CN113694055B - 沉香四醇在制备治疗血管性痴呆疾病的药物中的应用 - Google Patents
沉香四醇在制备治疗血管性痴呆疾病的药物中的应用 Download PDFInfo
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Abstract
本发明提供在制备预防和治疗血管性痴呆疾病的药物中的应用,以及沉香四醇PFC24在制备改善血管性痴呆疾病的药物中的应用。沉香四醇(PFC24)在血管性痴呆小鼠动物模型上表现出显著的治疗作用,且无明显毒性反应。PFC24能用作为治疗血管性痴呆的药物。
Description
技术领域:
本发明属于医药技术领域,尤其涉及沉香四醇在制备预防和治疗血管性痴呆的药物中的应用。
背景技术:
痴呆症是获得性神经变性,在多个认知领域严重影响社会或职业功能[Arvanitakis Z,Shah RC,Bennett DA.Diagnosis and management of dementia.JAMA,2019,322,1589-1599]。年龄的增长是主要的风险因素,由于世界人口的老龄化和缺乏有效的治疗方法,预计到2050年,受影响的人数将增加两倍,费用接近4万亿美元[Iadecola C,Duering M,Hachinski V,Joutel A,Pendlebury ST,Schneider JA,Dichgans M.Vascularcognitive impairment and dementia:JACC scientific expert panel.Journal of theAmerican College of Cardiology,2019,73,3326-3344]。痴呆症经常与1种以上的神经病变有关,通常是老年痴呆症(Alzheimer's disease,AD)与血管性痴呆(Vasculardementia,VaD)[Arvanitakis Z,Shah RC,Bennett DA.Diagnosis and management ofdementia.JAMA,2019,322,1589-1599]。VaD是最常见的痴呆原因之一,约占15%的病例[O'Brien JT,Thomas A.Vascular dementia.The Lancet,2015,386,1698-1706],是一种脑血管疾病,以脑出血、缺血、缺氧等脑血管因素为特征,造成脑部血流供应不足,脑组织主要是海马和皮质进一步受损[Iadecola C,Duering M,Hachinski V,Joutel A,Pendlebury ST,Schneider JA,Dichgans M.Vascular cognitive impairment and dementia:JACCscientific expert panel.Journal of the American College of Cardiology,2019,73,3326-3344],导致人类的学习和记忆功能障碍。该病的临床表现与其他痴呆症相似[Borelli CM,Grennan D,Muth CC.Causes of memory loss in elderly persons.JAMA,2020,323,486-486]。尽管此疾病很严重,但由于缺乏明确的诊断标准和有效的特异性生物标志物,诊断受到阻碍。因此,迫切需要寻找特异有效的生物标志物,以提高诊断水平,尽早发现,提高治疗效率,发现病理特征,监测临床试验[Llorens F,Hermann P,Villar-PiquéA,Diaz-Lucena D, K,Hansson O,Santana I,Schmitz M,Schmidt C,VargesD.Cerebrospinal fluid lipocalin2as a novel biomarker for the differentialdiagnosis of vascular dementia.Nature Communications,2020,11,619]。