痛”,金原出版,1985)。进而,大家知道,心肌梗塞的治疗采取的PTCA(Percutaneous Transluminal CoronaryAngioplasty)中,在进行气球或导管处置后,血管再狭窄或再闭塞的发生率高。而伴有由这些处置引起的血管再狭窄或再闭塞的心脏病也包括在缺血性心脏病中。本说明书中使用的缺血性心脏病的术语,应该最广义地解释为包括所有的这些疾病,而在任何意义上都不能作局限性解释。
应激性溃疡中包括消化性溃疡,更具体的是包括胃溃疡及十二指肠溃疡。大家知道作为消化性溃疡的初次病因,应激成为外因性的病因,本发明的药品可以适用于成为主要病因的溃疡。本发明的药品除了明确病因是应激的情况之外,也可以应用于怀疑其存在的情况下。
皮炎中,例如除接触毒性化学物质和光,引起接触性皮炎(暂时刺激性接触皮炎、变应性接触皮炎、光毒性接触皮炎、光变应性接触皮炎等,大城户编、皮肤科治疗手册、南山堂、1989)之外,还包括湿疹组(急性湿疹及慢性湿疹等)、特应性皮炎(新生儿至乳儿期、幼儿至学龄期及成人期间的特应性皮炎等)、脂溢性皮炎、自体致敏性皮炎、药疹等。本发明的药品除全身给药之外,也可以针对皮炎部位局部给药。
动脉硬化是表现为动脉壁改变、硬化及功能降低的局限性动脉病变的总称,包括中膜硬化、小动脉硬化及粥样(アテロ一ム)硬化等病态。本发明药品的提供对象动脉硬化可以是其中任何一种,动脉的部位也没有特别限定,例如冠状动脉、主动脉、肾动脉及四肢动脉等任何部位都可以。而且,本发明药品的适用对象可以是动脉硬化初期的血管内皮细胞的泡沫细胞化、泡沫细胞的细胞坏死及脂肪堆积于动脉硬化病灶等任何病变时期的动脉硬化。本发明药品的提供对象除了完全动脉硬化之外,还包含动脉硬化形成过程中的病变,需要从最广义来解释。本发明药品还有降低血中脂肪的作用,可以用于高血脂病的预防及/或治疗。
在本说明书中,“预防及/或治疗”的术语,应从最广义解释为:除了预防上述疾病的发病及发病后上述疾病的治疗之外,还包括抑制上述疾病的发展、改善或减轻上述疾病的病状、预防上述疾病的再发等,而在任何意义上都不能作局限性解释。
本发明药品的给药途径没有特别限制,可以选择口服或非口服的任何给药途径。作为本发明的药品,可以直接使用按上述说明的方法制造的胶状贵金属分散物或干燥状态的贵金属微粒。在水中或有机溶媒中,或者在水与有机溶媒的混合物中制造的金属微粒是以胶状存在的,把这种胶状的贵金属分散物作为本发明的药品,可以直接使用。另外,把贵金属微粒聚集起来,形成团状的水性悬浮剂,作为本发明药品使用也可以。进而,想要除去溶媒时,经加热等操作,除去溶媒可以获得干燥状态的微粒。经其操作所获的干燥微粒,也可以作为本发明药品使用。清凉饮料水,含铂微粒的水(如“白金玄水”、アイノベツクス株式会社)、急性肠胃炎或慢性肠胃粘膜炎的治疗药,铂·钯胶体制剂(“内服用浆料(パプラ一ル)”,株式会社東洋厚生制药所)等,也可以作为本发明药品使用。
本发明的药品可以作为用该行业众所周知的方法,能够制造的口服或非口服用药品的成分给药。适合于口服的药品成分可举出,如片剂、胶囊剂、散剂、细粒剂、颗粒剂、液剂、糖浆剂等。适合于非口服的药品成分可举出,如注射剂、点滴剂、栓剂、吸入剂、点眼剂、点鼻剂、点耳剂、软膏剂、乳剂、经皮吸收剂、经粘膜吸收剂及贴敷剂等。上述药品成分,可以与有效成分贵金属微粒同时,用一种或两种以上的制剂添加物制造。作为制剂用的添加物,可以举出,如赋形剂、分解剂或辅助分解剂、结合剂、润滑剂、涂敷剂、色素、稀释剂、基质(主药)、溶解剂或辅助溶解剂、等渗剂、pH调节剂、稳定剂、喷剂、粘合剂等。从事该行业者可以按照药品成分适当选择它们。
本发明药品的给药量没有特别限制,可以根据疾病种类、预防或治疗目的、患者年龄、体重、症状等适当选择。例如,口服的情况下,成人每天服用的贵金属微粒重量,可以在0.001~1,000mg的范围内。
实施例
下面用实施例对本发明作进一步具体说明,但本发明的范围,并不限定于下述的实施例。
