贯郁胶囊的药学研究及其治疗抑郁症的药效学研究和机理探讨

【作者】 王景霞；

【导师】 高学敏；

【作者基本信息】 北京中医药大学 ， 临床中药学， 2005， 博士

【摘要】 抑郁症(depression)是情感性精神障碍(mood disorders)的主要类型,是一种以显著而持久的心境低落为主要特征的综合征。随着社会经济的发展,生活节奏加快,人们的压力增加,情感冲击加大,造成抑郁症发病率逐年增高。此外,作为合并症,抑郁症状的缓解也与躯体疾病的康复密切相关。抑郁症的发病机理尚不清楚,对抑郁症的治疗目前还建立在假说的基础上,存在种种不足。临床对抑郁症的治疗主要依靠西药,虽然有一定效果,但均有不同程度的副作用和依赖性。当前对抑郁症发病机制的研究以及开发疗效好、副作用小的新药是该领域的研究重点。 中医药学对于情志因素引起的抑郁等精神失调疾病有独到的认识和深厚的临床实践基础,因而,在中医药理论的指导下,运用现代科学研究方法,开发研制高效低毒的抗抑郁中药新制剂,是中医药工作者需不断探索的课题。 临床上抑郁症的发病往往不是单一的某一证型,而常见多种复合证型,通过对文献的整理分析,结合临床研究,我们认为:抑郁症初期常为实证,多是肝气郁结,肝郁化火,气滞痰郁复合发病同时常兼有脾虚的症状,其病机为:情志内伤,肝失条达,气失疏泄导致精神抑郁,肝气郁滞,气郁化火,炼液为痰,痰火扰心,心主神明的功能失常而抑郁,同时肝郁乘脾,脾失运化,凝液为痰,痰郁气阻导致心下脘痞,不思饮食,精神运动迟缓等抑郁症状。所以,我们在中医药理论指导下,在总结前人的经验,并结合临床研究和现代科学研究成果的基础上,拟定了治疗抑郁症的科研处方“贯郁汤”。由于中药复方治疗抑郁证临床用药大多停留在汤剂水平,没有固定的工艺和可遵循的标准,不易重复验证,为了克服这些缺点,我们把所设计的抗抑郁复方制成工艺固定、质量可控的胶囊剂,即“贯郁胶囊”。 对“贯郁胶囊”的处方、药学、药效毒理学等方面进行了研究,并对“贯郁胶囊”治疗抑郁症的机理进行了多方面的探讨,主要研究结果如下: 1 贯郁胶囊处方论证 1.1 处方组成 君药:贯叶金丝桃;臣药:郁金、石菖蒲;佐药:人参、远志、合欢花。 1.2 功能主治 疏肝解郁,清热化痰,宁心安神。用于肝郁化火、痰热扰心所致的抑郁症。症见精神抑郁,烦躁易怒,胸胁胀痛,心悸不宁,失眠健忘,多梦易醒,心下脘痞,不思饮食,四肢倦怠,舌红,苔黄腻,脉滑数。 2 贯郁胶囊药学研究 2.1 贯郁胶囊生产工艺研究 采用正交设计优选其生产工艺,最佳工艺为:石菖蒲,加 8 倍量水,浸泡 2h,水蒸气蒸馏法,提取 15h,得挥发油,挥发油用β-环糊精包合,水煮液备用。贯叶金丝桃、人参 60%乙醇浸泡 2h,回流提取 1 次,加 10 倍量乙醇,回流 1h,滤液回收乙醇,浓缩,干燥,成干膏。郁金、远志、合欢花加水浸泡 4h,与石菖蒲提油后的药渣合并,煎煮 2 次,第一次加 10 倍量水,第二次加 8 倍量水,每次 1.5h,合2贯郁胶囊的药学研究及其治疗抑郁症的药效学研究和机理探讨并两次水煎液,再与石菖蒲提油的水液混合,浓缩至相对密度为 1.04(60℃热测),加 95%乙醇使含醇量达 60%,于 4℃冷藏 24h,抽滤,回收乙醇,浓缩,干燥,成干膏。将以上干膏与β-环糊精包合物混合,粉碎,过 60 目筛,装胶囊。β-环糊精包合挥发油的方法:按照挥发油∶β-环糊精为 1∶4 的比例,取β-环糊精,然后加 10 倍量水,加热溶解,放至 30℃,将挥发油用 95%乙醇溶解,边滴加挥发油边搅拌,5min 内滴加完毕,然后再搅拌 15min,于 4℃冷藏过夜,抽滤,晾干,得β-环糊精包合物。2.2 贯郁胶囊质量标准研究贯郁胶囊内容物为棕褐色药粉,味苦微酸。应用薄层色谱法,对成品中含有的石菖蒲、人参、远志等中药进行了鉴别。按《中国药典》2005 年版附录ⅠL 项下内容设定检查项,对样品进行了检查,其中装量差异,水分,崩解时限,微生物限度均符合规定;重金属不超过 10ppm,砷盐低于 2ppm。采用 HPLC 法对方中君药贯叶金丝桃中的金丝桃苷进行了含量测定,贯郁胶囊含贯叶金丝桃以金丝桃苷计,每粒不得少于 0.5mg。3 贯郁胶囊药效学研究3.1 小鼠强迫游泳实验小鼠灌胃给药 7 天,于末次给药 1h 后,将小鼠放入水中,观察 6min,记录后4min 内累计不动时间。实验结果表明:贯郁胶囊 1.2g/kg、0.6g/kg 均能明显缩短小鼠强迫游泳不动时间,与空白组比较差异显著(P<0.01,P<0.05)。3.2 小鼠悬尾实验小鼠灌胃给药 7 天,于末次给药 1h 后,将小鼠尾端用胶布固定,使其呈倒悬状态,适应 1min 后,记录 5min 之内的不动时间。实验结果表明:贯郁胶囊 1.2g/kg、0.6g/kg 均能明显缩短小鼠悬尾不动时间,与空白组比较差异显著(P<0.01,P<0.05)。3.3 大鼠慢性应激实验造模大鼠采用孤养的方法,并接受 21 天的不可预知的应激刺激,包括:电击足底(36 伏电压,每隔 1min 电击一次,一次持续 10 秒,共 20 次),冰水游泳(4℃,5min),热烘(45℃,5min),夹尾(1min),潮湿饲养(200ml 水,24h),昼夜颠倒,24h 禁食,24h 禁水等。每组每天随机给予一种刺激。造模同时给药,观察药物对模型大鼠体重、行为学的影响。实验结果表明:模型组大鼠体重的增长明显缓慢,体重明显低于空白组(与空白组比较,P<0.01);蔗糖水的消耗量明显降低(与空白组比较,P<0.01);水平运动和垂直运动量明显减少(与空白组比较,P<0.01);跳台行为学出现明显变化,表现为反应更多还原