目前,临床治疗痴呆症的策略主要是对症治疗,包括胆碱酯酶抑制剂(galantamine、donepezil、carbamate)、N-甲基-D-天门冬氨酸拮抗剂美满霉素,以及一些中药等[Iadecola C,Duering M,Hachinski V,Joutel A,Pendlebury ST,Schneider JA,Dichgans M.Vascularcognitive impairment and dementia:JACC scientific expert panel.Journal of theAmerican College of Cardiology,2019,73,3326-3344;Dichgans M,Markus HS,Salloway S,Verkkoniemi A,Moline M,Wang Q,Posner H,Chabriat HS.Donepezil inpatients with subcortical vascular cognitive impairment:a randomised double-blind trial in CADASIL.The Lancet Neurology,2008,7,310-318;Kavirajan H,Schneider LS.Efficacy and adverse effects of cholinesterase inhibitors andmemantine in vascular dementia:a meta-analysis of randomised controlledtrials.The Lancet Neurology,2007,6,782-792;Jia J,Wei C,Chen S,Li F,Tang Y,QinW,Shi L,Gong M,Xu H,Li F.Efficacy and safety of the compound Chinese medicineSaiLuoTong in vascular dementia:a randomized clinical trial.Alzheimer's&Dementia:Translational Research&Clinical Interventions,2018,4,108-117;Man SC,Chan KW,Lu J-H,Durairajan SSK,Liu L-F,Li M.Systematic review on the efficacyand safety of herbal medicines for vascular dementia.Evidence-BasedComplementary and Alternative Medicine,2012,2012,426215]。但这些化学药物的治疗对象单一,用药后有很大的个体差异,只对部分患者有效。因此,研究和开发新药,对VaD的治疗很有必要。
沉香是瑞香科植物白木香Aquilaria sinensis(Lour.)Spreng.含有树脂的心材[《中华人民共和国药典》2020版]。沉香主要含有倍半萜和2-(2-苯乙基)色酮类成分[Li W,Chen H-Q,Wang H,Mei W-L,Dai H-F.Natural products in agarwood and Aquilariaplants:chemistry,biological activities and biosynthesis.Natural ProductReports,2021,38,528-565]。沉香四醇是沉香质量控制的指标成分之一[《中华人民共和国药典》2020版]。到目前为止,尚未见到沉香四醇在VaD研究方面的报道。
发明内容:
针对现有技术存在的上述空白,本发明开展了沉香四醇在VaD药理模型上的评价。结果显示沉香四醇(PFC24)在血管性痴呆小鼠动物模型上表现出显著的治疗作用,且无明显毒性反应。故此,本发明提供了沉香四醇(PFC24)在制备预防和治疗血管性痴呆疾病的药物中的应用。
为了实现本发明的上述目的,本发明提供了如下的技术方案:
沉香四醇PFC24在制备预防和治疗血管性痴呆疾病的药物中的应用。
沉香四醇PFC24在制备改善血管性痴呆疾病的药物中的应用。
根据所述的应用,其中沉香四醇PFC24的给药剂量为20-50mg/kg。优选的给药剂量为20mg/kg。
本发明的沉香四醇(PFC24)用作为药物时,可直接使用,或者以药物组合物的形式使用。该药物组合物中含有0.1-99%的沉香四醇(PFC24),优选为0.5-90%的有效成分沉香四醇(PFC24),特别优选为20-50mg/kg的PFC24给药剂量,其余为药物学和药剂学上可接受的,对人和动物无毒的药用辅料或载体。本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如使活性成分与一种或多种载体混合,然后将其制成所需的剂型。