例1
在连接着丙烯冷却管和三通旋塞阀的100ml双口茄底烧瓶中,加入聚(1-乙烯基-2-吡咯烷酮(和光纯药株式会社制,0.1467g),用23ml蒸馏水溶解开。把此溶液搅拌10分钟后,加入在蒸馏水中溶解有氯铂酸(H2PtCl6·6H2O,和光纯药株式会社制)的1.66×10-2M溶液(2ml),再搅拌30分钟。反应装置内换成氮气,加入特级乙醇25ml,保持在氮气气氛下,在100℃条件下,进行了两小时回流。测定反应液的UV,确认了铂离子峰值的消失和由于金属固体特有的散射峰值的饱和,结束了还原反应。把有机溶剂减压馏去,制造含有铂微粒(平均粒径为2.4±0.7nm)的铂胶体。在下面的实施例中,这种铂胶体用PVP-Pt表示。同样,用聚丙烯酸钠(アルドリツチ社制,对应于Pt,为125倍单位)代替聚(1-乙烯基-2-吡咯烷酮),制造了平均粒径为2.0±0.4nm的铂胶体。在下面的实施例中,这种铂胶体用PAA-Pt表示。
例2
对6~8周龄的B6SJL-TgN(SODIG93A)Gur小鼠(患肌肉萎缩性侧索硬化症的试验小鼠),任意给与0.66μM、0.066μM或6.6nM上述铂胶体(PVP-Pt),进行饲养。大约从16周开始,在用普通水饲养的对照组小鼠中,发现肌肉萎缩性侧索硬化症的典型症状,后腿变得不能动,前腿只能爬了。另一方面,给与铂胶体的小鼠中,证实根据给药量,上述症状有所改善。给药量为6.6nM的小鼠组中的小鼠,虽然发现行走时后腿不太灵等异常,但是可以行走了。给药量为0.066μM的小鼠组中的小鼠,虽然发现后腿发抖,但是能很快站立起来,给药量为0.66μM的小鼠组中的小鼠,没有发现症状,具有和正常小鼠同样的行走能力。
例3
对3周龄及7周龄的B6SJL-TgN(SODIG93A)Gur小鼠,给与0.5μM上述铂胶体(PVP-Pt,用量为铂给药量),用红外线传感器测定接收到的小鼠移动次数。移动次数少,意味着由于肌肉萎缩性侧索硬化症发病造成运动量降低。把用水取代铂胶体给药的B6SJL-TgN(SODIG93A)Gur小鼠,作为比较组(病态小鼠),与正常小鼠进行了比较。用7周龄小鼠实验的结果,如图1所示。给与本发明药品的组中,由肌肉萎缩性侧索硬化症发病造成运动量的降低得以抑制。
例4
把大白鼠(日本Charles River(チヤ一ルス·リバ一)公司,LEW/CrJ系,100~130g,7周龄)在5天的检疫期间和其后8天的驯化期间后,用于实验。大白鼠在室温20~26℃、湿度为40~70%、明暗各12小时的条件下,用固体饲料(CRF-1,オリエンタル酵母工业株式会社),以自由摄饵的方式,进行饲养。把引起炎症的试剂(Mycobacteriumbutyricum,Difco),用流动石蜡,制成浓度为1.0mg/0.1mL的悬浮液在醚麻醉下,用装有27G针头(结合菌素皮内试验针)的聚丙烯制一次性注射器,注射到左侧后腿脚掌皮内。引起炎症的试剂在给药开始之日的给药之前,按0.1mg/只,注射。
把本发明药品,即上述铂胶体(PAA-Pt)用装有25G针头的聚丙烯制一次性注射器,注射到尾静脉内。注射次数为一天一次,注射开始之日为给药一天,给药期为20天。给药量为0.05μmol/kg、0.5μmol/kg、5μmol/kg。作为对照,把生理盐水,同样,注射到尾静脉内。
大白鼠每组为10只,在给药1,2,4,7,9,11,14,16,18天之前,和剖验日,用大白鼠后腿脚掌浮肿容积测定装置(TK-101CMP,有限公司Unicom),测定了两侧后腿脚掌容积。用下式,从给药1天及各测定日的脚掌容积,计算出浮肿率。浮肿率(Δ%)=(各测定日的脚掌容积(mL)-给药1天的脚掌容积(mL))÷给药1天的脚掌容积(mL)×100
在剖验日,用醚之类麻醉,从腹部大动脉放血致死后,把两条后腿在大腿骨中央切断,用20%中性缓冲福尔马林固定。固定后,用软X线摄影装置(SOFROM SRO-505C,株式会社SOFROM)拍摄软X线照片。骨损伤情况,通过观察描图机上照射的软X线胶片,给损伤程度,记分。得分,根据下面的判定标准,对跟骨、跗骨、中足骨及胫骨进行判断,求出四个部位的总分。骨损伤分数
