CN115607545B - 依达拉奉在自闭症谱系障碍治疗中的应用 - Google Patents
依达拉奉在自闭症谱系障碍治疗中的应用 Download PDFInfo
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Abstract
本发明属于制药领域,涉及依达拉奉在自闭症谱系障碍治疗中的应用。
Description
技术领域
本发明属于制药领域,具体涉及一种依达拉奉的新用途,尤其涉及依达拉奉在制备用于治疗自闭症谱系障碍的药物中的应用。
背景技术
自闭症谱系障碍(Autism Spectrum Disorders,ASD)是由一种或多种原因导致的有生物学基础的神经发育障碍,在医学界至今没有一种普适特效药。它存在于全世界范围的各个阶层中,男孩的发病率要高于女孩3~4倍,主要具有社会沟通的交往障碍、兴趣狭隘及行为刻板重复两大类核心症状。一般从1.5岁左右家长能够逐渐发现患儿与其它儿童有所不同,确诊年龄一般为3~5岁。近年来,自闭症的发病率统计结果逐年上升,美国疾病控制中心于2007年、2009年发布自闭症患者的检出率分别为1/150、1/110,根据美国8岁儿童的数据,2012年到2020年自闭症患病率从1/68上升到1/54。我国自闭症儿童估计人数将近300万人,而实际人数估计达700万。自闭症普遍偏高的发病率已经引起了当前国内外的学者、教育者、医学工作者等本领域专业技术人员对自闭症的相关研究。自闭症已成为除癌症、心脏病之外影响人类生命健康的又一杀手。
目前为止,自闭症的发病机制尚不明确,近年研究认为其可能与多种因素有关,包括:1、遗传因素(如拷贝数变异、单基因突变(如Shank3、FMR1)、多位点基因的累积效应等);2、表观遗传学调控(包括DNA甲基化、蛋白修饰介导的染色质重组以及非编码RNA等);3、脑内免疫反应异常;4、孕期药物暴露(如丙戊酸钠(Valproic acid,VPA))等。由于自闭症病因未明造成临床诊断和治疗困难,尚未发现普适的治愈方法。目前自闭症的社交情绪障碍主要干预手段是非药物干预方案,即社交障碍训练(如游戏疗法、录像示范法、音乐疗法、图片交换沟通系统(PECS)等)和情绪障碍训练(情绪认知及理解训练、心理理论训练等)。但据统计,将近三分之二的患儿无法在成年之后独立生活,需要有人对其终生的照顾看护,进而给家庭带来沉重的经济和精神压力,也给社会带来沉重的负担。因此临床迫切需要药物性治疗方案。
依达拉奉(Edaravone,EDA)是吡唑啉酮衍生物中的一种,其化学名为3-甲基-1-苯基-2-吡唑林-5-酮,分子式C10H10N2O,结构式如下所示:
EDA的核心结构或活性中心是2-吡唑啉-5-酮,对自由基清除活性起主要作用,取代基对活性影响不大(Bioorg.Med.Chem.Lett.13(2003)3789-3792)。
EDA为含氮杂环化合物,呈碱性,易与酸反应成盐,其药学可接受的盐包括本领域常见的无机酸盐和有机酸盐,其中无机酸盐包括盐酸盐、碳酸盐、磷酸盐等,有机酸盐包括柠檬酸盐、酒石酸盐、乙酸盐、草酸盐、水杨酸盐、苹果酸盐、乳酸盐等。
EDA类似物包括位于吡唑啉环的3位甲基可以是乙基、丙基等低级(C1-6)烷基,或低级烷氧基,例如甲氧基、乙氧基等;或者3位的甲基可以是H,而4位的H可以被低级烷基或烷氧基取代。依达拉奉的衍生物包括酯,即吡唑啉环的5位酮转化为烯醇(J.Radiat.Res.,52,15-23(2011)),与羧酸反应生成酯,例如,甲酯、乙酯等。所述酯(前体)在体内水解后,再转化成酮。另外,苯基也任选被一个或多个取代基取代,所述取代基选自低级烷基、低级烷氧基、硝基、卤素等。
EDA衍生物包括Bioorg.Med.Chem.Lett.16(2006)的表1-2和图2中公开的多达18种EDA衍生物,其中EDA的苯环(R1),位置3(R3)和位置4(R4)可进一步被修饰,具有相似的氧化电势(Epa)和羟基自由基清除活性(IC50)。
EDA衍生物包括Bioorg.Med.Chem.Lett.(2015)中证实的21种EDA衍生物,具有同样的抗聚集性质(http://dx.doi.org/10.1016/j.bmcl.2015.11.022)。