所述的药学上可接受的载体是指药学领域常规的药物载体,例如:稀释剂、赋形剂如水等,填充剂如淀粉、蔗糖等;黏合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;湿润剂如甘油;崩解剂如琼脂、碳酸钙和碳酸氢钠;吸收促进剂如季铵化合物;表面活性剂如十六烷醇;吸附载体如高岭土和皂黏土;润滑剂如滑石粉、硬脂酸钙和硬脂酸镁、以及聚乙二醇等。另外还可以在组合物中加入其它辅剂如香味剂、甜味剂等。
与现有技术相比,本发明优益性在于:
1.本发明对沉香四醇(PFC24)发掘了新的医疗用途,开拓了沉香四醇(PFC24)一个新的应用领域。提供了沉香四醇(PFC24)在制备预防和治疗血管性痴呆疾病的药物中的应用。
2、本发明的产品沉香四醇(PFC24)来源丰富、价廉、未见毒副作用,制备工艺简单,并可做成口服剂型、注射剂型、片剂等,使用方便。
3、通过药效学研究发现,本发明的产品沉香四醇(PFC24)在20-50mg/kg的PFC24给药剂量对血管性痴呆具有明显治疗效果,对血管痴呆模型鼠的行为学有明显改善作用。能有效地作为抗血管痴呆药物使用。
附图说明:
图1为沉香四醇(PFC24)的化学结构式。
图2为小鼠分组首剂给药后一周体重变化。图2注:实验结果以Mean±SEM表示,采用Sigma Stat3.5统计分析软件对数据进行分析处理。多组比较统计采用双因素方差分析Two-way ANOVA中Student-Newman-Keuls Method进行统计分析,Sigma Plot 10.0图形软件作图。
图3为沉香四醇(PFC24)给药一个月各组大鼠逃避潜伏期。图3注:实验结果以Mean±SEM表示,采用Sigma Stat3.5统计分析软件对数据进行分析处理。多组比较统计采用双因素方差分析Two-way ANOVA中Student-Newman-Keuls Method与Dunn’s Method进行统计分析,Sigma Plot 10.0图形软件作图。
图4沉香四醇(PFC24)给药一个半月各组大鼠逃避潜伏期。图4注:实验结果以Mean±SEM表示,采用Sigma Stat3.5统计分析软件对数据进行分析处理。多组比较统计采用双因素方差分析Two-way ANOVA中Student-Newman-Keuls Method进行统计分析,Sigma Plot10.0图形软件作图。
具体实施方式:
下面结合附图,用本发明的实施例来进一步说明本发明的实质性内容,但并不以此来限定本发明。
实施例1:
沉香四醇(PFC24)的制备:
干燥的中药沉香(2.9kg)粉碎,90%乙醇(10L)60℃超声提取30min,重复5次,浓缩提取液后得到浸膏(459.3g)。然后将浸膏悬浮于1L水中,依次用等体积石油醚和乙酸乙酯萃取5次,回收溶剂得石油醚萃部位(0.7g)和乙酸乙酯萃取部位(374.8g)。
乙酸乙酯萃取部位用等量的80~100目硅胶拌样,经正相硅胶柱层析划段,先用石油醚-乙酸乙酯混合溶剂(50:1,30:1,20:1,10:1,5:1,3:1,2:1,1:1,0:1,v/v)进行梯度洗脱,在同一支色谱柱上,接着用乙酸乙酯-甲醇进行梯度洗脱(5:1,3:1,2:1,1:1,0:1,v/v)。乙酸乙酯-甲醇洗脱(5:1,3:1,v/v)部分(151.0g)继续用正相硅胶柱层析划段,二氯甲烷-甲醇体系进行梯度洗脱(50:1,30:1,20:1,10:1,5:1,1:1,v/v)。在二氯甲烷-甲醇(10:1)洗脱部分,用薄层色谱检测所得组分,合并相同组分,得到PFC24(20.0g)。
实施例2:
沉香四醇(agarotetrol,PFC24)的波谱数据:无色固体,CAS登记号69809-22-9,分子式C17H18O6;[α]D 18-17.9(c 0.20,MeOH);1H NMR(methanol-d4,500MHz)δH 7.24(5H,m,H-2′~6′),6.13(1H,s,H-3),4.73(1H,d,J=4.0Hz,H-5),4.55(1H,d,J=7.4Hz,H-8),4.03(1H,dd,J=7.4,2.4Hz,H-7),4.00(1H,dd,J=4.9,2.4Hz,H-6),3.04(2H,t,J=7.8Hz,H2-7′),2.94(2H,m,H2-8′);13C NMR(methanol-d4,126MHZ)δC 182.0(C,C-4),171.2(C,C-2),165.4(C,C-8a),141.2(C,C-1′),129.6(CH,C-3′,C-5′),129.4(CH,C-2′,C-6′),127.4(CH,C-4′),121.8(CH,C-4a),114.1(CH,C-3),74.0(CH,C-6),72.4(CH,C-7),70.1(CH,C-8),66.7(CH,C-5),36.3(CH2,C-8′),33.7(CH2,C-7′)。其波谱数据跟文献[Yoshii E,Koizumi T,Oribe T,Takeuchi F,Kubo K.The structure of agarotetrol,a novel highlyoxygenated chromone from agarwood(jinko).Tetrahedron Letters,1978,19,3921-3924]一致,化学结构式图1所示。