0:正常
1:轻度骨损伤、密度降低
2:中度骨损伤、密度降低
3:重度骨损伤及变形
在图2中显示出本发明药品对浮肿率的效果。在图3中显示出本发明药品对骨损伤的效果。证实了本发明药品对浮肿及骨损伤有良好的治疗效果。从病理上看,虽然在炎症细胞对患部的浸润上,没有发现给药组与对照组之间的差别,但是在浮肿、化脓、骨损伤等组织损伤情况方面发现给药组与对照组比较,有显著改善。
例5
对兔子(北山レベス株式会社。Kb1:Jw(SPF)系,2.00~2.80kg、12周龄)进行5天检疫及两天以上的驯化,进行体重测定和一般状态的观察,把一般状态及体重变化没有发现异常的兔子,用于实验。兔子在室温20~26℃、湿度40~70%、明暗各12小时的条件下,按每天100g的比例,给与固体饲料(RC4,オリエンタル酵母工业株式会社)进行饲养。
对13~16周龄的兔子按30mg/mL/kg,从耳廓注射戊巴比妥钠,麻醉后固定于背位。把气管插管插入气管后,连接到人工呼吸器(NEW ENGLANDINSTRUMENTS INC.,141A),(设定条件:40~60次/分、20~30mL/次,根据麻醉状况,在麻醉范围内调整),维持呼吸。血压是用与插入大腿动脉的动脉插管连结的压力传感器(TP-300T,日本光电工业株式会社),传导至畸变压力放大器(AP-601G,日本光电工业株式会社)及血压测定装置(AP-611G,日本光电工业株式会社),记录在记录器(WT-645G,日本光电工业株式会社)上。心电图(第2诱导)是由针电极诱导至生物电放大器(AB-621G,日本光电工业株式会社),记录在记录器(WT-645G,日本光电工业株式会社)。
在实施试验兔子的第4肋骨和第5胁骨之间打开胸腔。切开胸包膜,使心脏露出胸腔,用带针的缝合线(3/8圆形圆针,日本商事株式会社)结扎左冠状动脉(LCA),进行30分钟的闭锁(缺血)。闭锁30分钟后,拆开结扎的缝合线(为能够随时结扎LCA,缝合线原封不动留在胸腔内),开放血管(再次供血)。60分钟后缝合胸部,把兔子放回到饲养室内。
开放约48小时后,用戊巴比妥进行上述同样的麻醉后,从兔子的颈大动脉处放血使动物死亡。开胸摘出心脏,把心脏放到生理盐水中洗净。结扎洗净心脏的LCA,从大动脉的切口处灌入1~1.5mL左右的0.5%伊凡斯蓝进行染色。染色后,进行切片,对心脏只进行左心室切片,使心肌平行于心底部距心突部以5mm间隔进行切片,(每只兔子6个切片),切片后放入装有1%TTC磷酸缓冲液的烧杯中,在设定37℃的恒温槽中加温10分钟。加温后,给切片的心肌拍片,分成非缺血部分(伊凡斯蓝染色部分:A)、缺血部非梗塞部分(伊凡斯蓝非染色部分中的TTC染色部分:B)、及梗塞部分(伊凡斯蓝非染色部分中的TTC非染色部分;C),分别测定其重量。从测得的重量算出,缺血领域重量(B+C的6片总量)对整个左心室重量(A+B+C的6片总量)的比例,及梗塞领域重量(C的6片总量)对缺血领域重量的比例。1%TTC磷酸缓冲液的调制,是把磷酸缓冲片溶解于注射液中形成磷酸缓冲液,并使TTC为1w/v%。0.5%伊凡斯蓝的调制,是把伊凡斯蓝溶解于注射液中,使其成为0.5w/v%。
用生理盐水稀释PAA-Pt并注射到静脉中。于再供血前5分钟,从大腿静脉一次给药(0.5μg/kg),继续给药到再供血结束时,持续给药(0.5μg/kg/hr)。一次注射量为0.1mL/kg,持续给药为1mL/kg/hr。另外,再供血结束后,经过24小时再度一次注射药剂。作为对照,把生理盐水与上述给药组进行同样的一次给药及持续给药(一次给药量为0.1mL/kg,持续给药量为1mL/kg/hr)。结果如表1所示。从表1的结果中可以证实,本发明的药品,可有益减少心肌缺血再供血障碍典型病例中的梗塞部分及缺血部分。特别是在给与5μmol/kg组中,具有极其显著的作用。
