CN116919931A - 烟草提取物在制备预防和/或治疗糖尿病药物中的应用 - Google Patents
烟草提取物在制备预防和/或治疗糖尿病药物中的应用 Download PDFInfo
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Abstract
本发明公开了烟草提取物在制备预防和/或治疗糖尿病药物中的应用,属于医药技术领域;本发明通过实验证实,烟草提取物中的活性成分茄尼醇能够对2型糖尿病发挥优异的治疗效果,尤其是早期2型糖尿病的治疗,能够降低肥胖小鼠的体重、腹部脂肪和肝脏重量,改善小鼠毛发粗糙凌乱、多食、多饮、多尿的高血糖状态,降低空腹血糖值,且能够缓解胰岛素抵抗和葡萄糖耐受症状;并且与阳性药物二甲双胍相比,茄尼醇在较低浓度范围内即具有良好效果,即茄尼醇具有较高的生物利用度。
Description
技术领域
本发明属于医药技术领域,尤其涉及一种烟草提取物在制备预防和/或治疗糖尿病药物中的应用。
背景技术
糖尿病(diabetes mellitus,缩写为DM,简称diabetes)是一种复杂的全身慢性代谢性疾病,长期的代谢紊乱使得病人伴有典型的高血糖、高胰岛素血症和高甘油三酯血症。糖尿病分为1型糖尿病(T1DM)和2型糖尿病(T2DM),其中2型糖尿病约占个体的95%。1型糖尿病的特征是与胰腺β细胞破坏相关的胰岛素绝对缺乏,而2型糖尿病主要是由于胰岛素抵抗(Insulin resistance,IR)和胰岛素分泌不足。不论是哪一种糖尿病,如果不进行治疗,可能会引发许多并发症。一般病征有视力模糊、头痛、肌肉无力、伤口愈合缓慢及皮肤搔痒。急性并发症包括糖尿病酮酸血症与高渗透压高血糖非酮酸性昏迷;严重的长期并发症则包括心血管疾病、中风、慢性肾脏病、糖尿病足、以及视网膜病变等。近些年糖尿病的发病率大幅上升,全球患病人数已经超过4.22亿,到2035年将达到5.92亿,造成全球公共卫生极重的负担,病人生活品质严重下降。
目前临床上应用的口服抗糖尿病药物,具有较多不良反应,如包括低血糖、体液潴留、骨质疏松和心力衰竭等。因此,有必要开发新的副作用小的抗糖尿病药物来控制糖尿病的进展。天然产物,包括草药配方及其提取物,几千年来一直以独特的理论和疗法体系用于治疗人类疾病,也已经成为糖尿病药物发现的重要资源。如类黄酮类槲皮素、芦丁、柚皮苷、芹菜素、山奈酚等,多酚类表没食子儿茶素没食子酸酯,白藜芦醇、姜黄素、花青素等,萜类化合物脱落酸、积雪草酸、甘草次酸、芳樟醇等,生物碱类小劈碱、苦参碱、秋水仙碱等,醌类大黄素、丹参酮,百里醌等,植物多糖类,多肽类等(Pharmaceuticals(Basel).2021Aug;14(8):806)。尽管有诸多候选的植物天然活性成分用于糖尿病疾病的治疗研究,由于抗糖尿病活性的差异,还没有达到理想的效果。
