CN106109977A - 治疗肝阳上亢型突发性耳聋的中药制剂 - Google Patents
治疗肝阳上亢型突发性耳聋的中药制剂 Download PDFInfo
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Abstract
本发明提供了一种治疗肝阳上亢型突发性耳聋的中药制剂,其原料药包括柴胡、酒黄芩、生栀子、龙胆草、石菖蒲、天麻、钩藤、木通、车前子、生地黄、当归、葛根、磁石、龙齿、琥珀、远志、酸枣仁、僵蚕、全蝎、地龙和蜈蚣。其能够减少听力损伤程度,使听力恢复正常的时间缩短,达到较好的治疗目的,综合疗效评价,优于使用西药,通过一定的实验室研究及安全性评估后,适用于临床推广应用。
Description
技术领域
本发明涉及中医药技术领域,尤其涉及一种治疗肝阳上亢型突发性耳聋的中药制剂。
背景技术
突发性耳聋是指突然发生的、原因不明的感音神经性听力损失。临床特点:听力一般在数分钟或数小时,少数可在72小时以内,下降至最低点;可伴有耳鸣及眩晕;除第VIII颅神经外,无其他颅神经症状。据文献报导每年发病率在5~10万人,多见于成人。突发性耳聋发病无明显性别差异,无地域或流行群集现象。突发性耳聋是耳鼻喉科常见病、多发病之一,同时也是一种急性耳病。
随着现代生活节奏的加快,各种社会压力的加大,导致突发性耳聋的发病趋势逐渐升高,患者发病多与不良情绪刺激有关,突聋患者心理异常发生率较高。在现代著作与资料中,对于突发性耳聋的病因病机主要与肝胆功能失调密切相关。肝胆功能失调是突发性耳聋的主要致病因素,肝为将军之官,主升发疏泄,喜条达,而恶抑郁,若暴怒伤肝,肝气郁结而上逆,阻塞清窍,或情志抑郁,郁而化火,肝火循经上扰耳窍,故出现耳聋、耳鸣、眩晕等症状。肝胆功能失调对耳窍的影响虽然是多方面、多环节、多途径的,但其基本病理变化是肝火上扰,瘀阻清窍,耳窍失养。其引起突发性耳聋的现代病理机制可能是由于患者情绪突然变化,引起神经体液调节的改变,血流变指数增高,儿茶酚胺水平升高,使红细胞聚集能力增强,血液粘稠度增加,血液瘀滞,促进血栓形成和内耳微循环障碍,导致内耳供血不足,引起组织水肿,缺氧及代谢紊乱,使内耳末稍感受器受损,从而导致突发性耳聋的发生。
中医对其病因病机有较好的认识,因此,按照相应的理法方药组方用药,对证治疗,有很好的治疗作用,清肝泻火、理气通窍,用药及时能够减少听力损伤程度,使听力恢复正常的时间缩短,达到较好的治疗目的。
发明内容
本发明所要解决的技术问题是提供了一种治疗肝阳上亢型突发性耳聋的中药制剂,中医对其病因病机有较好的认识,因此,按照相应的理法方药组方用药,对证治疗,有很好的治疗作用,清肝泻火、理气通窍,用药及时能够减少听力损伤程度,使听力恢复正常的时间缩短,达到较好的治疗目的,综合疗效评价,优于使用西药,通过一定的实验室研究及安全性评估后,适用于临床推广应用。
为解决上述技术问题,本发明提供了一种治疗肝阳上亢型突发性耳聋的中药制剂,其原料药包括柴胡、酒黄芩、生栀子、龙胆草、石菖蒲、天麻、钩藤、车前子、生地黄、当归、葛根、磁石、龙齿、琥珀、远志、酸枣仁、僵蚕、全蝎、地龙和蜈蚣。
其中,所述中药制剂中龙胆草和蜈蚣重量比例为2∶1。
其中,所述中药制剂中蜈蚣的重量不超过12g。
其中,所述中药制剂中各原料药的重量分别为柴胡14g~16g、酒黄芩11g~13g、生栀子11g~13g、龙胆草12g~24g、石菖蒲14g~16g、天麻14g~16g、钩藤14g~16g、车前子14g~16g、生地黄29g~31g、当归19g~21g、葛根29g~31g、磁石29g~31g、龙齿29g~31g、琥珀29g~31g、远志9g~11g、酸枣仁29g~31g、僵蚕14g~16g、全蝎9g~11g、地龙8g~10g和蜈蚣6g~12g。
其中,所述中药制剂中各原料药的重量分别为柴胡15g、酒黄芩12g、生栀子12g、龙胆草20g、石菖蒲15g、天麻15g、钩藤15g、车前子15g、生地黄30g、当归20g、葛根30g、磁石30g、龙齿30g、琥珀30g、远志10g、酸枣仁30g、僵蚕15g、全蝎10g、地龙9g和蜈蚣10g。
其中,所述中药制剂是内服药剂。
其中,所述中药制剂是颗粒冲剂。
本发明提供的中药制剂制备成颗粒冲剂的方法,其包括:
第一步,按重量称取地龙,清洗,沥干,加2倍于其重量的水,在37℃搅拌匀浆,离心,取上清液进行膜滤过,浓缩,浓缩液经冷冻干燥,即得第一粉末;
