CN109568329A - 甘草酸及其药学上可接受的盐在制备抗抑郁药物中的应用 - Google Patents
甘草酸及其药学上可接受的盐在制备抗抑郁药物中的应用 Download PDFInfo
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- glycyrrhizic acid
- antidepressant
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
本发明提供了甘草酸及其药学上可接受的盐在制备抗抑郁药物中的应用,具体是甘草酸及其药学上可接受的盐作为唯一活性成分在制备抗抑郁药物中的应用、作为抗抑郁药物增效剂的应用、或在联合使用抗抑郁药治疗难治性抑郁症中的应用。本发明经临床试验表明,甘草酸和/或甘草酸药学上可接受的盐对抗抑郁药物有明显的增效作用,在临床中应用能够快速、安全、有效的改善抑郁症的症状。因此,甘草酸和/或甘草酸药学上可接受的盐可作为唯一活性成分制备抗抑郁药物、可用于制备抗抑郁药物增效剂或联合使用抗抑郁药治疗难治性抑郁症,用于不同抑郁症的治疗,不仅能提高药物的抗抑郁作用,而且廉价易得、安全无毒,具有良好的临床应用前景。
Description
技术领域
本发明涉及医药技术领域,具体涉及甘草酸及其药学上可接受的盐在制备抗抑郁药物中的应用,尤其涉及甘草酸及其药学上可接受的盐作为唯一活性成分用于制备抗抑郁药物、作为抗抑郁药物增效剂以及在联合使用抗抑郁药治疗难治性抑郁症中的应用。
背景技术
甘草酸是甘草中最主要的活性成分。甘草是我国传统中药材,应用历史悠久,东汉《神农本草》称甘草为"美草"和"密甘",列为上品。中医药认为,甘草味甘、平,是补脾益气,止咳祉疾,缓急止痛,调和诸药,解毒的良药。美国FDA将甘草提取物列为安全无毒物质。甘草酸及其系列产品,具有抗炎、抗病毒和保肝解毒及增强免疫功能等作用。由于甘草酸有糖皮质激素样药理作用而无严重不良反应,临床被广泛用于治疗各种急慢性肝炎、支气管炎和艾滋病,还具有抗癌防癌、干扰素诱生剂及细胞免疫调节剂等功能。近年来,甘草酸在医药、化工、食品、日用化工等行业也得到了广泛的应用。
但未见甘草酸作为抗抑郁药、抗抑郁药物增效剂以及联合使用抗抑郁药物治疗难治性抑郁症的报道。
发明内容
本发明的目的在于提供甘草酸及其药学上可接受的盐在制备抗抑郁药物中的应用。
本发明的第一方面,提供甘草酸及其药学上可接受的盐作为唯一活性成分在制备抗抑郁药物中的应用。
本发明的第二方面,提供甘草酸及其药学上可接受的盐作为抗抑郁药物增效剂的应用。
优选的,甘草酸及其药学上可接受的盐作为抗抑郁药物增效剂的应用中,所述甘草酸和/或甘草酸药学上可接受的盐的用量为在抗抑郁药物有效浓度中加入150mg-450mg/日。
本发明的第三方面,提供甘草酸及其药学上可接受的盐在联合使用抗抑郁药治疗难治性抑郁症中的应用。
本发明的第四个方面,提供一种抗抑郁症的药物组合物,所述药物组合物的活性成分是甘草酸和/或甘草酸药学上可接受的盐。
本发明的第五个方面,提供一种抗抑郁症的药物组合物,所述药物组合物的活性成分是抗抑郁药物和甘草酸和/或甘草酸药学上可接受的盐。
本发明所述的甘草酸化学结构式如下:
本发明中所述甘草酸可以从常用中草药甘草用本领域技术人员公知方法进行提取得到,或通过文献方法制备得到,例如,可参考如下文献公开的制备方法:刘文丛.甘草酸及甘草次酸衍生物的研究.吉林农业大学,2004:1-45;张娟,杨中林,李萍.甘草中甘草酸的制备工艺研究.中成药,2007,29(5):686-689;徐建军,马清河,李海齐,范晓雯.甘草酸提取工艺研究.新疆中医药,2013,31(1):40-43.),也可以通过市售方式购买得到。
