CN112870206B - 甘露糖在制备预防脑型疟疾药物中的应用 - Google Patents
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Abstract
本发明公开了甘露糖在制备预防脑型疟疾药物中的应用。本发明主要考察了甘露糖在预防患疟小鼠发生脑型疟疾中的作用,重点是解决如何预防脑型疟疾这一严重的疟疾并发症的发生,发明的难点在于寻找能够用于预防脑型疟疾的药物。本发明的创新点在于调整已知药物的用量及使用途径,用于脑型疟疾的预防。
Description
技术领域
本发明属于医药开发技术领域,特别是涉及一种甘露糖在制备预防脑型疟疾药物中的应用。
背景技术
疟疾是由疟原虫感染人体所导致的一种寄生虫病,受疟原虫感染的雌性按蚊是传播媒介。据世界卫生组织发布的《2019年世界疟疾报告》,2018年全球共发生2.28亿疟疾病例,其中40.5万人死于疟疾。我国于2010年启动消除疟疾行动计划,自2017年以来,无本地疟疾感染病例报告。2019年中国疟疾发病数为2487例,较2018年减少31例;死亡人数为19人,较2018年增加13例。2020年是我国实现消除疟疾目标年,及时发现、诊断和治疗输入性疟疾病例,是实现消除疟疾的关键。疟疾的临床表现根据疾病进程表现不一,包括发热、寒颤和头疼等较为普通的症状;随着疾病进展,可出现更为严重的症状,包括严重贫血、代谢性酸中毒相关的呼吸窘迫、多脏器功能衰竭以及脑型疟疾,这些改变统称为重症疟疾。其中,脑型疟疾是恶性疟原虫感染人类引起的一种最为严重的神经系统并发症,死亡率可达10%-20%,且多为儿童;即使患脑型疟疾的病人存活并恢复,仍有约26%的患者遗留长期的生理、神经和认知等方面的功能障碍。因此,脑型疟疾是一个亟待解决的严峻临床问题和社会问题。青蒿素为基础的联合疗法是当前最有效的抗疟疾药物,对无并发症的疟疾治疗效果较好。然而,脑型疟疾进展迅速,上述疗法并不能有效预防或延缓脑型疟疾的发生,且目前仍缺乏有效的早期诊断方法和治疗药物。可见,对脑型疟疾的有效预防才是重中之重,寻找预防疟疾严重并发症即脑型疟疾的药物就显得尤为重要。目前尚无研究报道尝试应用甘露糖治疗疟疾或预防脑型疟疾的发生。
发明内容
本发明克服了常用疟疾治疗药物在预防疟疾严重并发症—脑型疟疾发生中的技术的缺陷,提供一种应用甘露糖预防脑型疟疾发生的治疗手段。本发明的目的是解决目前尚无有效药物能够预防疟疾感染后严重并发症脑型疟疾发生的问题。
为实现上述目的,本发明公开了的技术内容如下:
甘露糖在制备预防脑型疟疾药物中的应用。其中预防脑型疟疾指的是降低脑型疟疾导致的死亡率。所述甘露糖的用量为20%甘露糖代替饮用水每日饮用+20%甘露糖200μl灌胃(隔日1次)。
本发明更加详细的说明如下:
(1)由于伦理的限制,无法在人体进行脑型疟疾研究,小鼠脑型疟疾模型是目前研究脑型疟疾唯一的体内研究模型工具。因此,我们利用人脑型疟疾动物模型—小鼠实验性脑型疟疾模型来研究甘露糖在预防脑型疟疾发病中的作用。
(2)构建小鼠脑型疟疾模型(通常在疟原虫感染后的5-9天小鼠会发生脑型疟疾并迅速死亡),从感染疟原虫当天起饮用20%甘露糖,并隔日灌胃给予20%甘露糖1次,可预防小鼠脑型疟疾的发生,而应用常规饮用水组的小鼠则在感染疟原虫后的5-9天出现神经系统症状,发生脑型疟疾而死亡。
(3)本发明所提出的甘露糖给药剂量和途径对正常未感染小鼠无明显副作用。
本发明主要考察了甘露糖在预防患疟小鼠发生脑型疟疾中的作用,重点是解决如何预防脑型疟疾这一严重疟疾并发症的发生,发明的难点在于寻找能够用于预防脑型疟疾的药物,本发明的创新点在于发现已知药物的新用途,调整已知药物的用量及使用途径,用于脑型疟疾的预防。
本发明的试验结论如下:
(1)甘露糖可预防脑型疟疾的发生。甘露糖显著抑制疟原虫感染的C57BL/6小鼠脑型疟疾的发生(Kaplan-Meier方法绘制生存曲线,Log-rank test进行统计分析,**** P <0.0001),见图1。
(2)连续应用甘露糖对正常小鼠无明显副作用,小鼠一般状况良好,未出现肝、肾功能损伤等副作用,见图2。
附图说明
图1为甘露糖预防脑型疟疾的发生情况说明;
图2为甘露糖的应用对正常小鼠无明显副作用情况说明;
A. 连续饮用20%甘露糖+20%甘露糖200μL灌胃(隔日1次)对正常小鼠的体重仅有轻微影响(双因素方差分析);B.20%甘露糖连续应用20天后正常小鼠的肝功能(谷丙转氨酶和谷草转氨酶)和肾功能(尿素氮和肌酐)未受损(单因素方差分析)。ns, P> 0.05;*,P<0.05。
具体实施方式
下面通过具体的实施方案叙述本发明。除非特别说明,本发明中所用的技术手段均为本领域技术人员所公知的方法。另外,实施方案应理解为说明性的,而非限制本发明的范围,本发明的实质和范围仅由权利要求书所限定。对于本领域技术人员而言,在不背离本发明实质和范围的前提下,对这些实施方案中的物料成分和用量进行的各种改变或改动也属于本发明的保护范围。本发明所用原料及试剂均有市售。
