CN116509882A - 芦丁钠在噪声性听力损失防治中的应用 - Google Patents
芦丁钠在噪声性听力损失防治中的应用 Download PDFInfo
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- sodium
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
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- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于听力损失防治领域,提供了芦丁钠在噪声性听力损失防治中的应用。所述芦丁钠为芦丁的C7‑OH被碱金属元素钠取代得到的盐。本发明利用易于透过血脑屏障/血迷路屏障的芦丁钠,克服了药物难以进入内耳的难题。并通过对噪声性听力损失模型动物干预,验证了芦丁钠具有明显改善噪声性听力损失模型听力阈移的作用。这表明芦丁钠对噪声性听力损失具有明显的防治作用。
Description
技术领域
本发明属于听力损失防治领域,具体地,涉及芦丁钠的新用途,更具体地,涉及芦丁钠在噪声性听力损失防治中的应用。
背景技术
噪声性听力损失是由于过度地暴露于噪声环境中,以内耳毛细胞损伤为主要特征的听觉系统进行性听力下降,已成为当前职业性残疾中的主要致残因素之一。例如军事、采矿和制造业等职业性噪声暴露已成为全球重要公共卫生问题。据世界卫生组织报道,全球范围内超过10亿12-35岁人群因暴露于各类型噪声面临听力损失风险,且这一数量仍在不断增长。这将严重影响相关人群的生活质量和身心健康。然而目前除了隔绝噪声环境外,临床上还没有一款真正意义上的治疗药物,因此加强噪声的医学防治具有重要意义。
噪声对内耳的损伤机制复杂多样,其中最主要的是毛细胞的损伤,同时也常常伴随螺旋神经节神经元退化和侧壁萎缩。噪声暴露后即刻可在内耳检测到大量活性氧产生,而大量研究都证实了毛细胞内产生的大量活性氧是耳蜗损伤的关键因素。噪声诱导内耳细胞产生细胞因子和趋化因子,引导免疫细胞定向迁移到损伤位置修复或清除受损细胞,同时噪声导致侧壁血迷路通透性增加,单核细胞等免疫细胞浸润引起过度免疫反应。氧化应激和免疫反应又可相互作用,进一步加重了听力损失。
由于噪声引起内耳氧化应激、炎症反应和血管通透性等变化,实验研究中一般针对此进行相应治疗。N-乙酰-L-半胱氨酸、蛋氨酸、依布硒啉等可作为活性氧清除剂,有助于减少耳蜗活性氧暴露从而对噪声性听力损失发挥防护作用;人参皂苷、燕麦提取物AVN、迷迭香提取物、白藜芦醇和甘露醇等作为植物提取物类抗氧化剂,均能降低内耳氧化应激水平,防治作用明显;皮质类固醇、氢气等通过其抗炎作用,调节耳蜗炎性细胞,减少噪声造成的耳蜗创伤;盐酸山莨菪碱、烟酸、丹参、银杏叶、丹参和葛根素等能够抑制血小板聚集,调节微血管,可有效地增加内耳微环境的氧供应,进而起到防治噪声性听力损伤的作用。虽然很多研究都报道对听力损失有明显的防治作用,但是因为内耳血迷路的存在限制了很多药物进入内耳并形成有效的治疗浓度。
芦丁是从槐花米、荞麦花、芸香叶、橙皮等植物中提取的一种天然黄酮苷,具有抗炎、抗氧化、降低血管通透性等作用。而芦丁钠作为芦丁的一种衍生盐类,研究发现其可以穿越类似于血迷路的血脑屏障,因而推测其易于进入内耳并形成有效的治疗浓度。目前关于芦丁钠的研究有两类:(1)芦丁钠可通过增强肝细胞中的自噬活性加快新陈代谢和延长寿命。(2)芦丁钠可增强小胶质细胞吞噬相关受体的表达和再循环,促进小胶质细胞募集到斑块并增强Aβ吞噬作用,进而逆转了阿尔兹海默症小鼠的学习和记忆缺陷。现有技术中,关于芦丁钠防治噪声性听力损失的作用,目前还未见报道。
发明内容
本发明的目的是针对现有技术中的不足,提供芦丁钠在防治噪声性听力损失中的应用,其原因是芦丁钠可发挥良好的降低氧化应激、抑制炎症和降低血管通透性等作用,进而有效改善噪声暴露所致的毛细胞存活,防止或减轻听力损失。
本发明提供一种芦丁钠在制备噪声性听力损失防治产品中的应用,所述芦丁钠为芦丁的C7-OH被碱金属元素钠取代得到的盐,化学结构式如下所示:
根据本发明,所述噪声性听力损失是指由于超过限制的噪声暴露而引起的以听力下降为主要表现的感音神经性听觉损伤。