【Abstract】 Depression is a psychosis, which is characterized by various manifestations of affective disorder. It affects patients’ working, learning and living so that they have difficulty adapting themselves to society , even induce suicidal behavior at last. With intense social competition and fast working pace, more and more people will feel tensive, exhausted and melancholy. Incidence rate of depression will show an upward tendency. Furthermore, relief of depression is related to the rehabilitation of body disease. Psychopathology of depression is not known. Treatment on depression that is based on the hypotheses has a variety of defects. Today, the research is focused on the pathogenesis of depression and the new drugs that are effective and have fewer side effects. On the basis of the traditional theories, traditional Chinese medicine (TCM) had played more and more important role in treating depression. Guided by TCM’s theories, combining with contemporary theories, experimental and clinical results of TCM and Western medicine, developing new Chinese herbal preparation with good curative effects and fewer side effects is a new project. It will be of great importance to improve the effect of TCM on treating depression and understand the mechanism of treating depression of classical prescriptions. “Guanyu Capsule” is created to treat depression due to pathogenic fire derived from stagnation of liver-qi and phlegm-heat attacking the heart, accompanied by deficiency of the spleen. Our studies include prescription, pharmacy, action, toxicology and mechanism exploration. 1 The demonstration of Guanyu Capsule’s prescription 1.1 Ingredients The chief herb: Herba Hyperici Perforati, adjuvant herb: Radix Curcumae, Rhizoma Acori Talarinowii, assistant herb: Radix Ginseng, Radix Polygalae, Flos Albiziae. 1.2 Action and indications Action: To disperse the depressed liver-energy, clear heat and eliminate phlegm, and tranquilize mind. Indications: Depressive disorders due to pathogenic fire derived from stagnation of liver-qi and phlegm-heat attacking the heart, with manifestation of deprementia, restlessness, tantrum, gas pain of chest and hypochondrium, palpitation, insomnia, morbid forgetfulness, dreaminess, festless sleep, painful abdominal mass, poor appetite, lassitude, red tongue, yellow and greasy fur, slide and rapid pulse. 2 Pharmaceutical research of Guanyu Capsule 2.1 production technology research of Guanyu Capsule Orthogonal design was used to optimize the production technology. The optimization technology: Rhizoma Acori Talarinowii was macerated for 2h and isolated volatile oil with 8 times volume of water for 15h, filtered, and decoction was reserved. The volatile oil was included by β-cyclodextrin. Radix Curcumae, Radix Polygalae, Flos Albiziae and Rhizoma Acori Talarinowii gruffs were macerated for 4h and extracted in sequence two times with 10 and 8 times volume of water for 1.5h respectively. The above decoctions were combined, concentrated to a thin extract with a relative density of about 1.04, added ethanol to a content of 60% ethanol, stored at 4℃ for 24h, filtered. The filtrate was recovered ethanol, concentrated and dried. Taking 60% ethanol as solvent, Herba Hyperici Perforati and Radix Ginseng were macerated for 2h and extracted with 10 times volume of ethanol for 1h, filtered, and the filtrate were recovered ethanol, concentrated and dried. To combine the above extraction and β-cyclodextrin inclusion compound, crush, mix well, pack into capsules. Preparation ofβ-cyclodextrin inclusion compound of volatile oil from Rhizoma Acori Talarinowii: To adopt the method of stirring, oil:β-CD was 1:4, and the inclusion temperature and time were at 30℃ and for 15 minutes. 2.2 Study on quality standards for Guanyu Capsule The content of Guanyu Capsule is dark brown powder, sour flavor and bitter. Weight variation, water determination, disintegration time, microbial limit were all in line with rule. Rhizoma Acori Talarinowii, Radix Ginseng and Radix Polygala were identified by TLC. The content of hy更多还原