实施例3:
PFC24的小鼠急性毒性实验。
1.实验材料
(1)实验试剂:PFC24,生理盐水。
(2)器材:电子天平,注射器,灌胃针。
(3)实验动物分组:1)给药前禁食12h,鼠龄:7~9周,首剂给药后观察一周。2)昆明鼠30只,雌雄各半,正常组、10mg/kg组、20mg/kg组、50mg/kg组、100mg/kg组每组各6只,给药前禁食12h,鼠龄:7~9周,首剂给药后观察一周。
2.实验步骤
(1)实验准备阶段:配制化合物浓度5mg/mL(0.4~0.5mL/20g,按0.4mL/20g为灌胃最大量计算)生理盐水作为溶剂,对照组不给药。
(2)正式实验:根据体重进行给药。给药后12h内每隔一小时观察小鼠状态以及体重。给药后一周每日早上进行体重称量以及观察小鼠反应。
3.观察与记录
首日给药后4h内每小时密切观察小鼠活动状态和死亡情况,每天对各组小鼠进行称重,统计死亡数量以及解剖观察内脏是否发生病变等,连续观察1~2周。
4.结果
PFC24在0~100mg/kg剂量下对小鼠无明显毒性反应。
为了进一步明确PFC24剂量不同对小鼠是否存在不良反应,本发明细化了分组如2)分组,在正常对照组、50mg/kg、100mg/kg组的基础上加入10mg/kg组、20mg/kg组。通过一周的观察记录。发现四组给药组小鼠与正常组小鼠相比精神状态与对外界反应等无明显差异,其中体重变化如图2所示,发现四组给药组小鼠体重差异与正常组小鼠体重差异相比无明显差异。本发明进一步得到PFC24在0~100mg/kg剂量内对小鼠无明显不良反应。
5.结论
PFC24在0~100mg/kg剂量内对于小鼠并无性别、神经、应激、饮食等因素的明显毒性反应,可进行其他临床前试验的研究。
实施例4
PFC24的药效学研究。
1.实验材料
1.1实验动物
健康Sprague-Dawley大鼠,SPF级,体重250~280g,雄性,合格证号:SCXK(滇)K2015-0002,由昆明医科大学实验动物中心提供。以标准饲料喂养并自由饮水,动物饲养于可控制的实验环境(温度:25℃,相对湿度60%~70%,白天和黑夜各12h)。
1.2主要试剂与主要设备
试剂:异氟烷购自深圳市瑞沃德生命科技有限公司(批号:217170701),氯霉素滴眼液购自四川美大康华康药业有限公司(批号:17022828);注射用硝普钠购自武汉人福药业有限责任公司(批号:21018014-1)。
设备:异氟烷气体麻醉机购自深圳市瑞沃德生命科技有限公司;Morris水迷宫分析系统购自上海欣软科技有限公司。
2.实验方法
2.1实验分组
将SD大鼠随机分为假手术组(Sham)、模型组(Model)、PFC24 20mg/kg给药组、PFC24 50mg/kg给药组。
2.2模型制备
本次实验采用双侧颈总动脉永久性结扎(2-VO)加腹腔注射硝普钠的方法。
建立血管性痴呆大鼠模型。首先称重,记录大鼠体重,手术时将大鼠置于麻醉诱导盒中以5%的异氟烷气体麻醉,麻醉完全后,取出,取仰卧位给老鼠套麻醉面罩,以200g,0.2mL/min的2%异氟烷气体给以持续麻醉,手术期间保证大鼠自主呼吸。皮筋固定四肢,颈部皮肤剪毛,用75%乙醇将颈部皮肤区消毒后剪开颈正中皮肤,长约1cm,钝性分离肌肉组织,找到颈总动脉,仔细剥离附着的迷走神经后分离出颈总动脉,在其近心端与远心端处分别以4号鱼线进行双重结扎并剪断。左边依法结扎。术中动作轻柔,避免钳夹和过分牵拉迷走神经,注意无菌原则,术毕,滴入氯霉素滴眼液,防止感染,再逐层缝合。缝合后腹腔注入硝普钠溶液,将大鼠放于干净笼子中,术中保持37℃左右,保温,至苏醒。假手术组手术程序同上,仅暴露双侧颈总动脉但不进行结扎离断。
造模一周后,水迷宫筛模,将造模成功的大鼠按痴呆程度分为各实验组,给予相应受试药进行灌胃处理连续45天,动态给药。痴呆标准:造模后的大鼠在水迷宫实验中进行测试,5天假手术组大鼠的平均逃避潜伏期作为参考值,计算模型鼠5天的平均逃避潜伏期与参考值之差占该鼠的平均逃避潜伏期的比值,该值X>20%为痴呆鼠。该比值20%≤X≤30%为轻度痴呆,30%≤X≤40%为中度痴呆,X>40%为重度痴呆。
