CN104546815B - 丁酸钠在制备预防噪声性听力损伤的药物中的应用 - Google Patents
丁酸钠在制备预防噪声性听力损伤的药物中的应用 Download PDFInfo
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- CN104546815B CN104546815B CN201410833757.9A CN201410833757A CN104546815B CN 104546815 B CN104546815 B CN 104546815B CN 201410833757 A CN201410833757 A CN 201410833757A CN 104546815 B CN104546815 B CN 104546815B
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Abstract
本发明提供一种丁酸钠的预防噪声性听力损伤的应用，属于生物医药技术领域。本发明经过对小鼠模型进行噪声性听力损伤的实验测试，发现丁酸钠能够降低噪声暴露后听觉脑干诱发电位阈移，并提高噪声暴露后耳蜗毛细胞存活率，对多个频率的噪声都具有很好的预防噪声性听力损伤的效果，尤其对噪声性耳聋、炮震性耳聋等疾病具有良好的预防作用，能够用于制备预防噪声性听力损伤的药物和/或保健品，具有良好的研究和应用前景，可填补目前预防噪声性耳聋药物的空白。
Description
技术领域
本发明属于生物医药技术领域，涉及丁酸钠的新用途，具体涉及丁酸钠在预防噪声性听力损伤中的应用。
背景技术
噪声性听力损伤是指长时间暴露在高强度噪声环境中引起的进行性感音神经性耳聋。噪声性耳聋是一种累积性疾病，一般经历听觉适应，听觉疲劳，早期噪声性耳聋和噪声性耳聋等4个阶段。早期临床表现为4KHz听阈提高，如继续发展可出现高频听力损失，并逐渐向低频段发展，出现500Hz到8KHz的听力普遍下降，伴持续性高调耳鸣。
噪声性耳聋的预防方法有两种，一是避免噪声接触，二是佩戴噪声防护耳罩或耳塞。然而，噪声防护设备只能减少30％的噪声损伤，而且对低频噪声的防护较差，在某些作业环境中噪声防护设备的使用受到限制。目前没有可预防噪声性耳聋的药物。
噪声性耳聋的治疗药物可分为四类。第一类为抗氧化剂类，包括α-硫辛酸、谷胱甘肽、N-乙酰半胱氨酸等；第二类为神经营养剂类，包括水溶性辅酶Q10、红细胞生成素、三磷酸腺苷等；第三类为改善内耳微循环类，包括阿魏酸、丁咯地尔、山莨菪碱等；第四类为Ca2+拮抗剂，包括地佐环平、尼莫地平等。然而，一般噪声性耳聋是不可逆损伤，药物治疗只能促进暂时性听阈提高的恢复，对永久性听力提高没有治疗作用。
综上所述，目前噪声性耳聋的预防措施主要是避免接触噪声，使用噪声防 护设备有部分预防作用，但实际使用效果不佳。药物对噪声性听力损伤的治疗效果有限。噪声性耳聋的防治要点是预防。然而，噪声性耳聋的有效预防药物仍是尚待解决的问题。
丁酸钠(Sodium butyrate)又称丁酸钠盐、正丁酸钠等，分子式C4H7NaO2，是一种短链脂肪酸盐。迄今为止，丁酸钠已经有多种生物活性被相继报道。
丁酸钠具有亲水性和亲脂性，能透过细胞膜抑制有害菌生长，促进肠道内有益菌生长，调整胃肠道微生态平衡，可以治疗水土不服引起的腹泻；丁酸钠为肠道细胞提供快速能量来源；丁酸钠具有抑制组蛋白去乙酰化酶的功能；丁酸钠预处理可以对抗心急缺血/在灌注引起的炎症；丁酸钠可以抑制皮肤肿瘤细胞增殖；丁酸钠可以减轻毒毛旋花子甙和脑缺血引起的脑神经细胞损伤，预防肺炎球菌脑炎引起的记忆障碍。
然而，迄今还未见丁酸钠预防噪声性听力损伤方面活性的报道，也未见丁酸钠预防噪声性耳聋的相关报道。
发明内容
本发明的目的在于提供丁酸钠的预防噪声性听力损伤的应用，丁酸钠能够显著预防噪声性听力损伤，能够用于制备预防噪声性听力损伤的药物和/或保健品。
为达到上述目的，本发明采用的技术方案为：
丁酸钠在制备预防噪声性听力损伤的药物和/或保健品中的应用。
所述的预防噪声性听力损伤的药物和/或保健品为预防噪声性耳聋的药物和/或保健品。
所述的预防噪声性听力损伤的药物和/或保健品为预防炮震性耳聋的药物和 /或保健品。
所述的预防噪声性听力损伤的药物和/或保健品为预防噪声频率为2～50kHz、噪声强度为100～120dB的广谱噪声对听力损伤的药物和/或保健品。