实施例1
甘露糖在制备预防脑型疟疾药物中的应用的实验方法及结果如下:
一、试验方法:
(1)由于伦理的限制,无法在人体内进行脑型疟疾的研究,小鼠脑型疟疾模型是目前研究脑型疟疾最常用的动物模型。因此,我们利用人脑型疟疾动物模型——小鼠实验性脑型疟疾模型来研究甘露糖在预防脑型疟疾发病中的作用。根据文献报道,采用6至8周龄雌性C57BL/6小鼠,经尾静脉注射1×104个伯氏疟原虫ANKA株感染的红细胞(体积200μl),使小鼠感染疟疾。通常感染后5至9天为脑型疟疾的发病时间,患脑型疟疾的小鼠会在出现典型脑型疟疾症状后1天内迅速死亡。由此构建小鼠的脑型疟疾模型,建模成功率可达100%。采用临床症状评分法对患疟小鼠是否发生脑型疟疾进行评估。脑型疟疾的典型症状包括毛发竖起、弓背、共济失调、偏瘫、抽搐和昏迷,出现1个症状积1分,评分≥4分即可诊断为脑型疟疾。
(2)甘露糖,即D-(+)-甘露糖(购自生工生物工程上海股份有限公司,货号A600554-0500)于饮用水中配制成20%甘露糖溶液。
(3)按照(1)所述方法构建小鼠脑型疟疾模型,随机分为实验组和对照组(N = 10-12只/组)。从感染疟原虫当天起,分别对实验组和对照组的感染小鼠经灌胃给予体积200μl的20%甘露糖溶液或等体积饮用水(隔日灌胃1次),同时将实验组小鼠饮用水更换为20%甘露糖溶液,对照组仍为常规饮用水。每日根据临床症状评分法每日对两组小鼠是否发生脑型疟疾进行评估,并记录小鼠死亡情况。
(4)评估应用20%甘露糖对正常未感染小鼠身体状况的影响。采用4至6周龄雌性BALB/C小鼠,随机分为实验组、对照组和空白对照组,每日分别对实验组和对照组小鼠经灌胃给予体积200μl的20%甘露糖溶液或等体积饮用水(隔日灌胃1次),同时将实验组小鼠饮用水更换为20%甘露糖溶液,对照组仍为常规饮用水;空白对照组常规饮水,无灌胃操作。每日称量小鼠体重;至用药第20天经眼球取血收集血清,检测肝功能和肾功能相关生化指标以评估药物副作用。
二、实验结果表明:
(1)对于C57BL/6小鼠构建的脑型疟疾模型,对照组小鼠于感染疟原虫后5-9天出现脑型疟疾症状并在1-2天内迅速死亡,死亡率达100%;而甘露糖应用组(实验组)的感染小鼠大部分均未出现脑型疟疾的症状,因脑型疟疾导致的死亡率仅为35%。两组的生存率差异具有统计学意义,说明20%甘露糖的应用可预防脑型疟疾的发生,详见图1。
(2)对正常小鼠应用上述相同剂量的甘露糖或饮用水发现,20%甘露糖的应用仅对小鼠体重有轻微影响(见图2A),小鼠的一般状况良好,可能是由于甘露糖部分影响葡萄糖能量代谢所致。为了评估长期应用大剂量甘露糖是否会产生副作用,我们检测用药20天的小鼠血清中谷丙转氨酶、谷草转氨酶、肌酐和尿素氮的水平,结果也提示,与空白对照组和饮用水组(对照组)相比,实验组小鼠长期应用甘露糖未造成肝、肾功能损伤(见图2B)。
在详细说明的较佳实施例之后,熟悉该项技术人士可清楚地了解,在不脱离上述申请专利范围与精神下可进行各种变化与修改,凡依据本发明的技术实质对以上实施例所作任何简单修改、等同变化与修饰,均属于本发明技术方案的范围。且本发明亦不受说明书中所举实例实施方式的限制。
Claims (2)
1.甘露糖在制备预防脑型疟疾药物中的应用。
2.权利要求1所述的应用,其中预防脑型疟疾指的是降低脑型疟疾导致的死亡率。
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WO2015146849A1 (ja) * | 2014-03-25 | 2015-10-01 | 国立大学法人香川大学 | 希少糖を有効成分とするマラリア伝播阻止剤およびマラリア原虫の発育阻害剤 |
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DE102006035618A1 (de) * | 2006-07-31 | 2008-02-07 | Curevac Gmbh | Nukleinsäure der Formel (I): GlXmGn, insbesondere als immunstimulierendes Adjuvanz |
WO2015146849A1 (ja) * | 2014-03-25 | 2015-10-01 | 国立大学法人香川大学 | 希少糖を有効成分とするマラリア伝播阻止剤およびマラリア原虫の発育阻害剤 |
WO2016123530A1 (en) * | 2015-01-30 | 2016-08-04 | The Regents Of The University Of Michigan | Compositions and methods for delivering pharmaceutical agents |
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