第二步,按重量称取僵蚕、全蝎和蜈蚣,用相对于三者重量之和4~6倍的体积百分比浓度为70%的乙醇溶液加热回流提取两次,每次提取2小时,提取液合并后回收乙醇至无醇味,继续浓缩至60℃时测定相对密度为1.10~1.20的浸膏,得提取浸膏,得到的浸膏上D101大孔吸附树脂,用水洗脱,弃去水洗液,再用体积百分比浓度为70%的乙醇溶液洗脱,收集乙醇洗脱部分,回收乙醇,浓缩至60℃时测定相对密度为1.30~1.40的浸膏;
第三步,取余下原料药组分,混合在一起,加相对于混合物质量3~5倍的水,煎煮2小时,煎煮液过滤,滤渣再次加相对于混合物质量3~5倍的水,煎煮2小时,煎煮液过滤,两次过滤后的煎煮液合并,浓缩至60℃时测定相对密度为1.30~1.40的浸膏;
第四步,将第一步获得的粉末、第二步获得的浸膏以及第三步获得的浸膏混合,将获得的混合物与糊精按质量比4∶1比例混合均匀后,于75℃减压干燥,粉碎,随后加入淀粉混匀,淀粉使用质量与混合糊精后的物质质量相同,用12~14%的水制颗粒,60℃干燥,分装,每袋5g。
有益的技术效果
本发明提供的用于治疗肝阳上亢型突发性耳聋的中药制剂,能够减少听力损伤程度,使听力恢复正常的时间缩短,达到较好的治疗目的,综合疗效评价,优于使用西药,通过一定的实验室研究及安全性评估后,适用于临床推广应用。
具体实施方式
现代医学研究发现,对于突发性耳聋的病因病机主要与肝胆功能失调密切相关。肝胆功能失调是突发性耳聋的主要致病因素,肝为将军之官,主升发疏泄,喜条达,而恶抑郁,若暴怒伤肝,肝气郁结而上逆,阻塞清窍,或情志抑郁,郁而化火,肝火循经上扰耳窍,故出现耳聋、耳鸣、眩晕等症状。肝胆功能失调对耳窍的影响虽然是多方面、多环节、多途径的,但其基本病理变化是肝火上扰,瘀阻清窍,耳窍失养,治疗当以清泻肝火、化瘀通窍。
基于该治疗原则,本发明提供了一种治疗肝阳上亢型突发性耳聋的中药制剂,其原料药包括柴胡、酒黄芩、生栀子、龙胆草、石菖蒲、天麻、钩藤、车前子、生地黄、当归、葛根、磁石、龙齿、琥珀、远志、酸枣仁、僵蚕、全蝎、地龙和蜈蚣。
本发明中药制剂以龙胆草、蜈蚣为君药组,其中龙胆草与蜈蚣的比例在2∶1左右,其效果最佳,若龙胆草用量不足,则清肝泻火力度不够,难以扑灭燎原之火,肝火向上循经犯清窍,在中克罚脾土,从下影响肾膀;蜈蚣为虫类药,性走窜,通经络,但有小毒,若剂量较小,则通络通窍功效不足,若剂量增大,恐其毒性影响机体,将其最优比例控制在2∶1左右,能取全效,进一步,为控制蜈蚣的毒性不影响机体,使用量控制在12g以下,二药配伍,以求速效。本发明中药制剂使用栀子、柴胡、酒黄芩三药配合君药龙胆草清热燥湿、泻肝胆火,栀子有苦寒泻火之功,清热利湿,主治肝胆实热;柴胡苦,微寒,归肝胆经,疏肝解郁,通窍聪耳,引诸药入肝胆经,黄芩入心、肺、胆、大肠经,清热燥湿,泻火解毒,酒制后,其性走上,善于清上焦之热;使用僵蚕、全蝎、地龙三位虫类药物配合君药蜈蚣,三药均少量使用,其性善走窜,助蜈蚣化瘀通络开窍,诸药合用,助君药功效,为臣药组。
该病的发生多火热为邪,热邪伤阴耗血,本发明中药制剂加入当归养血活血,生地黄配合葛根养阴生津、清热凉血,酸枣仁配合远志养心血、安心神;本病的发生来自于肝火上炎、瘀阻清窍,故本发明中药制剂加入石菖蒲开窍聪耳,宁神益智息鸣;天麻、钩藤平肝潜阳、息风止痉,擅于清肝火,磁石、龙齿镇静安神、息鸣聪耳,琥珀与酸枣仁同用,安神定志,诸药合用,共奏平肝潜阳、安神定志之功效,为佐药。本发明中药制剂一个特色为给邪以出路,使用柴胡配合车前子,柴胡有舒肝解郁功效,同时引药入肝胆经,车前子淡渗利湿,导热下行,一内一外,一上一下,分消邪热,为使药组。方中重用活血化瘀通窍、宁神息鸣之药,加强活血化瘀的作用,改善耳蜗微循环,从而有效地缓解内耳缺血缺氧。诸药合用,共凑清肝通窍,活血化瘀,安神解郁之功,标本兼顾,使肝火平息,耳脉通利,耳窍复其清空之态。综观全方,泻中有补,利中有滋,降中有升,祛邪而不伤正,泻火而不伐胃,使火降热清,配伍严谨,为清肝通窍之良方,创立了治疗本病的新思路、新方法。
柴胡:性味苦,辛,微寒。归肝、胆经。具有解表退热,疏肝解郁,升举阳气之功效。《本草纲目》:“治阳气下陷,平肝、胆、三焦、包络相火,及头痛、眩晕,目昏、赤痛障翳,耳聋鸣,诸疟,及肥气寒热,妇人热入血室,经水不调,小儿痘疹余热,五疳赢热。”
川芎:性味辛,温。归肝、胆、心包经。具有活血行气,祛风止痛之功效。《本草汇言》:“芎,上行头目,下调经水,中开郁结,血中气药……尝为当归所使,非第治血有功,而治气亦神验也……味辛性阳,气善走窜而无阴凝粘滞之态,虽入血分,又能去一切风,调一切气。”