所述的预防噪声性听力损伤的药物和/或保健品为降低噪声暴露后听觉脑干诱发电位阈移的药物和/或保健品。
所述的预防噪声性听力损伤的药物和/或保健品为提高噪声暴露后耳蜗毛细胞存活率的药物和/或保健品。
所述的预防噪声性听力损伤的药物为由丁酸钠和药用辅料制成的药物制剂。
所述的药物制剂的剂型为胶囊剂、片剂、丸剂、颗粒剂或口服液体制剂。
所述的药用辅料为填充剂、崩解剂、粘合剂、润滑剂、矫味剂中的一种或几种。
所述的填充剂为乳糖、微晶纤维素、预胶化淀粉、淀粉、糊精、甘露醇、纤维素、蔗糖、葡萄糖、山梨醇、木糖醇中的一种或几种；
所述的崩解剂为交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联羟丙基甲基纤维素中的一种或几种；
所述的粘合剂为聚维酮、羟丙基纤维素、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、乙基纤维素中的一种或几种；
所述的润滑剂为微粉硅胶、硬脂酸镁、硬脂酸锌、硬脂酸钙、硬脂酸、氢化植物油、棕榈酸、滑石粉、聚乙二醇、十二烷基硫酸钠、十二烷基硫酸镁中的一种或几种；
所述的矫味剂为蔗糖、单糖浆、甘油、山梨醇、甘露醇、甜菊甙、糖精钠 中的一种或几种。
相对于现有技术，本发明的有益效果为：
本发明经过对小鼠模型进行噪声性听力损伤的实验测试，发现丁酸钠具有很好的预防噪声性听力损伤的效果，能够用于制备预防噪声性听力损伤的药物和/或保健品，具有良好的研究和应用前景，可填补目前预防噪声性耳聋药物的空白。
进一步的，本发明通过实验研究，发现丁酸钠能够显著预防噪声频率为2～50kHz、噪声强度为100～120dB的广谱噪声对听力造成的损伤，能够降低噪声暴露后听觉脑干诱发电位阈移，并提高噪声暴露后耳蜗毛细胞存活率。表明丁酸钠具有很好的预防噪声性耳聋及炮震性耳聋等疾病的作用。
具体实施方式
本发明提供了一种丁酸钠(其结构式如式(1)所示)的新用途，即丁酸钠在预防噪声性听力损伤中的用途，其中所述的噪声性听力损伤包括噪声性耳聋和炮震性耳聋。
本发明所述的丁酸钠为市场采购获得，购自美国化学文摘服务社(Chemical Abstracts Service,CAS)识别码为CAS NO.：156-54-7。
本发明所述的丁酸钠在预防噪声性听力损伤时，可以和药学上可接受的辅料混合，按照常规的药物制剂工艺，制备成任何一种适合临床上使用的药物制剂，例如胶囊剂、片剂、丸剂、颗粒剂、口服液体制剂等。
其中药学上可接受的辅料包括药学上可接受的填充剂、崩解剂、粘合剂和 润滑剂、矫味剂等。合适的填充剂如乳糖、微晶纤维素、预胶化淀粉、淀粉、糊精、甘露醇、纤维素、蔗糖、葡萄糖、山梨醇、木糖醇等。合适的崩解剂如交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联羟丙基甲基纤维素等。合适的粘合剂如聚维酮、羟丙基纤维素、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、乙基纤维素等。合适的润滑剂如微粉硅胶、硬脂酸镁、硬脂酸锌、硬脂酸钙、硬脂酸、精制氢化植物油、棕榈酸、滑石粉、聚乙二醇、十二烷基硫酸钠、十二烷基硫酸镁等。合适的矫味剂如蔗糖、单糖浆、甘油、山梨醇、甘露醇、甜菊甙、糖精钠等。
本发明通过CBA/J小鼠噪声性耳聋模型，评价丁酸钠对噪声性听力损伤程度的影响，实验结果发现，丁酸钠可以有效减轻多个频率的听力损伤。
动物实验结果显示：丁酸钠能够显著预防噪声频率为2～50kHz、噪声强度为100～120dB的广谱噪声对听力的损伤，能够降低噪声暴露后听觉脑干诱发电位阈移，并提高噪声暴露后耳蜗毛细胞存活率，表明丁酸钠具有很好的预防噪声性耳聋及炮震性耳聋等疾病的作用。
下面对本发明的实验过程及实验结果进行详细说明，从而详细阐述丁酸钠对噪声性听力损伤的预防作用。
1.材料
1.1试剂
丁酸钠，购自美国Sigma#B5887
1.2动物
清洁级雄性CBA/J小鼠，12周龄，20-25g，第四军医大学动物中心
1.3仪器
SS-1型声刺激器，2*50W功率放大器，AZ8928型噪声分析仪(中国杭州爱华仪器有限公司)，荧光显微镜(日本olymplus)，脑干听觉诱发电位检测仪(美国TDT公司)。
1.4组别及药物剂量设置
模型组 NaCl(0.9％)
丁酸钠组 1.2g/kg·d 100mg/ml