进一步地,所述噪声性听力损失为由于超过限制的噪声暴露所致暂时性听阈位移和/或永久性听阈位移为主要表现的听力损失。
根据本发明,优选地,所述芦丁钠作为所述防治产品的唯一活性成分。所述防治产品的形式可以为药物、试剂、食品和保健品中的一种或多种。
进一步地,所述芦丁钠可以单独使用或者与其他许多化学物质组合以药物组合物的形式使用,无论这些化学物质是否具有生物活性或治疗疾病的功能,包括辅助功能如协同放大作用、拮抗或缓解芦丁钠的副作用等,这些化学物质可以为包括药学上可接受的载体、食品、天然产物、化学合成药物或人类用药等中的一种或多种;优选包括药学上可接受的载体或者食品等中的一种或多种;进一步优选药学上可接受的载体。
根据本发明一种优选实施方式,所述产品为药物组合物,所述药物组合物包含治疗有效量的芦丁钠、其药学上可接受的盐或它的前药,以及药学上可接受的载体。
本发明所用术语“可接受的”,指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。
本发明所用术语“药学上可接受”这里指一种物质,如载体或稀释液,不会使化合物的生物活性或性质消失,且相对无毒,如,给予个体某物质,不会引起不想要的生物影响或以有害的方式与任何其含有的组分互相作用。所述药学上可接受的载体可选自粘合剂、崩解剂、表面活性剂、吸收促进剂、润湿剂、乳化剂、吸附剂、润滑剂、起泡剂、填充剂、增量剂、稀释剂、赋形剂、防腐剂、着色剂、抗氧化剂和保护剂中的至少一种。更具体地,药学上可接受的载体的例子包括水、盐水、磷酸缓冲盐水、葡萄糖、甘油和乙醇中的一种或多种。在许多情况下,在该组合物中最好包括等渗剂,例如,糖、诸如甘露醇、山梨醇、山梨醇的多元醇和氯化钠等中的一种或多种。
进一步地,所述药物组合物的剂型可以为片剂、颗粒剂、硬胶囊、软胶囊、液体型胶囊、滴丸或口服液体制剂。
本发明所用术语“防治”,包括预防、缓和、抑制或改善疾病的症状或状况;抑制并发症的产生;抑制疾病或症状的产生,如控制疾病或情况的发展;减轻疾病或症状;使疾病或症状减退;减轻由疾病或症状引起的并发症,或预防或治疗由疾病或症状引起的征兆。如本文所用,某一化合物或药物组合物,给药后,可以使某一疾病、症状或情况得到改善,尤指其严重度得到改善,延迟发病,减缓病情进展,或减少病情持续时间。无论固定给药或临时给药、持续给药或断续给药,可以归因于或与给药有关的情况。
本发明的有益效果在于:
内耳存在限制药物进入的最大障碍是血迷路屏障,本发明选用的药物芦丁钠,易于穿越内耳血迷路屏障。经芦丁钠对噪声暴露大鼠听力损失的防治作用药理学实验表明,芦丁钠能显著预防、治疗和延缓噪声暴露所致的听力下降,表明其具有防治噪声性听力损失的作用,因此可作为防治噪声性听力损失的药物。本发明不仅提供了芦丁钠新的治疗用途,也为防治噪声性听力损失提供了新的药物。
本发明的其它特征和优点将在随后具体实施方式部分予以详细说明。
附图说明
通过结合附图对本发明示例性实施方式进行更详细的描述,本发明的上述以及其它目的、特征和优势将变得更加明显。
图1所示为噪声暴露后第1天和第14天各组在不同声刺激下的听力阈值。
具体实施方式
下面将更详细地描述本发明的优选实施方式。虽然以下描述了本发明的优选实施方式,然而应该理解,可以以各种形式实现本发明而不应被这里阐述的实施方式所限制。
以下实施例中所使用的芦丁为黄色粉末,HPLC纯度≥98%,以下发明过程仅简述在本发明中具有显著意义的实验内容。
实施例:
芦丁钠对噪声性听力损失的防治作用
(一)动物分组及处理
健康成年雄性Wistar大鼠,体质量250-300g,从维通利华购买,饲养于军事科学院军事医学研究院环境医学与作业医学研究所实验动物中心。动物于实验前适应性饲养3天,随机分为3组,其中:实验对照组,共6只Wistar大鼠,给予0.1M NaOH水溶液(1M HCl调pH=9.0)灌胃。噪声组,共6只Wistar大鼠,给予0.1M NaOH水溶液(1M HCl调pH=9.0)灌胃。给药组,共6只Wistar大鼠,给予芦丁钠200mg/kg/日。所述芦丁钠的制备包括:将芦丁溶于0.1MNaOH水溶液中,1M HCl调pH=9.0,配制成20mg/mL溶液,灌胃法给药。暴露前3天开始给药直至暴露后第7天结束给药,共计连续给药11天。
(二)实验动物噪声暴露