香附:性味辛、微苦、微甘、平。归肝、脾、三焦经。具有疏肝解郁、调经止痛、理气调中之功效。《本草求真》:“香附,专属开郁散气,与木香行气,貌同实异,木香气味苦劣,故通气甚捷,此则苦而不甚,故解郁居多,且性和于木香,故可加减出入,以为行气通剂,否则宜此而不宜彼耳。”现代药理研究发现香附水煎剂可明显增加胆汁流量,并对肝细胞功能有保护作用。
石菖蒲:性味辛、苦、温。归心、胃经。具有开窍醒神、化湿和胃、宁神益智之功效。《神农本草经》:“主风寒湿痹,咳逆上气,开心孔,补五脏,通九窍,明耳目,出音声。久服轻身,不忘,不迷惑,延年。”
龙胆草:性味苦,寒,归肝、胆经。具有清热燥湿,泻肝胆火之功效。《药品化义》:“胆草专泻肝胆之火,主治目痛颈痛,两胁疼痛,惊痫邪气,小儿疳积,凡属肝经热邪为患,用之神妙。”
天麻:天麻性味甘、平,归肝经。具有息风止痉、平抑肝阳、祛风通络之功效。《本草汇言》:“主头风,头痛,头晕虚旋,癫痫强痉,四肢孪急,语言不顺,一切中风,风痰。
钩藤:性味甘、凉,归肝、心包经。具有清热平肝,息风止痉之功效。《本草纲目》:“大人头旋目眩,平肝风,除心热,小儿内钓腹痛,发斑疹。
龙骨:性味甘、涩、平,归心、肝、肾经。具有镇静安神、平抑肝阳、收敛固涩之功效。《本草纲目》:“益肾镇静,止阴疟,收湿气,脱肛,生肌敛疮。”
牡蛎:性味成,微寒。归肝、胆、肾经。具有重镇安神、平肝潜阳、软坚散结、收敛固涩之功效。《海药本草》:“主男子遗精,虚劳乏损,补肾正气,止盗汗,去烦热,治伤寒热痰,能补养安神,治孩子惊痫。”
栀子:性味苦,寒。归心、肺、三焦经。具有泻火除烦,清热利湿,凉血解毒之功效。《神农本草经》:“主五内邪气,胃中热气,面赤酒疱齄鼻,白癞赤癞疮疡。
生地黄:性味甘、苦寒。归心、肝、肾经。具有清热凉血、养阴生津之功效。《神农本草经》:“主折跌绝筋,伤中,逐血痹,填骨髓,长肌肉,作汤除寒热积聚,除痹。生者尤良。”
葛根:性味甘、辛、凉。归脾、胃经。具有解肌退热、透疹、生津止渴、升阳止泻之功效。《名医别录》:“疗伤寒中风头痛,解肌发表,出汗,开腠理,疗金疮,止痛,胁风痛。”“生根汁,疗消渴,伤寒壮热。”
炒酸枣仁:性味甘、酸、平,归心、肝、胆经。具有养心益肝、安神、敛汗、生津之功效。《名医别录》:“主心烦不得眠,……虚汗,烦渴,补中,益肝气,坚筋骨,助阴气。”
远志:性味苦、辛、温,归心、肾、肺经。具有安神益智、祛痰开窍、消散痈肿之功效。《神农本草经》:“主咳逆伤中,补不足,除邪气,利九窍,益智慧,耳目聪明,不忘,强志,倍力。”
地龙:性味咸、寒,归肝、脾、膀胱经。具有清热息风,通络,平喘,利尿之功效。《本草纲目》:“性寒而下行,性寒故能解诸热疾,下行故能利小便,治足疾而通经络也。”“主伤寒疟疾,大热狂烦,及大人小儿小便不通,急慢惊风,历节风痛。”地龙水煎液具有良好的解热作用,地龙提取物具有抗血小板聚集和抗凝作用。
所述中药制剂中各原料药的重量分别为柴胡14g~16g、酒黄芩11g~13g、生栀子11g~13g、龙胆草12g~24g、石菖蒲14g~16g、天麻14g~16g、钩藤14g~16g、车前子14g~16g、生地黄29g~31g、当归19g~21g、葛根29g~31g、磁石29g~31g、龙齿29g~31g、琥珀29g~31g、远志9g~11g、酸枣仁29g~31g、僵蚕14g~16g、全蝎9g~11g、地龙8g~10g和蜈蚣6g~12g。
所述中药制剂中各原料药的重量分别为柴胡15g、酒黄芩12g、生栀子12g、龙胆草20g、石菖蒲15g、天麻15g、钩藤15g、车前子15g、生地黄30g、当归20g、葛根30g、磁石30g、龙齿30g、琥珀30g、远志10g、酸枣仁30g、僵蚕15g、全蝎10g、地龙9g和蜈蚣10g。
本发明提供的中药制剂是内服药剂,优选制备成颗粒冲剂。
本发明提供的颗粒剂的制备方法具体为:
第一步,按重量称取地龙,清洗,沥干,加2倍于其重量的水,在37℃搅拌匀浆,离心,取上清液进行膜滤过,浓缩,浓缩液经冷冻干燥,即得第一粉末;
第二步,按重量称取僵蚕、全蝎和蜈蚣,用相对于三者重量之和4~6倍的体积百分比浓度为70%的乙醇溶液加热回流提取两次,每次提取2小时,提取液合并后回收乙醇至无醇味,继续浓缩至60℃时测定相对密度为1.10~1.20的浸膏,得提取浸膏,得到的浸膏上D101大孔吸附树脂,用水洗脱,弃去水洗液,再用体积百分比浓度为70%的乙醇溶液洗脱,收集乙醇洗脱部分,回收乙醇,浓缩至60℃时测定相对密度为1.30~1.40的浸膏;