EDA衍生物还包括专利申请No.201710036907.7中所公开的式(I)化合物,尤其是式(Ia)化合物(BE)。该专利申请文件的内容全部并入本申请说明书引作参考。
依达拉奉是强烈的合成氧自由基清除剂,具有抗氧化作用,以减少氧化性应激,并且经由非酶促脂质过氧化和脂氧合酶途径抑制脂质过氧化。依达拉奉由MitsubishiTanabe Pharm Corp.(日本大阪)首先开发研制的,用于改善急性脑梗死所致的神经症状、日常生活活动能力与功能障碍,上市剂型为注射剂。目前,依达拉奉在国内外已广泛用于治疗、急性缺血性中风(AIS),还用于治疗过量活性氧(ROS)相关疾病,诸如心血管病和中风。
CN105816423B公开了依拉达奉的多种制剂(例如固相分散体制剂)及其有效治疗人类氧化性应激相关疾病的用途;CN108403691A公开了依达拉奉可以用于预防和治疗白内障;CN105616405A公开了依达拉奉通过直接作用于Aβ、抑制Aβ聚集和促进Aβ纤维解聚,从而阻断或延缓脑淀粉样血管病(CAA)的进展;CN109431966A公开了一种依达拉奉药物组合物及其舌下制剂,包括依达拉奉或其盐以及甘露醇;CN107773545A公开了依达拉奉与(+)-2-camphol的舌下药物组合物;以及CN105878171A公开了一种依达拉奉鼻腔给药制剂(上述6件专利申请文件的内容全部并入本申请说明书引作参考)。
CN112912072A公开了一种在需要的对象中治疗或减缓神经元炎症进展的方法,包括共同给予第一化合物和第二化合物,其中第一化合物和第二化合物独立地是(a)式(I)化合物,…(c)依达拉奉或利鲁唑,…(e)非甾体抗炎药(NSAID),或者(f)抗炎肽。其还具体公开了第一化合物是色甘酸钠,第二化合物是NSAID,以及其中神经元炎症是ALS、ASD、缺血性中风和朊病毒病。
TW201912152A公开了一种方法,其用于治疗或预防神经系统病症等,该方法包括向个体施用d-美沙酮(methadone)等。其另教导了d-美沙酮可与依达拉奉联用,以及神经系统病症包括AD、ASD等。
然而,现有技术尚无依达拉奉单独用于治疗自闭症谱系障碍(ASD)的报道。
发明内容
本发明的目的在于提供一种依达拉奉的新用途,即用于治疗自闭症谱系障碍(ASD)。
首先,本发明提供了一种依达拉奉或其药学可接受的盐或类似物或衍生物(优选作为唯一活性成分单独)在制备用于治疗自闭症谱系障碍(ASD)的药物中的应用。
另一方面,本发明还提供了一种用于治疗自闭症谱系障碍的药物组合物,包含依达拉奉或其药学可接受的盐或类似物或衍生物,以及一种或多种可药用赋形剂。
根据本发明,依达拉奉还可与一种或多种治疗ASD的其他药物(例如色甘酸/盐、NSAID,d-美沙酮等)联用(先后或同时施用),或与一种或多种其他治疗ASD的药物(例如包括但不限于色甘酸/盐、NSAID和d-美沙酮)组成药物组合物。
根据本发明,药物组合物的给药方式为静脉滴注、肌肉注射、口服、经皮、舌下、鼻内、眼内、内耳、直肠、或阴道内途径给药。优选的,药物组合物的给药方式为口服给药。
在本发明的一种实施方式中,所述口服给药的药物剂型为固体制剂,优选为固相分散体制剂,其包括活性成分依达拉奉或其可药用盐,聚合物载体选自Soluplus、聚乙二醇(PEG)、羟丙基甲基纤维素(HPMC)、羟丙基甲基纤维素乙酸酯(HPMCAS)、羟丙基纤维素(HPC)和壳聚糖(其中优选Soluplus和/或HPMC,更优选Soluplus),以及任选的表面活性剂TPGS1000。所述药物组合物中,依达拉奉的单位剂量为0.001-1000mg,优选0.01-500mg,更优选0.1-100mg,最优选1-50mg,例如1mg,2mg,3mg,4mg,5mg,10mg,15mg,20mg,25mg,30mg,35mg,40mg,45mg和50mg。
本发明涉及一种依达拉奉或其药学可接受的盐或类似物或衍生物治疗自闭症谱系障碍(ASD)的方法,其包括给需要的对象施用治疗有效量的依达拉奉或其药学可接受的盐或类似物或衍生物。