例6
对大白鼠(日本Charles River公司,CrJ:CD(SD)IGS系,140~210g,雄性6周龄)进行5天检疫之后再用两天驯化后,用于实验。大白鼠在室温20~26℃、湿度40~70%、明暗各12小时的条件下,用固体饲料(CRF-1,オリエンタル酵母工业株式会社)经自由摄饵,进行饲养。把本发明药品上述的铂胶体(PAA-Pt)用装有25G注射针的丙烯制一次性注射器,在尾静脉内(2mL/kg),一天注射一次,或一天一次口服(5mL/kg)。同样,作为对照,在尾静脉内注射生理盐水。
取试验体,于30分钟后放入束缚用的不锈钢制笼(4.5×4.5×18cm、10连串)中,放在23℃±1的水槽中,浸泡至胸部呈剑状突起。水浸束缚7小时后用颈椎脱臼的方法使大白鼠安乐死,把胃摘出。把摘出的胃,用生理盐水10mL填充其内部,再将其用1%的福尔马林浸泡,固定到第二天。固定后,沿大弯切开,在生理盐水中轻轻洗涤后,测定其溃疡的长度。计算短径/长径中的长径,把总和作为其个体的值。
用溃疡的长径,算出各个组平均值±标准误差(mm)。显著误差检定是比较每个给药途径媒介组和PAA-Pt组,F测定后,同方差的情况下,进行Student的t检定,非同方差的情况下,进行Aspin-Welch的t检定。有意标准以不满5%为有意,分不满5%(P<0.05)和不满1%(P<0.01),表示。束缚3小时中,给与生理盐水组的溃疡直径(平均值)为19.86mm(标准偏差8.41mm),给与PAA-Pt组的溃疡直径(平均值)为7.27mm(标准偏差2.57mm,p=0.00566353)。而束缚7小时中,给与生理盐水组的溃疡直径(平均值)为43.88mm(标准偏差11.96mm),给与PAA-Pt组的溃疡直径(平均值)为19.84mm(标准偏差7.50mm,p=0.00191338)。
表1
组 | 动物编号 | 梗塞量(g) | 梗塞量+缺血量(g) | 全左心室量(g) | 梗塞领域(%) | 缺血领域(%) |
Vehicle(生理盐水) | 101 | 0.94 | 2.17 | 5.43 | 43.3 | 40.0 |
102 | 0.60 | 2.16 | 5.19 | 27.8 | 41.6 | |
104 | 1.20 | 2.09 | 5.46 | 57.4 | 38.3 | |
106 | 1.05 | 2.13 | 6.28 | 49.3 | 33.9 | |
107 | 1.09 | 2.09 | 5.41 | 52.2 | 38.6 | |
108 | 1.00 | 2.88 | 6.15 | 34.7 | 46.8 | |
109 | 0.49 | 1.66 | 5.65 | 29.5 | 29.4 | |
111 | 0.77 | 1.47 | 5.19 | 52.4 | 28.3 | |
113 | 0.63 | 1.89 | 5.47 | 33.3 | 34.6 | |
平均标准误差 | 42.2 | 36.8 | ||||
3.7 | 2.0 | |||||
PAA-Pt0.5μmol/kg | 201 | 0.73 | 1.57 | 5.15 | 46.5 | 30.5 |
202 | 0.99 | 2.46 | 5.31 | 40.2 | 46.3 | |
205 | 0.28 | 1.92 | 5.08 | 14.6 | 37.8 | |
206 | 0.61 | 1.37 | 5.35 | 44.5 | 25.6 | |
207 | 0.46 | 2.19 | 5.30 | 21.0 | 41.3 | |
平均标准误差 | 33.4 | 36.3 | ||||
6.5 | 3.7 | |||||
PAA-Pt5μmol/kg | 301 | 0.11 | 2.05 | 5.94 | 5.4 | 34.5 |