优选的,本发明所述的甘草酸是豆科植物甘草的干燥根及根茎的提取物中的主要活性成分。
本发明所述的甘草酸药学上可接受的盐选自甘草酸二铵、甘草酸单铵盐、甘草酸一钾盐、甘草酸二钾盐等中的一种。
优选的,本发明所述的甘草酸药学上可接受的盐为甘草酸二铵,甘草酸二铵为中药甘草有效成分甘草酸的第三代提取物。甘草酸二铵可以从常用中草药甘草用本领域技术人员公知方法进行提取得到;或通过文献方法制备得到,例如,可参考如下文献公开的制备方法:林强,霍清.双水相体系萃取甘草酸盐的研究.中草药,2002,33(8):702-704;李立威,代旭勇,程志刚.18α-H-甘草酸二铵的制备.中国现代应用药学,2008,25(4):309-312.;靳颖华,张洁.甘草酸二铵缓释片的制备及释放度测定.中国医药导刊,2009,11(6):1047,1049;周宝华.种植甘草中甘草酸、甘草酸单铵盐生产工艺研究及工业化设计.兰州理工大学,2011:1-84;吴云珍,宋旭莹,陆纪宏.甘草酸二铵肠溶胶囊的制备与质量控制.医药导报,2011,30(11):1507-1509,也可以通过市售方式购买得到。
优选的,甘草酸药学上可接受的盐作为抗抑郁药物增效剂的应用中,所述甘草酸药学上可接受的盐为甘草酸二铵,甘草酸二铵的加入量为在抗抑郁药物中加入150mg-450mg/日。
本发明所述中所述的抑郁症主要是指:符合美国精神疾病诊断标准第五版(Diagnostic and Statistical Manual of Mental Disorders:DSM-V)或国际疾病分类第10版(International Classification of Diseases-10,ICD-10)中关于抑郁症的诊断标准。
本发明所述的甘草酸及其药学上可接受的盐作为唯一活性成分制备抗抑郁药、作为抗抑郁药物增效剂以及甘草酸在联合使用抗抑郁药治疗难治性抑郁症的用途,其中的抗抑郁药物包括但不局限于:三环类抗抑郁药(TCA)、单胺氧化酶抑制剂(MAOI)、选择性5-羟色胺再摄取抑制剂(SSRIs)、选择性5-羟色胺和去甲肾上腺素再摄取抑制剂(SNRIs)、特异性5-羟色胺和去甲肾上腺素重摄取抑制剂(NaSSA)、选择性去甲肾上腺素再摄取抑制剂(NARI)、5-羟色胺拮抗/回收抑制剂(SARI)、去甲肾上腺素和多巴胺能再摄取抑制剂(NDRI)、褪黑素类似物、植物类抗抑郁药物等。
本发明经临床试验表明,甘草酸及其药学上可接受的盐对抗抑郁药物有明显的增效作用,在临床中应用能够快速、安全、有效的改善抑郁症的症状。因此,甘草酸及其药学上可接受的盐可作为唯一活性成分制备抗抑郁药物的试验疗效是能够快速、安全、有效的改善抑郁症的症状;甘草酸及其药学上可接受的盐可用于制备抗抑郁药物增效剂产品或联合使用抗抑郁药治疗难治性抑郁症,用于不同抑郁症的治疗。
本发明的有益效果:
本发明为甘草酸及其药学上可接受的盐开辟了新的用途,将其用于制备抗抑郁药物或抗抑郁药物的增效剂产品以及联合使用抗抑郁药治疗难治性抑郁症,不仅能提高药物的抗抑郁作用,而且廉价易得、安全无毒,具有良好的临床应用前景。
附图说明
图1为本发明实施例1中不同测量点的HAMD量表评分。
图2为本发明实施例1中多种血清生物学指标的结果。
图3为本发明实施例1中介效应分析示意图。
图4为本发明实施例1中高炎组和低炎亚组在不同测量点的HAMD量表评分。
图5为本发明实施例1中各组治疗的有效率和缓解率统计分析结果。
具体实施方式