本发明还涉及依达拉奉或其药学可接受的盐或类似物或衍生物,用于治疗自闭症谱系障碍(ASD),或者用于治疗自闭症谱系障碍(ASD)的药物,该药物包含依达拉奉或其药学可接受的盐或类似物或衍生物。
本发明出人意料地发现依达拉奉治疗自闭症谱系障碍具有非常好的疗效,特别是在改善社交障碍、刻板行为方面具有突出的治疗效果。
定义
术语“药学上可接受的”意指由管理机构例如EMEA(欧洲)和/或FDA(US)和/或任何其它国家管理机构批准在动物中优选在人类中使用。
术语“赋形剂”是指与治疗药物一起施用的稀释剂、辅助剂或载体。适当的药学赋形剂的实例描述在由E.W.Martin编写的“Remington’s药物科学(Remington’sPharmaceutical Sciences)中。
本发明提供了依达拉奉治疗自闭症谱系障碍的合适的给药方式。考虑到给药的便利性,以及增加患者的用药依从性,优选通过口服给药。
本发明口服给药的制剂的制备方法可以参考本领域常规方法制备得到,特别优选参考CN105816423B公开的方法制备依达拉奉或其药学可接受盐的口服给药制剂。
在本发明中,依达拉奉或其药学可接受的盐或类似物或衍生物有时又统称为“依达拉奉”,交互使用。
根据本发明,依达拉奉的给药剂量在0.1mg/kg至100mg/kg之间。其中对治疗而言,给药剂量优选为0.1-50mg/kg,例如0.1mg/kg,0.5mg/kg,1.0mg/kg,2.0mg/kg,3.0mg/kg,5.0mg/kg,10.0mg/kg,15mg/kg,20mg/kg,25mg/kg,30mg/kg,35mg/kg,40mg/kg,45mg/kg或50mg/kg等,每日两次至每周两次给药。
本发明制剂给药的剂量和频率可以根据患者病情而变化,有时需要以相对短的间隔、相对高剂量(例如,5.0-35mg/kg),直至减轻或终止疾病的进展,优选直至患者表现出疾病症状的部分或完全改善。本发明的药物可以通过胃肠外、局部、静脉内、口服、皮下、动脉内、颅内、鞘内、腹膜内、鼻内或肌内方式给药。尽管其它途径同样有效,但典型的给药途径是口服,其次是肌内注射。这种类型的注射最通常在臂或腿部肌肉中施行。
附图简述
为了更清楚地描述本发明的技术方案,下面将结合附图作简要介绍。显而易见,这些附图仅是本申请记载的一些具体实施方式。本发明包括但不限于这些附图。
图1示出造模后,VPA造模组和正常组捋毛时间对照;
图2示出造模后,VPA造模组和正常组三箱社交实验结果;
图3示出治疗14天、28天后,实验动物的社交指数(social index,SI)自身前后对照;
图4示出治疗14天和28天后,实验动物的社交指数(SI)组间对照;
图5示出治疗28天后,实验动物的捋毛时间(grooming time)的自身前后对照;
图6示出治疗28天后,实验动物的捋毛时间的组间比较;
图7示出前额叶脑区(PFC)的SOD活力检测结果;
图8示出小脑脑区(CE)的SOD活力检测结果;
图9示出前额叶脑区(PFC)的GST活力检测结果;
图10示出海马脑区(HIP)的GST活力检测结果;
图11示出海马脑区(HIP)的GSH活力检测结果;
图12示出血清中GSH活力检测结果;和
图13示出血清中Cys含量检测结果。
具体实施方式
为了进一步理解本发明,下面将结合实施例对本发明的优选方案进行描述。这些描述只是举例说明本发明的技术方案的特征和优点,而非限制本发明的保护范围。
实验目的
测试依达拉奉在丙戊酸钠(Valproic acid,VPA)诱导的大鼠自闭症模型的治疗作用。
自闭症模型建立
SD孕鼠25只,第12.5天单次腹腔注射500mg/kg丙戊酸钠(VPA),21天分娩,留雄性子代设为VPA组;对照组孕鼠5只,第12.5天单次腹腔注射等量生理盐水,21天分娩,留雄性子代,设为CON组。
子代幼鼠成长至第25天,进行旷场实验,观察捋毛时间,反应动物的重复刻板行为);进行三箱社交实验,观察社交指数(Social Index,SI),社交指数=(动物进入陌生鼠区域时间-动物进入空笼区域时间)÷(动物进入陌生鼠区域时间+动物进入空笼区域时间),反应实验动物的社交能力。结果发现,与CON组比较,VPA组动物的捋毛时间显著增加(图1,p<0.005)。在三箱社交实验中,与CON组比较,VPA组动物的社交指数(Social Index,SI)显著降低(图2,p<0.0001)。以上结果表明,VPA组动物出现明显的社交障碍和重复刻板行为,造模成功。