2.3 Morris水迷宫实验
水迷宫主要由盛水的水池和一个可调节高度和可移动位置的站台所组成。水池的水深大小鼠分别为1.6m和1.2m。池壁标明4个入水点,将水池等分为4个象限。Morris水迷宫实验中一般分为定位航行实验和空间探索实验两个阶段。
定位航行实验(place navigation test)/隐藏平台实验(the test of gainingconcealed platform):连续训练动物5天,每天4次,上下午各2次,每天所放象限的顺序与前一天不同。本次实验所放象限顺序依次为2→3→4→1;4→1→2→3;1→4→3→2;3→2→4→1;2→3→1→4。实验时让大鼠面朝池壁从不同象限放入水中,直到大鼠找到平台。规定的时间为90s,找到平台后让大鼠在平台上停留10s。如果动物在规定时间内未找到平台,则实验者帮助其找到平台并在平台上停留10s。每次训练间隔时间为30s。
空间探索实验(spatial probe test):在最后一次定位航行实验结束后的第二天,撤去平台,将动物从平台所在象限的对面象限面朝池壁放入水中,让动物在水池中自由游泳,实验进行2次。潜伏期(动物进入迷宫到找到平台所需时间),游泳路程,目标象限停留时间、路程,动物穿越平台的时间、路程、次数,搜索策略等可作为该实验的检测指标。
3.结果
3.1在给药一个月后,20mg/kg PFC24明显对血管性痴呆大鼠有改善作用。
为了进一步明确PFC24对血管性痴呆是否有治疗作用。本发明进行水迷宫对一个月给药后的给药组、正常组、模型组大鼠进行认知功能检测。如图3所示,逃避潜伏期是判断大鼠认知功能改变最重要的指标。本发明发现相比模型组大鼠,Sham组大鼠的认知功能明显优于模型组大鼠,说明造模成功。同时本发明发现相比模型组,20mg/kg给药组大鼠的认知功能明显提高;而50mg/kg组大鼠的认知功能也有提高的趋势(无统计学意义)。所以20mg/kg的PFC24给药剂量对血管性痴呆具有明显治疗效果,而50mg/kg效果不显著。
3.2在给药一个半月后,相对于一个月给药,20mg/kg PFC24对血管性痴呆大鼠的改善作用更明显。
为了进一步明确PFC24给药的时间对血管性痴呆的治疗是否有影响。本发明进行水迷宫对各组大鼠进行认知功能检测。如图4所示,本发明发现相比模型组大鼠,Sham组大鼠的认知功能明显优于模型组大鼠;同时本发明发现相比模型组,20mg/kg给药组大鼠的认知功能明显提高且相对给药1月10mg/kg药效更加明显;而50mg/kg组大鼠的认知功能也有提高的趋势(无统计学意义);但相比于一个月50mg/kg给药组,药效减弱。所以20mg/kg的PFC24给药剂量对血管性痴呆具有明显治疗效果,而50mg/kg效果不显著。
4.结论
通过药效学研究发现,20mg/kg剂量PFC24对血管痴呆模型鼠的行为学有明显改善作用。
实施例5
片剂:沉香四醇(PFC24)10mg,乳糖180mg,淀粉55mg,硬脂酸镁5mg。
制备方法:将沉香四醇(PFC24)、乳糖和淀粉混和,用水均匀湿润、把湿润后的混合物过筛并干燥,再过筛,加入硬脂酸镁,然后将混合物压片,每片重250mg,化合物含量为10mg。
实施例6:
安瓿剂:沉香四醇(PFC24)2mg,氯化钠10mg。
制备方法:将沉香四醇(PFC24)和氯化钠溶解于适量的注射用水中,过滤所得溶液,在无菌条件下装入安瓿瓶中。
实施例7:
注射用冻干剂:沉香四醇(PFC24)10mg,碳酸氢钠2mg,甘露醇252mg。
制备方法:将碳酸氢钠、甘露醇,加注射用水溶解,加活性碳吸附30min除热原,过滤除去活性碳,在滤液中加入沉香四醇(PFC24),超声处理使溶解,用1N盐酸调节pH为5.0-7.0,微孔滤膜滤过,加注射用水,分装,冷冻干燥,上塞,轧盖,即得。
实施例8:
胶囊剂:沉香四醇(PFC24)10mg,乳糖187mg,硬脂酸镁3mg。
制备方法:将沉香四醇(PFC24)与助溶剂混和,过筛,均匀混合,把得到的混合物装入硬明胶胶囊,每个胶囊重200mg,活性成分含量为10mg。
本发明的保护范围不仅仅局限于上述实施例,上述实施例只是为了帮助解释和说明本发明,而不是对本发明的保护范围进行限制,只要设计与本发明的设计相同或者是只要是等同替换的都落在本发明所要求保护的范围之内。
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