第三步,取余下原料药组分,混合在一起,加相对于混合物质量3~5倍的水,煎煮2小时,煎煮液过滤,滤渣再次加相对于混合物质量3~5倍的水,煎煮2小时,煎煮液过滤,两次过滤后的煎煮液合并,浓缩至60℃时测定相对密度为1.30~1.40的浸膏;
第四步,将第一步获得的粉末、第二步获得的浸膏以及第三步获得的浸膏混合,将获得的混合物与糊精按质量比4∶1比例混合均匀后,于75℃减压干燥,粉碎,随后加入淀粉混匀,淀粉使用质量与混合糊精后的物质质量相同,用12~14%的水制颗粒,60℃干燥,分装,每袋5g。
以下采用实施例来详细说明本发明的实施方式,借此对本发明如何应用技术手段来解决技术问题,并达成技术效果的实现过程能充分理解并据以实施。
实施例1颗粒剂1
称取地龙9g,清洗,沥干,加20g的水,在37℃搅拌匀浆,离心,取上清液进行膜滤过,浓缩,浓缩液经冷冻干燥,即得第一粉末,称取僵蚕15g、全蝎10g和蜈蚣10g,用1.8kg的体积百分比浓度为70%的乙醇溶液加热回流提取两次,每次提取2小时,提取液合并后回收乙醇至无醇味,继续浓缩至60℃时测定相对密度为1.20的浸膏,得提取浸膏,得到的浸膏上D101大孔吸附树脂,用2倍大孔吸附树脂体积的水洗脱,弃去水洗液,再用4倍大孔吸附树脂体积的体积百分比浓度为70%的乙醇溶液洗脱,收集乙醇洗脱部分,回收乙醇,浓缩至60℃时测定相对密度为1.50的浸膏,取柴胡15g、酒黄芩12g、生栀子12g、龙胆草20g、石菖蒲15g、天麻15g、钩藤15g、车前子15g、生地黄30g、当归20g、葛根30g、磁石30g、龙齿30g、琥珀30g、远志10g、酸枣仁30g,混合在一起,加1.3kg的水,煎煮2小时,煎煮液过滤,滤渣再次加1.3kg的水,煎煮2小时,煎煮液过滤,两次过滤后的煎煮液合并,浓缩至60℃时测定相对密度为1.50的浸膏,将获得的第一粉以及获得的浸膏混合,将获得的混合物与糊精按质量比4∶1比例混合均匀后,于75℃减压干燥,粉碎,随后加入淀粉混匀,淀粉使用质量与混合糊精后的物质质量相同,用12~14%的水制颗粒,60℃干燥,分装,每袋5g。
比较例1颗粒剂2
与实施例1制备方法相同,区别在于原料药中没有使用蜈蚣。
比较例2颗粒剂3
与实施例1制备方法相同,区别在于原料药中没有使用龙胆草。
比较例3颗粒剂4
与实施例1制备方法相同,区别在于蜈蚣的使用量是5g(龙胆草与蜈蚣用量比为4∶1)。
比较例4颗粒剂5
与实施例1制备方法相同,区别在于龙胆草的使用量为5g(龙胆草与蜈蚣用量比为1∶2)。
本发明小鼠急性毒性试验
清洁级KM小鼠,40只,雌雄各半,实验前置动物于室内适应环境一周,自由摄食、摄水,室温18~22℃,相对湿度65~70%,照明昼夜明暗交替。
采用本发明实施例1制备的颗粒剂,配置成含生药浓度为1.68g/ml的药剂,相当于生药量100.8g/kg/d,4℃保存,备用,使用时加热至36~39℃。
实验方法:按照随机数字表,将小鼠分为对照组和实验组(灌胃给药本发明实施例1制备的颗粒剂1,相当于生药量100.8g/kg/d)。灌胃给药量为0.1ml/10g体重,对照组灌胃蒸馏水0.1ml/10g体重。3次/日,连续给药14天,停药观察5天。记录小鼠体重、进食、饮水情况,记录灌胃给药后小鼠各项反应,灌胃给药间期小鼠各项生理反应,以及死亡情况。
结果与结论
通过急性毒理实验研究,观察14d小鼠灌胃给药后情况,灌胃给药给药前,各组动物体重、进食、饮水情况无统计学差异,灌胃给药给药后,各组小鼠体重变化、进食饮水情况,无统计学差异。行为学无明显异常,未出现死亡及其他毒性反应。
本实验组剂量(生药浓度100.8g/kg/d),小鼠与成人的给药剂量换算系数为10.01,因此小鼠给药剂量是临床成人用药(6.22g/kg/d)的162.22倍,现代药理学认为,对于药物急性毒性实验,最大耐受量相当于人临床日用剂量100倍以上而动物无死亡,无明显毒性反应情况出现时,该药是安全的。通过本急性毒性试验验证,无毒性反应,可以认定,本药品临床用药是安全的。
药物临床研究结果
研究对象:
选取2015年6月至2016年3月在耳鼻喉科就诊的符合入选条件的突发性耳聋患者240例(均为单耳患者),所有病人均参照2005年中华医学会耳鼻咽喉科学分会和中华耳鼻咽喉科杂志编委会济南会议标准颁布的诊断依据诊断为突发性聋,且属中医暴聋(肝火上扰型),入组病人均伴有不同程度的耳鸣。
分组方法:
所有患者依据就诊日期随机分为四组,治疗组60例,对照1组60例,对照2组60例,以及阳性对照组60例。四组患者平均年龄、性别、病程及耳聋耳鸣程度一般资料见表1、表2、表3:
表1平均年龄与发病到开始治疗的平均天数
表1可以看出,3组患者平均年龄、性别、病程时间无显著性差异(P>0.05)。
表2耳聋程度的一般情况比较
表2可以看出,3组患者耳聋程度无显著性差异(P>0.05)。
表3耳鸣程度的一般情况比较
组别 | 1级 | 2级 | 3级 | 4级 | 5级 |
对照组 | 6 | 13 | 21 | 14 | 6 |
治疗组 | 7 | 13 | 21 | 16 | 3 |
对照1组 | 5 | 15 | 17 | 19 | 4 |
对照2组 | 4 | 13 | 21 | 18 | 4 |
表3可以看出,无6级耳鸣患者,3组患者耳鸣程度无显著性差异(P>0.05)。
诊断标准
根据2005年中华医学会耳鼻咽喉科学分会和中华耳鼻咽喉科杂志编委会济南会议标准:1、突然发生的,可在数分钟、数小时或3天以内;2、非波动性感音神经性听力损失,可为轻、中或重度,甚至全聋。至少在相连的2个频率听力下降20dB以上,多为单侧,偶有双测同时或先后发生;3、病因不明(未发现明确原因包括全身或局部因素);4、伴耳鸣、耳堵塞感;5、伴眩晕、恶心、呕吐,但不反复发作;6、除第八对脑神经外,无其它脑神经受损症状。
中医辨证
参照《中医耳鼻咽喉科学》暴聋中医辨证属于肝火上扰型,见耳鸣如闻潮声或风雷声,耳聋时轻时重,多在情志抑郁或恼怒中加重。伴口苦,咽干,面红或目赤,尿黄,便秘,夜寐不宁,胸胁胀痛,舌红苔黄,脉弦数有力者。
分级标准
听力损失诊断标准:以纯音语言听阈0.25,0.5,1.0,2.0,3.0,4.0KHZ六个频率平均听力(PTA)损失计算。
轻度聋:听力损失在40db以内。
中度聋:听力损失在41-55db之间。
中重度聋:听力损失在56-70db之间。
重度聋:听力损失在71-90db之间。
极重度聋:听力损失在90db以上。
耳鸣程度分级标准:
1级耳鸣响度轻微,似有似无。
2级耳鸣响度轻微,但肯定能听到,仅在安静环境中出现,不影响正常生活如睡眠和工作
3级耳鸣较响,一般环境中均能听到,但对正常生活和工作无明显干扰。
4级任何环境下均能听见耳鸣,并且影响睡眠,注意力不集中,对工作有轻度干扰。
5级耳鸣很响有吵闹的感觉,严重影响睡眠和工作,并开始出现轻度烦躁、焦虑、抑郁等精神症状。
6级耳鸣极响,相当于患者体验过的最坏环境声,终日被耳鸣所困扰,无法睡眠,完全不能工作,并开始出现明显的烦躁、焦虑、抑郁等精神症状。
纳入标准及排除标准
纳入标准:
凡符合西医诊断标准且属中医肝火上扰型者:年龄在16-70岁之间;病程2个月以内;伴有耳鸣。
排除标准
不符合诊断标准者:伴有严重内科疾患和其他精神障碍的患者;意识不清楚,不能配合检查和治疗的突聋患者;先天性、外伤性、肿瘤、老年性、内耳免疫性疾病、感染性、传导性耳聋;发病后己使用其他中西药物者;妊娠期、哺乳期妇女或者为意向妊娠妇女;已知对本药组成成分过敏者或既往有药物过敏史者。
退出标准
依从性差,未按规定用药或擅自服用可能影响疗效的药物;资料不全,无法判定疗效者;治疗未到一疗程者。
治疗方法
设计:采用随机、双盲的临床试验方法。
用药
本发明实施例1制备的颗粒冲剂1;本发明比较例1制备的颗粒冲剂2;本发明比较例2制备的颗粒冲剂3;金纳多注射液(台湾济生化学制药厂股份有限公司);三磷酸腺苷注射液(辽宁可济药业有限公司);辅酶A注射液(上海第一生化药业有限公司)。
治疗方法
空白对照组:予0.9%氯化钠注射液250ml,金纳多注射液25ml,每日一次静点,另予0.9%氯化钠注射液250ml,ATP40mg,CoA100u,每日一次静点。14天为一疗程。
治疗组:予0.9%氯化钠注射液250ml,金纳多注射液25ml,每日一次静点,另予0.9%氯化钠注射液250ml,ATP40mg,CoA100u,每日一次静点,并配合本发明实施例1制备的颗粒冲剂1,日三次冲服,每次1袋。14天为一疗程。
对照1组:0.9%氯化钠注射液250ml,金纳多注射液25ml,每日一次静点,另予0.9%氯化钠注射液250ml,ATP40mg,CoA100u,每日一次静点,并配合本发明比较例1制备的颗粒冲剂2,日三次冲服,每次1袋。14天为一疗程。
对照2组:0.9%氯化钠注射液250ml,金纳多注射液25ml,每日一次静点,另予0.9%氯化钠注射液250ml,ATP40mg,CoA100u,每日一次静点,并配合本发明比较例2制备的颗粒冲剂3,日三次冲服,每次1袋。14天为一疗程。