动物分组、给药、检测
子代出生26天,将造模的VPA组随机分成6个组,安慰剂组(n=19,soluplus428mg/kg)、阳性药(色甘酸钠)组(n=14,色甘酸钠6.3mg/kg)、阳性药溶剂(NS)组(n=12,等剂量生理盐水)、EDA低剂量组(n=12,依达拉奉3mg/kg)、EDA中剂量组(n=12,依达拉奉10mg/kg)和EDA高剂量组(n=22,依达拉奉30mg/kg);另设CON组组(n=9)。阳性药组和阳性药溶剂组给予腹腔注射,安慰剂组和EDA各剂量组给予灌胃,每天1次,连续28天,给药14天后和给药28天后进行三箱社交实验,给药28天后进行旷场实验。动物处死后,安慰剂组和EDA各剂量组每组随机取6只动物,收集前额叶、海马和小脑和血液进行氧化应激相关指标检测,检测机体抗氧化能力。
结果
1、三箱社交实验结果
灌胃治疗前、灌胃治疗14天及28天后各组动物的社交指数(SI)请见表1。与治疗前比较,EDA各剂量组动物在持续灌胃治疗14天和28天后,社交指数明显显著升高,且28天治疗效果好于14天(图3);组间比较显示,治疗前,与CON组比较,各模型组动物社交指数显著降低;治疗14天后,与安慰剂组比较,EDA各剂量组和阳性药(色甘酸钠)组动物的社交指数显著提升(p<0.01),其中EDA中剂量组和高剂量组效果更好(p<0.001,p<0.0001);治疗28天后,与安慰剂组比较,EDA各剂量组动物的社交指数显著提升(p<0.05),EDA高剂量组效果更好(p<0.01),而阳性药(色甘酸钠)和阳性药溶剂组剂组则无显著差异(图4)。说明依达拉奉可以显著提升VPA诱导的自闭症模型大鼠的重社交指数,改善其社交障碍。
表1灌胃治疗前、灌胃治疗14天和灌胃28天后动物的社交指数(SI)(mean±SE)
2、治疗28天后旷场实验结果
灌胃治疗前和灌胃治疗28天后各组动物的捋毛时间请见表2。与治疗前比较,持续灌胃治疗28天后,EDA各剂量组以及安慰组和阳性药(色甘酸)组动物捋毛时间显著下降(p<0.05),其中EDA低剂量组和EDA中剂量组差异更显著(p<0.01)(图5)。组间比较显示,持续灌胃治疗28天后,与安慰剂组比较,EDA各剂量组动物捋毛时间显著降低(p<0.05),其中EDA低剂量组和EDA中剂量组差异更显著(p<0.01),阳性药溶剂组和阳性药(色甘酸钠)组无显著差异;与阳性药(色甘酸钠)组比较,EDA低剂量组和EDA中剂量组动物的捋毛时间显著降低(图6)。说明依达拉奉可以显著降低VPA诱导的自闭症模型大鼠的捋毛时间,改善其重复刻板行为。
表2灌胃治疗前和灌胃治疗28天后动物的捋毛时间(mean±SE)
3、氧化应激指标
灌胃治疗28天后,前额叶(PFC)和小脑(CE)超氧化物歧化酶(SOD)活力检测结果见表3。结果显示,与安慰剂组比较,EDA中剂量组和高剂量组前额叶脑区的SOD活力显著增加(p<0.05),EDA高剂量组增加更明显(p<0.001)(图7);EDA高剂量组小脑区的SOD活力显著(p<0.01)(图8)。
表3灌胃治疗28天后大鼠PFC和CE区域SOD活力(mean±SE)
组别 | 前额叶(PFC)SOD活力(U/mgprot) | 小脑(CE)SOD活力(U/mgprot) |
VPA+Vehicle | 130.8±10.3 | 67.52±14.92 |
VPA+EDA(3mg/kg) | 124.6±5.73 | 67.04±11.3 |
VPA+EDA(10mg/kg) | 203.4±14.37 | 83.07±3.39 |
VPA+EDA(30mg/kg) | 315±42.53 | 138.7±18.62 |
灌胃治疗28天后,前额叶(PFC)和海马(HIP)谷胱甘肽巯基转移酶(GST)活力检测结果见表4。结果显示,与安慰剂组比较,EDA高剂量组的前额叶(PFC)和海马(HIP)的GST活力显著提升(p<0.01)(图9,10)。
表4灌胃治疗28天后大鼠PFC和HIP区域GST活力(mean±SE)