下面结合本发明的实施例对本发明的实施作详细说明,以下实施例是在以本发明技术方案为前提下进行实施,给出了详细的实施方式,但本发明的保护范围不限于下述的实施例。
实施例1:基于抑郁症的炎性机制的甘草酸的抗抑郁临床疗效研究
材料和方法
1.试药
甘草酸类药物是临床常用的保肝药物,临床常用复方甘草酸苷、甘草酸单铵、甘草酸二铵等,各种甘草酸类药物作用机制基本一致,在体内经葡萄糖醛酸酶作用生成甘草次酸,具有保护肝细胞膜、抗炎、调节免疫、调节细胞色素P450酶系、解毒等作用,故本实施例选用甘草酸二铵肠溶胶囊作为试药观察甘草酸的抗抑郁临床疗效。
甘草酸二铵,为中药甘草有效成分的第三代提取物,是甘草酸单铵盐的更新换代产品,具有较强的抗炎、保护肝细胞膜及改善肝功能的作用,对多种肝毒剂所致肝脏损伤均有防治作用,并呈剂量依赖性;对复合致病因子引起的慢性肝损害,能明显提高存活率及改善肝功能。甘草酸二铵肠溶胶囊:江苏正大天晴药业股份有限公司,批准文号:国药准字H20040628。
抗抑郁药物:草酸艾司西酞普兰片:百适可:山东京卫制药有限公司,批准文号:国药准字H20080599;百洛特:四川科伦药业股份有限公司,批准文号:国药准字H20080788。
2.试验设计和设置
本实施例为随机、双盲、安慰剂对照临床试验。选取2017年1月至2017年12月在解放军第904医院(原第102医院)精神心理科住院的抑郁症患者60例。本实施例遵循最新版《赫尔辛基宣言》,本实施例已在中国临床实验注册中心注册(http://www.chictr.org.cn,注册号:ChiCTR1800015287),并经中国人民解放军第102医院医学伦理委员会批准批准。协议(伦理批件号:102LLWYH2017-02)。
3.入组标准及排除标准
入组标准:(1)年龄18~65岁;(2)小学以上文化程度;(3)符合美国精神疾病诊断标准DSM-5抑郁症的诊断标准;(4)HAMD17>17分;(5)患者本人和家属自愿接受临床试验要求并签署知情同意书。
排除标准:(1)患有其他精神神经疾病者;(2)服用SSRI类以外的抗抑郁药物;(3)直系亲属患有双相障碍或躁狂症者,随访中有躁狂发作史;(4)严重躯体疾病或颅脑外伤者:包括炎性疾病、血液系统疾病和自身免疫性疾病;(5)严重低钾血症者;(6)妊娠期及哺乳期;(7)物质依赖或滥用者;(8)3个月内服用过类固醇激素等药物者;(9)有听力及视色觉障碍者。
研究参与者可以选择在任何时候通知研究者要求退出研究,其数据将不纳入研究结果,且其任何待遇与权益不会因此而受到影响。
4.干预
对符合入组标准的60例抑郁症患者,随机按1:1进入治疗组(草酸艾司西酞普兰片+甘草酸二铵肠溶胶囊)和对照组(草酸艾司西酞普兰片+安慰剂)。治疗组患者给予甘草酸二铵肠溶胶囊150mg/次,每日3次,为期4周,对照组安慰剂以同样的方式给药4周。所有参加者在试验过程中均给予常规治疗剂量的SSRI类抗抑郁药物草酸艾司西酞普兰片。
5.观察与评价指标
在入组基线时、第2周末、第4周末分别对两组患者进行汉密尔顿抑郁量表17项版(HAMD-17)评定以评估患者抑郁症状,量表由经过培训的两名评定者对患者进行HAMD-17联合检查。抑郁治疗效果评定标准:汉密尔顿抑郁量表评分减分率≥50%为有效,汉密尔顿抑郁量表评分≤7分为治愈。