302 | 0.82 | 2.22 | 5.38 | 36.9 | 41.3 | |
303 | 0.28 | 2.23 | 6.28 | 12.6 | 35.5 | |
304 | 0.68 | 2.77 | 6.17 | 24.5 | 44.9 | |
305 | 0.78 | 2.14 | 5.12 | 36.4 | 41.8 | |
306 | 0.34 | 1.77 | 4.84 | 19.2 | 36.6 | |
307 | 1.65 | 2.42 | 5.17 | 68.2 | 46.8 | |
308 | 0.40 | 2.57 | 5.92 | 15.6 | 43.4 | |
309 | 0.78 | 2.39 | 5.59 | 32.6 | 42.8 | |
310 | 0.13 | 1.22 | 5.84 | 10.7 | 20.9 | |
平均标准误差 | 26.2* | 38.9 | ||||
5.8 | 2.4 |
*p<0.05对于Vehicle有显著误差(Student的t测定)
例7
用BALB/c系小鼠,每组4只,用新喹啉酮系合成抗菌药洛美沙星(ロメフロキサシン)(LFLX,以引起光促作用而著称),研究本发明药品对光促作用引起皮炎的作用(Tokura,Y.等,J.Immunol.,160,pp.3719-3728,1998;Watanabe,H.等,J.Biol.Chem.,279,pp.1676-1683,2004)。用UVA(12J/cm2)对给与LFLX2mg/0.2ml(i.p.)的小鼠,进行腹部剃毛部分照射,起光促作用。在含2%羧基乙烯基聚合物的水溶液中,加入1mM的PAA-Pt,制成凝胶状软膏,从光促作用的第2天至第5天(在第5天光照射后涂敷)按0.3g/ear,涂敷于耳廓两侧。对阳性对照组,只涂敷2%(w/w)羧基乙烯基聚合物。在第5天把2mg/0.2ml的LFLX给药至腹腔内(i.p.),用UVA(20J/cm2),照射两耳廓。对非光促作用组,在第5天只给与2mg/0.2ml(i.p.)的LFLX和用UVA(20J/cm2)照射。其结果是:照射24小时后(第6天)涂敷铂胶体组中,与阳性对照组比较,耳廓肿胀明显为轻度。再观察用UVA(20J/cm2)照射第10天的发红现象,涂敷铂胶体组中耳廓的红斑、肿胀明显地减轻。(图4)。
表2
小鼠组 | 耳廓肿胀(平均值±SEM、μm) |
阳性对照组 | 52.5±4.5 |
PAA-Pt涂敷组 | 26.9±4.1* |
阴性对照组 | 11.3±3.5 |
*:p<0.001(n=8)
例8
用BALB/c系小鼠,每组4~6只,在试验开始的第1天及第2天,把1%TCSA(3,3’,4’,5-四氯水杨酰替苯胺、橄榄油-丙酮(1∶4)混合物中)100μl涂敷于小鼠的背部剃毛处,用UVA(16J/cm2)照射涂敷处,起光促作用(Suzuki,K.等,J.Dermatol.Sci.,23,pp.138-144,2000)。从光促作用的第2天开始至第5天(第5天在光照射后涂敷),在耳廓两侧涂敷0.3g/ear,在耳廓上半抗原涂敷。作为阳性对照,只涂敷2%(w/w)羧基乙烯基聚合物。第5天,在小鼠两耳的其它部分涂敷40μl的0.1%TCSA,以40厘米的距离照射UVA(16J/cm2)。对于非光促作用组,在第5天只进行40μl的0.1%TCSA涂敷和UVA(16J/cm2)的照射。照射24小时后,测定耳朵的厚度。其结果,在铂胶体涂敷组中,和阳性对照组比较,光接触皮炎反应轻。
表3
小鼠组 | 耳廓肿胀(平均值±SEM、μm) |
阳性对照组(n=4) | 36.2±5.5 |
PAA-Pt涂敷组(n=6) | 14.2±4.0* |
阴性对照组(n=4) | 9.2±3.2 |
*:p<0.05 v.s.阳性对照
例9