对于烟草植物而言,最早从15世纪末出现在人类视野里的是因为烟草的药用价值。美洲土著民将烟草视为“万灵药或者圣药(holy herb或者God’sremedy)”,用于治疗多种疾病,如支气管炎、牙痛、喉咙痛、胸膜炎、黄疸、癫痫、鼻炎、肠胃炎、腹泻、头痛、耳炎、百日咳、梅毒、关节炎、皮炎、感冒、烧伤、脓疮溃烂、蚊虫叮咬等,还可止血、退热、抗疲劳、增白牙齿等。20世纪后期,随着医学的发展,人们的注意力转向了影响大脑和神经发育的疾病,尤其是老年人群高发病率的神经退行性疾病如阿尔兹海默症和帕金森病等,烟草的医用价值再次得到重视(J Herb Med.2020Aug;22:100374)。烟草植物提取成分茄尼醇(Solanesol,C45H74O)是由九个异戊二烯单元组成的非环状萜烯醇,在烟草中的干重含量可高达4%,在其它茄科类番茄、马铃薯、茄子、辣椒等的茎叶中也有存在。长久以来,茄尼醇主要作为医药中间体,用于合成辅酶Q10、维生素K12和抗癌增效剂。茄尼醇特殊的全反式链节结构,使之具有脂质抗氧化作用和很强的自由基吸收能力,茄尼醇还具有抗菌消炎和神经保护的潜在作用。已报道茄尼醇相关的专利,主要集中在茄尼醇的提取分离纯化方面,较少数专利是关于茄尼醇衍生物的制备方法以及茄尼醇修饰的前药制备方法上。现有专利“一种茄尼醇的复合物及其制作方法(CN1395939A)”在背景技术中提到“茄尼醇是某些具有临床疗效的重要药物的有效成分,在临床上显示了较强的抗癌活性,能够抗菌消炎,对于治疗充血性心脏病所致的浮肿、肺充血、心绞痛,治疗急慢性肝炎、亚急性肝坏死,治疗坏血病,十二指肠溃疡,胃溃疡、坏死性牙周炎、凝血、止血等有良好作用”,但是事实上,截至目前相关的研究进展,茄尼醇的药理学研究数据显示,上述除了可能具有牙周炎治疗的效果、抗菌消炎、以及酒精性肝损伤外,并没有该专利中提到的诸多活性。
发明内容
本发明的目的在于克服上述现有技术的不足之处而提供一种烟草提取物在制备治疗和/或预防糖尿病药物中的应用。
为实现上述目的,在本发明的第一方面,本发明提供了一种烟草提取物在制备预防和/或治疗糖尿病药物中的应用。
作为本发明所述应用的优选实施方式,所述烟草提取物为茄尼醇。
作为本发明所述应用的优选实施方式,所述糖尿病为2型糖尿病。
作为本发明所述应用的优选实施方式,所述糖尿病为早期2型糖尿病。
本发明首次发现了烟草提取物的活性成分茄尼醇能够用于制备预防和/或治疗糖尿病药物;发明人研究发现,烟草提取物茄尼醇能够对2型糖尿病发挥优异的治疗效果,在小鼠模型实验中显示,茄尼醇能够降低肥胖小鼠的体重、腹部脂肪和肝脏重量,改善小鼠毛发粗糙凌乱、多食、多饮、多尿的高血糖状态,降低空腹血糖值,且能够缓解胰岛素抵抗和葡萄糖耐受等症状,尤其是能够有效改善早期2型糖尿病病症。
在本发明的第二方面,本发明提供了一种预防和/或治疗糖尿病的药物制剂,所述药物制剂包括茄尼醇或其药学上可接受的盐、异构体、前药、代谢产物、氮氧化合物、水合物、多晶型物或溶剂化物。
作为本发明所述药物制剂的优选实施方式,所述药物制剂还包括药学上可接受的载体。
作为本发明所述药物制剂的优选实施方式,所述药物制剂的剂型为胶囊剂、片剂、粉剂、口服剂、丸剂或注射剂。
优选地,所述药物制剂的剂型为口服剂。
在后期小鼠实验研究中,将茄尼醇以灌胃的方式给药的结果显示茄尼醇能够有效的降低空腹血糖,缓解胰岛素抵抗和葡萄糖耐受等症状,启示将茄尼醇以口服剂的方式服用能够取得优异的治疗糖尿病的效果,并且口服剂使用方便。
发明人研究发现,除了本发明所述药物制剂外,茄尼醇还能够与食品领域上可接受的辅料一起制备成食品,或者与保健品领域上可接受的辅料一起制备成保健品。
在本发明的第三方面,本发明提供了一种预防和/或治疗糖尿病的药物组合物,所述药物组合物包括茄尼醇或其药学上可接受的盐、异构体、前药、代谢产物、氮氧化合物、水合物、多晶型物或溶剂化物,和常见的预防和/或治疗糖尿病的药物。