组别 | 前额叶(PFC)GST活力(U/mgprot) | 海马(HIP)GST活力(U/mgprot) |
VPA+Vehicle | 34.63±5.68 | 76.76±9.62 |
VPA+EDA(3mg/kg) | 39.54±13.34 | 144.5±59.64 |
VPA+EDA(10mg/kg) | 46.93±13.31 | 117.7±28.12 |
VPA+EDA(30mg/kg) | 103.8±22.27 | 295.4±54.67 |
灌胃治疗28天后,海马(HIP)和血清中还原型谷胱甘肽(GSH)活力检测结果见表5。结果显示,与安慰剂组比较,EDA高剂量组海马脑区(HIP)GSH活力显著升高(p<0.05)(图11),血清中GST活力升高更显著(p<0.01)(图12)。
表5灌胃治疗28天后大鼠HIP和血清中GSH活力(mean±SE)
组别 | 海马(HIP)GSH活力(U/mgprot) | 血清GSH活力(U/mgprot) |
VPA+Vehicle | 31.33±4.2 | 5.65±1.32 |
VPA+EDA(3mg/kg) | 14.44±7.97 | 9.6±2.14 |
VPA+EDA(10mg/kg) | 49.39±10.34 | 10.35±1.92 |
VPA+EDA(30mg/kg) | 78.87±17.13 | 21.45±0.86 |
灌胃治疗28天后,血清中半胱氨酸(Cys)含量检测结果见表6。结果显示:治疗28天,EDA高剂量组动物血液中Cys含量显著高于安慰剂组(p<0.0001)(图13)。
表6灌胃治疗28天后血清中Cys含量(mean±SE)
组别 | 血清Cys含量(μmol/mL) |
VPA+Vehicle | 0.20±0.07 |
VPA+EDA(3mg/kg) | 0.35±0.05 |
VPA+EDA(10mg/kg) | 0.38±0.13 |
VPA+EDA(30mg/kg) | 1.15±0.10 |
氧化应激指标检测结果显示,依达拉奉能够提高VPA诱导的自闭症模型大鼠的抗氧化能力。
以上具体实施方式的说明只是用于帮助理解本发明的核心思想。应当指出,对于本领域的普通技术人员而言,在不脱离本发明原理的前提下,还可以对本发明的技术方案进行若干改进和修饰,但这些改进和修饰也落入本发明权利要求请求保护的范围内。
Claims (13)
1.依达拉奉或其药学可接受的盐作为唯一活性成分在制备用于治疗自闭症谱系障碍的药物中的应用。
2.根据权利要求1所述的应用,其中所述药物包含依达拉奉或其药学可接受盐和一种或多种可药用赋形剂。
3.根据权利要求2所述的应用,其中所述药物的给药方式选自静脉滴注、肌肉注射、口服、经皮、舌下、鼻内、眼内、内耳、直肠、或阴道内途径给药。
4.根据权利要求3所述的应用,其中所述药物的给药方式为口服给药。
5.根据权利要求1所述的应用,其中所述药物的剂型为固体制剂。
6.根据权利要求5所述的应用,其中所述药物的剂型为固体分散体制剂。
7.根据权利要求6所述的应用,其中所述固体分散体制剂包括活性成分依达拉奉或其可药用盐,聚合物载体,以及任选的表面活性剂TPGS1000。
8.根据权利要求7所述的应用,其中聚合物载体选自Soluplus、聚乙二醇(PEG)、羟丙基甲基纤维素(HPMC)、羟丙基甲基纤维素乙酸酯(HPMCAS)、羟丙基纤维素(HPC)和壳聚糖。
9.根据权利要求7所述的应用,其中所述依达拉奉或其药学可接受的盐的单位剂量为0.001-1000mg。
10.根据权利要求9所述的应用,其中所述依达拉奉或其药学可接受的盐的单位剂量为0.1-100mg。
11.根据权利要求10所述的应用,其中所述依达拉奉或其药学可接受的盐的单位剂量为1-50mg。
12.根据权利要求1所述的应用,其中所述依达拉奉或其药学可接受的盐的给药剂量为0.1-100mg/kg。
13.根据权利要求12所述的应用,其中所述依达拉奉或其药学可接受的盐的给药剂量为1-30mg/kg。
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