临床观察步骤
试验前:采集病史,询问症状,检查体征,进行声阻抗及电测听检查,确诊为突发性聋伴耳鸣患者,且辨证属中医暴聋(肝火上扰型)。按就诊时间先后随机入组试验,予耳鸣分级,并进行血液流变学检测。
试验中:观察患者服药后有无不良反应,并检查患者依从性。
试验后:再次进行电测听检查,重新进行耳鸣分级,并复查血液流变学。
观察指标
(1)电测听中反应的平均听力;(2)耳鸣的改善情况;(3)血液流变学指标变化。
疗效判定标准
听力疗效判定标准
据2005年中华医学会耳鼻咽喉科学分会和中华耳鼻咽喉科杂志编委会济南会议标准:
痊愈:受损频率听阈恢复至正常,或达到健耳水平,或达到此次患病前水平;显效:受损频率平均听力提高30db以上;有效:受损频率平均听力提高15-30db;无效:受损频率平均听力提高不足15db。
耳鸣疗效判定标准
痊愈:耳鸣消失;显效:耳鸣程度降低2个级别以上(包括2个级别);有效:耳鸣程度降低1个级别;无效:耳鸣无变化。
统计学方法
计量数据用表示,应用SPSS16.0软件,组间数据比较采用单因素方差分析,两组间比较用t检验,P<0.05表示有统计学意义。
结果
表4治疗组与对照组对听力的疗效比较
与对照组比较,*P<0.05;与治疗组比较,ΔP<0.05
治疗组与空白对照组治疗后听力总有效率之间有显著性差异(p<0.05),与治疗组比较,对照1组、对照2组疗效均较差,与治疗组有显著性差异(p<0.05),说明治疗组对听力改善的效果明显优于对照组,而通过比较对照组和治疗组,蜈蚣和蜈蚣和龙胆草缺一不可。
表5治疗组与对照组对耳鸣的疗效比较
组别 | 痊愈 | 显效 | 有效 | 无效 | 总有效率% |
对照组 | 8 | 9 | 26 | 17 | 71.67 |
治疗组 | 15 | 19 | 20 | 6 | 90.00* |
对照1组 | 11 | 18 | 18 | 13 | 78.33Δ |
对照2组 | 7 | 17 | 22 | 14 | 76.67Δ |
与对照组比较,*P<0.05;与治疗组比较,ΔP<0.05
与治疗组比较,对照1组、对照2组疗效均较差,与治疗组有显著性差异(p<0.05),说明治疗组对耳鸣改善的效果明显优于对照组,而通过比较对照组和治疗组,蜈蚣和蜈蚣和龙胆草缺一不可。
表6治疗组与对照组对血流变的疗效比较
与治疗前比较,*P<0.05;与治疗组比较,ΔP<0.05
经统计学处理,结果表明:三组治疗前后全血粘度、血浆粘度、红细胞聚集指数,有显著性差异,P<0.05,说明治疗组与对照1组、对照2组均能降低全血粘度、血浆粘度、红细胞聚集指数。
治疗组与对照组治疗后各项指标经t检验,P<0.05,有显著性差异,说明治疗组对血液流变学的影响高于对照组对血流变的影响。
对照组之间治疗后各项指标经t检验,P>0.05,但对其均值比较,去蜈蚣组血流变指标要高于去龙胆草组,因此,仅能说明现有实验方法对二对照组血液流变学的研究结果无显著差异。
药物药效实验研究
实验动物:选用耳廓反射灵敏的白色红目健康豚鼠50只(由青岛大学实验动物室提供),雌雄不限,体重250-350g,随机分为5组,每组10只。合格证号:SCXK(鲁)20140006。
治疗药物:本发明实施例1制备的颗粒冲剂1,比较例3制备的颗粒冲剂4(龙胆草与蜈蚣4∶1),比较例4制备的颗粒冲剂5(龙胆草与蜈蚣1∶2)。
阳性对照药:血府逐瘀胶囊(桃仁(炒)、红花、赤芍、川芎、枳壳(麸炒)、柴胡、桔梗、当归、地黄、牛膝、甘草),购自同仁堂药店,批准文号:国药准字Z10950063。
试剂:盐酸肾上腺素注射液,1mg/ml,购自青岛大学附属医院,生产批号:国药准字H53020781
血液检测及所需系列试剂由青岛大学医学院附属医院检验科承担及提供。
耳蜗标本制备所需系列试剂由青岛大学医学院附属医院动物中心实验室提供。
实验仪器:脑干诱发电位仪、SXE-1手术显微镜、光学显微镜、LDZ5-2离心机、全自动免疫计数器、紫外分光光度计、电热恒温水浴锅、高速离心沉淀机,所有仪器均由青岛大学医学院附属医院提供并承担检测。
实验方法
突发性耳聋模型复制
70只白色红目健康豚鼠,除空白组10只外,其余60只动物按照突发性耳聋模型制备方法造模,并给予适当改进,采用磁带录制AA30型高级纯音测听仪发出的4kHz掩蔽窄带噪声为噪声声源,经功率放大器放大至107dB(A)。用AWA5610B积分声级计监测。除空白组外,各组豚鼠置于隔音箱内,头部距离噪声源约15cm,作噪声暴露,每天1次,每次5小时,连续刺激3天后,各造模组豚鼠予以盐酸肾上腺素0.8mg/kg腹部皮下注射。1小时后行ABR阈值测定,确定造模成功。