同时在入组基线时、第2周末、第4周末分别对两组患者检测血液炎性因子(如:CRP、HMGB1、TNF-α、IL-1β、IL-6等)的表达以及糖皮质激素水平等,分析炎性因子水平与抑郁程度的相关性。血清标本采集与处理:两组均抽取清晨空腹肘部静脉血10ml,取5ml行血常规测定,另取5ml置于EP管中,离心后取上层血清,置于-80℃保存待测。采用免疫散射比浊法检测血清C反应蛋白(CRP)水平,采用酶联免疫吸附法(ELISA)检测白介素-1β(IL-1β)、白介素-6(IL-6)、肿瘤坏死因子(TNF-α)水平,采用放射免疫分析法检测血浆皮质醇(Cor)含量。
实验结果
1.基线资料
本实施例中人口社会学资料和部分临床资料基线值比较参见表1。
表1.人口社会学资料和部分临床资料基线值比较
注:α:卡方检验p值;β:曼恩·惠特尼检验的p值;γ:未配对t检验的p值。如果没有具体提及,数据显示为平均数±标准差。SSRI+PBO:选择性5-羟色胺再摄取抑制剂+安慰剂对照组;
SSRI+GZA:选择性5-羟色胺再摄取抑制剂+甘草酸组。
由表1可知,从人口社会学资料和部分临床资料基线值来看,两组在性别、婚姻状况、独生子女情况、吸烟史、年龄、受教育经历、BMI、腰围和HAMD量表评分基线值等方面没有统计学差异,提示两组患者在后续临床试验中具有可比性。
2.1疗效分析
由图1从不同测量点的HAMD量表评分来看,两组的总分均呈下降趋势。然而,连续测量方差分析的结果提示两组评分并无显著性差异。
SSRI+PBO组、SSRI+GZA组的HAMD累积减分值比较结果参见表2。由表2可知,对两组HAMD累积减分值进行协方差分析(两组各自HAMD量表评分基线值为协变量),结果提示SSRI+GZA组在服药1周、2周、4周这三个观测点的HAMD累积减分均高于SSRI+PBO组。
表2.两组HAMD累积减分值比较
2.2抑郁病情改善情况
SSRI+PBO组、SSRI+GZA组在不同时间点治疗有效率和缓解率比较结果参见表3。表3中,有效(Response)是指治疗后抑郁症状减轻。通常以主要疗效指标(量表评分)变化率≥50%来定义。缓解(Remission)是指治疗后抑郁症状几乎完全消失或完全消失。本例以主要疗效指标(量表评分)≤7来定义。
由表3可知,与HAMD累积减分结果类似,在第4周时,接受SSRI+GZA治疗的患者群体有效率和缓解率均较高,分别高达66.7%和46.7%。
表3.两组间不同时间点治疗有效率和缓解率比较
注:α:卡方检验;β:Fisher’s精确检验
3.血清生物学指标检测
多种血清生物学指标的结果参见图2,血清生物学指标的累积减低值比较参见表4。
由图2可知,多种血清生物学指标的结果,数据离散程度(标准差)较大。其中,为便于后续分析,CRP数值已进行对数转换。连续测量方差分析未检出显著性差异。
表4为对血清生物学指标的累积减低值进行协方差分析,结果提示在第4周时,SSRI+GZA组的TNF-α和IL-1β累积减低值均较SSRI+PBO组高。
表4.血清生物学指标的累积减低值比较
4.中介效应分析
依据前面提到的GZA合并用药对HAMD减分值及TNF-α、IL-1β等血清生理学指标产生的显著效应,结合既往临床与基础研究证据提示GZA干预能够缓解炎症,且以TNF-α和IL-1β为主的炎性因子可能与抑郁症状存在关联,推测:GZA合并用药的治疗方法可通过调节炎性因子(如:CRP、HMGB1、TNF-α、IL-1β、IL-6等)表达、改善机体免疫功能,从而产生更高效的抗抑郁作用。
如图3所示,c代表GZA干预对HAMD减分的总体效应,a代表GZA对TNF-α减低的效应,b代表TNF-α减低对HAMD减分的效应,c’代表扣除通过a*b这一中介途径后的GZA干预效应。换而言之,运用Andrew F.Hayes提供的bootstrap法,本实施例中介效应的规模为c-c’(亦可表示为a*b),即1.579(95%CI:0.124-3.514)。