1.5药物配制及给药途径
药物以NaCl(0.9％)溶解，腹腔注射，1.2g/kg。
2.方法
2.1造模方法
丁酸钠组小鼠腹腔注射丁酸钠1.2g/kg，每天1次，共3天。模型组腹腔注射同等容积的NaCl(0.9％)。每只小鼠单独放在9cm×9cm×9cm金属网状笼子内，之后放置在隔音通风的噪声暴露柜内，噪声频率为2-50kHz广谱噪声，噪声强度为106dB，噪声暴露2小时。噪声暴露后丁酸钠组小鼠腹腔注射丁酸钠1.2g/kg，每天1次，共7天。模型组腹腔注射同等容积的NaCl(0.9％)。
2.2观察指标
2.2.1听觉脑干诱发电位阈移
噪声暴露后2周，小鼠腹腔注射氯胺酮(10mg/kg)和甲苯噻嗪(10mg/kg)混合液麻醉后行听觉脑干诱发电位检测，检测值与小鼠实验前的检测的基础听觉脑干诱发电位值相减，得到噪声暴露后听觉脑干诱发电位阈移，即听力损伤的值。
2.2.2耳蜗毛细胞计数
噪声暴露后2周，小鼠行听觉脑干诱发电位检测后断头处死，取耳蜗4％多聚甲醛固定24小时，8％乙二胺四乙酸脱钙48小时后行基底膜铺片，异硫氰酸荧光素-鬼笔环肽染色后行耳蜗毛细胞计数。
2.2.3统计学处理
数据用表示，以SPSS11.0进行统计学处理，各组间两两比较用最小显著差异法。
3.实验结果
表1.丁酸钠对噪声暴露后小鼠听觉脑干诱发电位阈移的影响n＝10
| 4KHz | 8KHz | 12KHz | 24KHz | 32KHz | 48KHz | |
| 模型组 | 23.6±5.0 | 26.8±6.5 | 37.7±6.6 | 40.7±7.3 | 46.3±6.3 | 50.7±6.4 |
| 丁酸钠组 | 13.4±4.1* | 17.2±5.1* | 18.6±5.2** | 31.8±6.5* | 27.5±7.1** | 34.7±5.2** |
注：与模型组比较，*p<0.05，**p<0.01。
表2.丁酸钠对噪声暴露后小鼠耳蜗毛细胞存活率的影响n＝10
| 内毛细胞 | 外毛细胞 | |
| 模型组 | 89.6±5.3 | 81.3±6.2 |
| 丁酸钠组 | 98.2±6.1* | 96.7±7.6** |
注：与模型组比较，*p<0.05，**p<0.01。
4.结论
经过上述实验发现，具有很好的预防噪声性听力损伤的效果，能够在噪声环境下保护耳蜗毛细胞，对噪声性耳聋动物模型有很好的预防作用，说明丁酸钠具有预防噪声性耳聋的作用。
Claims (8)
1.丁酸钠在制备预防噪声性听力损伤的药物中的应用，其中所述的预防噪声性听力损伤的药物为预防噪声性耳聋或炮震性耳聋的药物。
2.如权利要求1所述的应用，其特征在于：所述的预防噪声性听力损伤的药物为预防噪声频率为2～50kHz、噪声强度为100～120dB的广谱噪声对听力损伤的药物。
3.如权利要求1所述的应用，其特征在于：所述的预防噪声性听力损伤的药物为降低噪声暴露后听觉脑干诱发电位阈移的药物。
4.如权利要求1所述的应用，其特征在于：所述的预防噪声性听力损伤的药物为提高噪声暴露后耳蜗毛细胞存活率的药物。
5.如权利要求1所述的应用，其特征在于：所述的预防噪声性听力损伤的药物为由丁酸钠和药用辅料制成的药物制剂。
6.如权利要求5所述的应用，其特征在于：所述的药物制剂的剂型为胶囊剂、片剂、丸剂、颗粒剂或口服液体制剂。
7.如权利要求5所述的应用，其特征在于：所述的药用辅料为填充剂、崩解剂、粘合剂、润滑剂、矫味剂中的一种或几种。
8.如权利要求7所述的应用，其特征在于：所述的填充剂为乳糖、微晶纤维素、淀粉、糊精、甘露醇、纤维素、蔗糖、葡萄糖、山梨醇、木糖醇中的一种或几种；
所述的崩解剂为交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联羟丙基甲基纤维素中的一种或几种；
所述的粘合剂为聚维酮、羟丙基纤维素、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、乙基纤维素中的一种或几种；
所述的润滑剂为微粉硅胶、硬脂酸镁、硬脂酸锌、硬脂酸钙、硬脂酸、氢化植物油、棕榈酸、滑石粉、聚乙二醇、十二烷基硫酸钠、十二烷基硫酸镁中的一种或几种；
所述的矫味剂为蔗糖、单糖浆、甘油、山梨醇、甘露醇、甜菊甙、糖精钠中的一种或几种。
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