分组及给药
随机选取10只白色红目健康豚鼠为空白组(正常对照组);将60只造模成功的白色红目健康豚鼠随机分为4组:模型组、阳性对照组(血府逐瘀胶囊水溶液组)、治疗组(颗粒冲剂1)、比较例3组(颗粒冲剂4)和比较例4组(颗粒冲剂5)。按照《中药药理实验方法学》中动物体表面积比率换算等效剂量灌胃给药(70kg人:400g豚鼠为1∶31.5);每日灌胃一次,连续给药2周。末次灌胃后禁食不禁水,于次日颈总动脉插管放血,采血进行相关检测。
空白组:5ml/kg蒸馏水灌胃;
模型组:5ml/kg蒸馏水灌胃。
阳性对照组(血府逐瘀胶囊水溶液组):2.818ml/kg;
治疗组:按生药量计25.9g/kg,制备为5ml/kg的药液;
比较例1组:按生药量计25.9g/kg,制备为5ml/kg的药液;
比较例2组:按生药量计25.9g/kg,制备为5ml/kg的药液;
听性脑干反应(ABR)
腹腔注射1%戊巴比妥钠进行麻醉,在隔音屏蔽室内进行测试,记录电极插入颅顶正中皮下,参考与接地电极分别插人同侧与对侧耳垂,耳机距测试耳外耳道口约1cm,刺激声为交替短声(click),重复率16次/s,平均叠加500次,测试70dBSPL强度下的I、III波潜伏期及I-III波间期,并测试ABR阈值。造模前后及试验结束分别测试1次。
采血与检测指标
豚鼠以2%戊巴比妥钠麻醉,从颈动脉插管放血,按文献方法测定血NO、ET、5-HT水平。
统计学处理
计量数据用表示,应用SPSS16.0软件,组间数据比较采用单因素方差分析,两组间比较用t检验,P<0.05表示有统计学意义。
实验结果
实验过程中,模型组、阳性对照组及治疗组豚鼠分别死亡2只、2只、1只,原因主要为注射肾上腺素造模及麻醉时刺入腹部过深误伤脏器或药量过大,灌胃时操作不当药液进入气管致豚鼠窒息。
造模后豚鼠的一般表现
造模过程中及造模后,除空白组外各豚鼠出现不同程度的易激惹及抑郁状态,不欲饮食,体重增长减缓,实验结束后个别豚鼠消瘦明显,表情呆滞,毛发枯乱。
空白组及治疗组豚鼠的体重、毛发及一般精神状况明显优于模型组和对照组。
对四组豚鼠ABR测试有关指标影响,结果见表7。
实验前四组豚鼠短声ABR反应阈及70dBSPL短声刺激下的I、III波潜伏期与I-III波间期均无显著性差异(P>0.05)。造模结束后,造模各组豚鼠ABR反应阈值明显提高,与空白组相比均有显著性差异(P<0.01);造模各组的I、III波潜伏期较前明显延长,与空白组相比均有显著性差异(P<0.01);I-III波间期较前延长,与空白组相比均有差异(P<0.05)。
表7实验后四组豚鼠ABR测试有关指标比较
与空白组比较,*P>0.05;与模型组比较,#P>0.05;与治疗组比较,ΔP<0.05
实验后,空白组豚鼠各项指标与实验前均无明显变化(P>0.05),模型、阳性对照组、比较3组、比较4组的ABR反应阈较空白组升高(P<0.05),治疗组虽有升高,但与空白组无显著差异(P>0.05),70dBPL短声刺激下的I、III波潜伏期,模型、阳性对照组及治疗组、比较3组、比较4组均较实验前延长(P<0.05),而波间期则无明显变化,与治疗组比较,对照组、比较3组、比较4组均有统计学差异(P<0.05)。
对突发性耳聋豚鼠血浆5-HT含量的影响,见表8。
表8对突发性耳聋豚鼠血浆5-HT含量的影响
与空白组比较,*P>0.05;与模型组比较,#P>0.05;与治疗组比较,ΔP<0.05
造模后豚鼠血浆5-HT含量明显升高,与空白组相比有显著性差异(P<0.05);2周灌胃治疗结束后,本发明中药制剂能够降低其升高,使之接近正常,与模型组比较差异有显著性(P<0.05),与空白组无显著差异(P>0.05);阳性对照组与模型组比较差异有显著性(P<0.05),但与空白组及治疗组相比仍有显著性差异(P<0.05)。比较组1与比较组2比较,比较组1在5-HT值要高于比较组2,说明去掉蜈蚣在相关治疗的改善上要弱于去掉龙胆草对相关指标的改善,但两组结果无统计学差异(P>0.05)。
对突发性耳聋豚鼠ET、NO含量的影响,结果见表9。
表9对突发性耳聋豚鼠ET、NO含量的影响
与空白组比较,*P>0.05;与模型组比较,#P>0.05;与治疗组比较,ΔP<0.05