5.1按CRP水平分组的回顾性疗效分析
考虑到合并抗炎治疗能够产生更优的抗抑郁效果,且CRP这一指标能够较好地反应机体近期炎症水平,故将前述纳入的患者按CRP水平分为高炎组和低炎亚组(以3mg/L为界,≤3mg/L为低炎亚组,>3mg/L为高炎组)进行回顾性分析,分析结果参见图4。由图4可知,连续测量方差分析在高炎与低炎亚组中的各个时间节点,均未发现HAMD评分在SSRI+PBO与SSRI+GZA间有显著性差异。
将两组根据CRP水平的再分组在不同时间点HAMD累计减分值比较,结果参见表5,由表5可知,与前述表2类似,对各个时点的HAMD累积减分值进行协方差分析。结果提示,在低炎患者中,SSRI+PBO与SSRI+GZA两组的效应没有统计学差异;而在高炎患者中,SSRI+GZA组在2周及4周时HAMD累积减分值均显著高于SSRI+PBO组,说明在高炎患者中合并抗炎治疗能产生更佳疗效。
表5.两组根据CRP水平的再分组在不同时间点HAMD累计减分值比较
与前述表3类似,对各个观察点的治疗效果(有效率及缓解率)进行统计分析,分析结果参见图5。由于对分组进行了进一步拆分,低炎亚组中SSRI+PBO与SSRI+GZA分别仅存14、13例,高炎亚组中SSRI+PBO与SSRI+GZA分别仅存12、17例。由于样本例数偏低,此处并未出现统计性差异,但由图5直观可以看出,SSRI+GZA组较SSRI+PBO组有效率与缓解率均高,且在高炎患者中尤甚。
综上所述,甘草酸对抗抑郁药物有明显的增效作用,在临床中应用能够快速、安全、有效的改善抑郁症的症状。
Claims (10)
1.甘草酸及其药学上可接受的盐作为唯一活性成分在制备抗抑郁药物中的应用。
2.甘草酸及其药学上可接受的盐作为抗抑郁药物增效剂的应用。
3.根据权利要求2所述的甘草酸作为抗抑郁药物增效剂的应用中,其特征在于,所述甘草酸和/或甘草酸药学上可接受的盐的用量为在抗抑郁药物中加入150mg-450mg/日。
4.甘草酸及其药学上可接受的盐在联合使用抗抑郁药治疗难治性抑郁症中的应用。
5.根据权利要求1-4任一项所述的应用,其特征在于,所述的甘草酸药学上可接受的盐选自甘草酸二铵、甘草酸单铵盐、甘草酸一钾盐或甘草酸二钾盐。
6.根据权利要求1-4任一项所述的应用,其特征在于,所述抗抑郁药物选自三环类抗抑郁药、单胺氧化酶抑制剂、选择性5-羟色胺再摄取抑制剂、选择性5-羟色胺和去甲肾上腺素再摄取抑制剂、特异性5-羟色胺和去甲肾上腺素重摄取抑制剂、选择性去甲肾上腺素再摄取抑制剂、5-羟色胺拮抗/回收抑制剂、去甲肾上腺素和多巴胺能再摄取抑制剂、褪黑素类似物或植物类抗抑郁药物。
7.一种抗抑郁症的药物组合物,所述药物组合物的活性成分是甘草酸和/或甘草酸药学上可接受的盐。
8.一种抗抑郁症的药物组合物,所述药物组合物的活性成分是抗抑郁药物和甘草酸和/或甘草酸药学上可接受的盐。
9.根据权利要求7或8所述的药物组合物,其特征在于,所述的甘草酸药学上可接受的盐选自甘草酸二铵、甘草酸单铵盐甘草酸一钾盐或甘草酸二钾盐。
10.根据权利要求7或8所述的药物组合物,其特征在于,所述抗抑郁药物选自三环类抗抑郁药、单胺氧化酶抑制剂、选择性5-羟色胺再摄取抑制剂、选择性5-羟色胺和去甲肾上腺素再摄取抑制剂、特异性5-羟色胺和去甲肾上腺素重摄取抑制剂、选择性去甲肾上腺素再摄取抑制剂、5-羟色胺拮抗/回收抑制剂、去甲肾上腺素和多巴胺能再摄取抑制剂、褪黑素类似物或植物类抗抑郁药物。
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