将噪声组和给药组所有受试大鼠置于铁丝笼中,置于声混响室地面,上方悬挂扬声器(Faital Pro,HF14AT,意大利)。由声音发生器(SKC,GZ009,中国)产生的110dB SPL宽频带噪声(2k-12kHz),经功率放大器(IBO,MX3600,中国)连接于扬声器。在大鼠耳朵等高位置用声级计(BSWA,308,中国)从不同方向校准声强。平均噪声暴露水平为110±1dB SPL,连续暴露4小时。
(三)听阈检测
噪声暴露后第1天、14天分别测量听力阈值变化情况。测量方法:将记录电极插入颅顶正中位置,参考电极置于同侧耳乳突位置,地线电极插于同侧后肢皮下,然后置于电屏蔽箱中。应用TDT RZ6测试系统,在click、4kHz、8kHz、16kHz、32kHz不同声刺激下记录ABR阈值。
(四)统计学处理
数据采用均值±标准差表示,使用GraphPad Prism 9.0.0版本对结果进行统计学分析,以P<0.05为有统计学意义差异。
(五)实验结果
噪声暴露后第1天和第14天各组在不同声刺激下的听力阈值如表1和图1所示。
表1.暴露后第1天和第14天各组不同声刺激的听力阈值
注:表1中,Control为实验对照组,Noise为噪声组,NaR为芦丁钠给药组,D1和D14表示噪声暴露后第1天和第14天;#:与Control相比,P<0.05;*:与Noise D1相比,P<0.05;&:与Noise D14相比。
如表1和图1所示:与Control相比,Noise D1和NaR D1不同声刺激的听力阈值均显著升高,说明噪声诱导的听力损失具有一致性;而与Noise D1相比,NaR D1组不同声刺激的听力阈值均显著降低。
Noise D14所有声刺激的听力阈值仍显著高于Control;NaR D14在声刺激为4kHz时的听力阈值已恢复到Control水平。NaR D14在4kHz、8kHz、16kHz声刺激时的听力阈值与Noise D14相比显著下降;而click和32kHz声刺激的听力阈值恢复较慢,但下降程度仍≥5dB。
以上结果表明芦丁钠对噪声诱导的听力阈移具有良好的防治作用。
(六)实验结论
芦丁钠能防治由于超过限值的噪声暴露而引起的以听力下降为主要表现的感音神经性听觉损伤,具有防治噪声性听力损失的作用。
本发明利用易于透过血脑屏障/血迷路屏障的芦丁钠,克服了药物难以进入内耳的难题。并通过对噪声性听力损失模型动物干预,验证了芦丁钠具有明显改善噪声性听力损失模型听力阈移的作用。这表明芦丁钠对噪声性听力损失具有明显的防治作用。
以上已经描述了本发明的各实施例,上述说明是示例性的,并非穷尽性的,并且也不限于所披露的各实施例。在不偏离所说明的各实施例的范围和精神的情况下,对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。
Claims (8)
1.芦丁钠在制备噪声性听力损失防治产品中的应用,所述芦丁钠为芦丁的C7-OH被碱金属元素钠取代得到的盐,化学结构式如下所示:
2.根据权利要求1所述的应用,其特征在于,所述噪声性听力损失为由于超过限制的噪声暴露而引起的以听力下降为主要表现的感音神经性听觉损伤。
3.根据权利要求1所述的应用,其特征在于,所述噪声性听力损失为由于超过限制的噪声暴露所致暂时性听阈位移和/或永久性听阈位移为主要表现的听力损失。
4.根据权利要求1-3中任意一项所述的应用,其特征在于,所述芦丁钠作为所述防治产品的唯一活性成分。
5.根据权利要求1-3中任意一项所述的应用,其特征在于,所述防治产品为药物、试剂、食品和保健品中的一种或多种。
6.根据权利要求5所述的应用,其特征在于,所述产品为药物组合物,所述药物组合物包含治疗有效量的芦丁钠、其药学上可接受的盐或它的前药,以及药学上可接受的载体。
7.根据权利要求6所述的应用,其特征在于,所述药学上可接受的载体选自粘合剂、崩解剂、表面活性剂、吸收促进剂、润湿剂、乳化剂、吸附剂、润滑剂、起泡剂、填充剂、增量剂、稀释剂、赋形剂、防腐剂、着色剂、抗氧化剂和保护剂中的至少一种。
8.根据权利要求6所述的应用,其特征在于,所述药物组合物的剂型为片剂、颗粒剂、硬胶囊、软胶囊、液体型胶囊、滴丸或口服液体制剂。
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