实验结束后,治疗组及阳性对照组血ET水平明显低于模型组(P<0.01),治疗组与空白组相比无显著性差异(P>0.05),阳性对照组与治疗组相比仍有显著性差异(P<0.05)。治疗组及阳性对照组血NO水平明显高于模型组(P<0.01或0.05),治疗组NO水平明显高于阳性对照组(P<0.05),但与空白组相比仍有显著性差异(P<0.05)。比较组1与比较组2比较,比较组1在5-HT值要高于比较组2,说明去掉龙胆草在相关治疗的改善上要弱于去掉蜈蚣对相关指标的改善,但两组结果无统计学差异(P>0.05)。
经治疗后治疗组豚鼠血与模型组相比NO明显升高而ET含量明显下降,恢复二者相对动态平衡,血5-羟色胺含量明显降低,豚鼠ABR阈值接近正常,故本发明中药制剂可通过调节血NO、ET水平,保持二者相对动态平衡,及阻止5-HT释放,改善突聋豚鼠内耳血液高凝状态,增加耳蜗血液供应,从而对突发性耳聋起到治疗作用。
所有上述的首要实施这一知识产权,并没有设定限制其他形式的实施这种新产品和/或新方法。本领域技术人员将利用这一重要信息,上述内容修改,以实现类似的执行情况。但是,所有修改或改造基于本发明新产品属于保留的权利。
以上所述,仅是本发明的较佳实施例而已,并非是对本发明作其它形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型,仍属于本发明技术方案的保护范围。
Claims (8)
1.一种治疗肝阳上亢型突发性耳聋的中药制剂,其特征在于:原料药包括柴胡、酒黄芩、生栀子、龙胆草、石菖蒲、天麻、钩藤、车前子、生地黄、当归、葛根、磁石、龙齿、琥珀、远志、酸枣仁、僵蚕、全蝎、地龙和蜈蚣。
2.如权利要求1所述的治疗肝阳上亢型突发性耳聋的中药制剂,其特征在于:龙胆草和蜈蚣重量比例为2∶1。
3.如权利要求1或2所述的治疗肝阳上亢型突发性耳聋的中药制剂,其特征在于:蜈蚣的重量不超过12g。
4.如权利要求1至3所述的治疗肝阳上亢型突发性耳聋的中药制剂,其特征在于:各原料药的重量分别为柴胡14g~16g、酒黄芩11g~13g、生栀子11g~13g、龙胆草12g~24g、石菖蒲14g~16g、天麻14g~16g、钩藤14g~16g、车前子14g~16g、生地黄29g~31g、当归19g~21g、葛根29g~31g、磁石29g~31g、龙齿29g~31g、琥珀29g~31g、远志9g~11g、酸枣仁29g~31g、僵蚕14g~16g、全蝎9g~11g、地龙8g~10g和蜈蚣6g~12g。
5.如权利要求1至4所述的治疗肝阳上亢型突发性耳聋的中药制剂,其特征在于:中各原料药的重量分别为柴胡15g、酒黄芩12g、生栀子12g、龙胆草20g、石菖蒲15g、天麻15g、钩藤15g、车前子15g、生地黄30g、当归20g、葛根30g、磁石30g、龙齿30g、琥珀30g、远志10g、酸枣仁30g、僵蚕15g、全蝎10g、地龙9g和蜈蚣10g。
6.如权利要求1至5所述的治疗肝阳上亢型突发性耳聋的中药制剂,其特征在于:所述中药制剂是内服药剂。
7.如权利要求1至6所述的治疗肝阳上亢型突发性耳聋的中药制剂,其特征在于:所述中药制剂是颗粒冲剂。
8.权利要求1至7所述中药制剂制备成颗粒剂的方法,其特征在于,包括:
第一步,按重量称取地龙,清洗,沥干,加2倍于其重量的水,在37℃搅拌匀浆,离心,取上清液进行膜滤过,浓缩,浓缩液经冷冻干燥,即得第一粉末;
第二步,按重量称取僵蚕、全蝎和蜈蚣,用相对于三者重量之和4~6倍的体积百分比浓度为70%的乙醇溶液加热回流提取两次,每次提取2小时,提取液合并后回收乙醇至无醇味,继续浓缩至60℃时测定相对密度为1.10~1.20的浸膏,得提取浸膏,得到的浸膏上D101大孔吸附树脂,用水洗脱,弃去水洗液,再用体积百分比浓度为70%的乙醇溶液洗脱,收集乙醇洗脱部分,回收乙醇,浓缩至60℃时测定相对密度为1.30~1.40的浸膏;
第三步,取余下原料药组分,混合在一起,加相对于混合物质量3~5倍的水,煎煮2小时,煎煮液过滤,滤渣再次加相对于混合物质量3~5倍的水,煎煮2小时,煎煮液过滤,两次过滤后的煎煮液合并,浓缩至60℃时测定相对密度为1.30~1.40的浸膏;
第四步,将第一步获得的粉末、第二步获得的浸膏以及第三步获得的浸膏混合,将获得的混合物与糊精按质量比4∶1比例混合均匀后,于75℃减压干燥,粉碎,随后加入淀粉混匀,淀粉使用质量与混合糊精后的物质质量相同,用12~14%的水制颗粒,60℃干燥,分装,每袋5g。
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