把Kb1:jw系兔子(SPF、雄性、体重1.80~2.70kg、北山ラベス株式会社)安排5天的检疫,然后再进行9天的驯化,进行饲养,在这期间要进行3次体重测定及每天进行一般状态的观察。饲料使用固体饲料(RC4,オリエンタル酵母工业株式会社)。然后,用0.5%胆固醇饲料(含有0.5%胆固醇、3%花生油、3%椰子油的饲料)进行14天的驯化饲养。选出总胆固醇值上升良好的兔子,分成4组,每组10只,使分组那一天的体重和总胆固醇的平均值基本相等。使兔子在室温20~26℃、湿度40~70%、明暗各12小时(照明:上午6时~下午6时)、换气次数12次/小时(用过滤器除菌的新鲜空气)的饲养室内进行饲养。用铝制的笼子(W:350×D:580×H:350mm、安装有自动消毒及自动给水装置)个别饲养。给饵量整个期间为100g/只/天。饮水量,通过自来水用自动给水装置自由摄取。
用生理盐水稀释PAA-Pt,用装有23G针头的聚丙烯制一次性注射器(テルモ株式会社),每天一次注射到耳廓静脉内。注射时间为70天(10周)。胆固醇负荷前、开始用药前、用药4周、7周、及10周后,从前一天开始,让其绝食18小时,从耳廓动脉抽到采血管内(テルモ株式会社、VP-AS054)约4mL血,用冷却离心机(CF 8DL、日立工机株式会社)对离心分离(约4℃、3000rpm、15分钟)的血清,进行总胆固醇(TC、COD·POD法)、甘油三酸酯(TG、GPO·HDAOS法)、HDL-C(直接法)及过氧化脂质(LPO、八木别法)的测定。
给药期满的第二天,在戊巴比妥钠(戊巴比妥钠注射液,大日本制药株式会社)麻醉下,开腹,从腹部大动脉放血致死后,开胸,进行剖验记录。之后,摘出大动脉(从大动脉起始部髂骨动脉),用10%中性缓冲福尔马林固定后,进行oil Red o染色。染色后的大动脉,用数字照相机(Finepix S1 Pro,富士照相胶卷株式会社)拍摄,计算出红色染色部位对应于图象解析的整个大动脉面积的比例。用所得的数值算出各组平均值±标准差。显著误差审定在媒介组和给药组中进行,危险率不足5%作为有意的审定法,经Bartlett检定后,同方差的情况下用Dunnett检定;非同方差的情况下,用Steel检定。给与生理盐水组中,动脉硬化损伤域(%)的平均值为45.5%(p=13.5)。给与铂胶体组中,动脉硬化损伤域(%)的平均值,在给与0.005μmol/kg组中为18.7%(p=6.7);在给与0.05μmol/kg组中为19.8%(p=4.0);在给与0.5μmol/kg组中为19.2%(p=4.1)。
工业上利用的可能性
本发明药品,作为预防及/或治疗肌肉萎缩性侧索硬化症和阿耳茨海默病等神经变性疾病、类风湿性关节炎等风湿性疾病、心肌梗塞等缺血性心脏病、应激性溃疡、皮炎、动脉硬化、高血脂的药品,是有用的。
Claims (14)
1、预防及/或治疗神经变性疾病、风湿性疾病、缺血性心脏病、应激性溃疡、皮炎、动脉硬化、高血脂的药品,其中,含有贵金属或贵金属的合金微粒作为有效成分。
2、根据权利要求1所述的药品,其特征在于:所述的药品是治疗神经变性疾病的。
3、根据权利要求2所述的药品,其特征在于:所述药品治疗的神经变性疾病是肌肉萎缩性侧索硬化症、阿耳茨海默病或帕金森氏病。
4、根据权利要求1所述的药品,其特征在于:所述的药品是治疗风湿性疾病的。
5、根据权利要求4所述的药品,其特征在于:所述药品治疗的风湿性疾病是类风湿性关节炎。
6、根据权利要求1所述的药品,其特征在于:所述的药品是治疗缺血性心脏病的。
7、根据权利要求6所述的药品,其特征在于:所述药品治疗的缺血性心脏病是急性期的心肌梗塞。
8、根据权利要求1所述的药品,其特征在于:所述的药品是治疗应激性溃疡的。
9、根据权利要求8所述的药品,其特征在于:所述药品治疗的应激性溃疡是应激性胃溃疡或应激性十二指肠溃疡。
10、根据权利要求1所述的药品,其特征在于:所述的药品是治疗皮炎的。
11、根据权利要求1所述的药品,其特征在于:所述的药品是治疗动脉硬化的。
12、根据权利要求1~11项所述的药品,其特征在于:所述的贵金属是选自钌、铑、铂中的一种或两种以上的贵金属。
13、根据权利要求1~11项所述的药品,其特征在于:所述的贵金属是铂。
14、根据权利要求1~13项所述的药品,其特征在于:所述的贵金属微粒是平均粒径为10nm以下的铂胶体。
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AU (1) | AU2004212823A1 (zh) |
CA (1) | CA2518311A1 (zh) |
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EP1842524B1 (en) * | 2004-12-13 | 2013-01-23 | APT Co., Ltd. | Cleaning liquid for oral cavity |
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JP2009155281A (ja) * | 2007-12-27 | 2009-07-16 | Univ Of Tokyo | 細胞透過性白金微粒子 |
JP5358030B2 (ja) * | 2012-03-07 | 2013-12-04 | 立比古 小川 | 還元パウダー及びその製造方法 |
CN104450864A (zh) * | 2014-12-18 | 2015-03-25 | 三诺生物传感股份有限公司 | 一种组合物及其应用 |
US20220218742A1 (en) | 2019-08-20 | 2022-07-14 | Yusei Miyamoto | Agent for reducing malodor of flatulence and/or stool |
JP7039083B1 (ja) * | 2021-07-29 | 2022-03-22 | 株式会社東洋厚生製薬所 | Ampk活性化剤 |
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CN107427593A (zh) * | 2015-02-04 | 2017-12-01 | 尤法玛有限公司 | 与胃泌素结合的钌和铟 |
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EP1598071A1 (en) | 2005-11-23 |
JPWO2004073722A1 (ja) | 2006-06-01 |
ZA200507288B (en) | 2007-03-28 |
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TW200418733A (en) | 2004-10-01 |
US7838043B2 (en) | 2010-11-23 |
CN100446776C (zh) | 2008-12-31 |
KR20060007365A (ko) | 2006-01-24 |
EP1598071A4 (en) | 2006-04-26 |
CA2518311A1 (en) | 2004-09-02 |
WO2004073722A1 (ja) | 2004-09-02 |
RU2353372C2 (ru) | 2009-04-27 |
RU2005129269A (ru) | 2006-03-10 |
JP4058072B2 (ja) | 2008-03-05 |
US20060204593A1 (en) | 2006-09-14 |
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ZA200507289B (en) | 2006-12-27 |
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