作为本发明所述药物组合物的优选实施方式,所述常见的预防和/或治疗糖尿病的药物为促胰岛素分泌剂。
优选地,所述促胰岛素分泌剂为磺脲类药物或格列奈类药物。
示例性的,所述磺脲类药物可为格列齐特、格列吡嗪、格列硅酮、格列美脲;所述格列奈类药物可为瑞格列奈、那格列奈、米格列奈。
作为本发明所述药物组合物的优选实施方式,所述药物组合物还包括药学上可接受的载体。
与现有技术相比,本发明的有益效果为:
本发明公开了烟草提取物在制备预防和/或治疗糖尿病药物中的应用,经实验证实,烟草提取物中的活性成分茄尼醇能够对2型糖尿病发挥优异的治疗效果,尤其是早期2型糖尿病的治疗,并且与阳性药物二甲双胍相比,茄尼醇在较低浓度范围内即具有良好效果,说明茄尼醇具有较高的生物利用度。具体地,在小鼠模型实验中通过灌胃给药方式进行研究,结果显示茄尼醇能够降低肥胖小鼠的体重、腹部脂肪和肝脏重量,改善小鼠毛发粗糙凌乱、多食、多饮、多尿的高血糖状态,降低空腹血糖值,且能够缓解胰岛素抵抗和葡萄糖耐受症状。
附图说明
图1为茄尼醇对db/db小鼠形态影响的结果图:
A为小鼠体重变化的结果图;
B为小鼠外观形态和肝脏形态观察图;
C为小鼠肝脏系数结果图;
D为小鼠腹部白色脂肪系数结果图;
图2为茄尼醇对糖尿病小鼠空腹血糖的影响结果图;
图3为茄尼醇对糖尿病小鼠摄食量和饮水量的影响结果图:
A为对小鼠摄食量影响结果图;
B为对小鼠饮水量影响结果图;
图4为茄尼醇对糖尿病小鼠葡萄糖耐量的调节作用结果图:
A为葡萄糖处理前后血糖值变化趋势图;
B为血糖曲线面积分析结果图;
图5为茄尼醇对糖尿病小鼠胰岛素抵抗的调节作用结果图:
A为胰岛素处理前后血糖变化趋势图;
B为血糖曲线面积分析结果图。
具体实施方式
为更好的说明本发明的目的、技术方案和优点,下面将结合具体实施例对本发明作进一步说明。
若无特殊说明,本发明使用的试剂、设备都是常规可得。
本发明实验数据中的显著性差异分析是采用Ordinary one-way ANOVA方差分析进行,其中**代表p<0.01,*代表p<0.05。
实施例
本发明实施例验证烟草提取物茄尼醇对糖尿病的作用,具体包括以下步骤:
一、实验部分
1、动物实验
本发明动物实验采用的自发性的2型糖尿病小鼠动物模型(BKS-DB小鼠,db/db小鼠),该模型为瘦素受体基因纯合突变的小鼠,由C57BL/KsJ近亲交配株常染色体隐性遗传衍化而来。该小鼠出生10天到14天出现高胰岛素血症,在4周左右贪食、肥胖,4~8周时胰岛β细胞障碍开始出现高血糖,在3~4个月达到血糖高峰期。db/db小鼠具有和人类2型糖尿病相似的症状,表现为多饮、多食、多尿、肥胖、高血糖、高胰岛素血症、脂代谢异常等,同时胰岛素分泌增加为正常值的数倍,组织中的胰岛素受体水平降低,结合力下降。形态学发现胰岛细胞萎缩,脂肪肝以及脾脏和淋巴结发育不全等。该小鼠还可见外周神经病变、心肌病变、伤口愈合延迟和雌性纯合子卵巢激素生成减弱等特征,其发病过程与2型糖尿病患者非常相似。加之db/db小鼠形态较为稳定,实验周期短,易于观察,因而该小鼠模型是糖尿病干预治疗研究的理想模型(中国临床药理学与治疗,2013,18(10):1196-1200;中国比较医学杂志,2017,8:12-15)。
本发明实验应用SPF级db/db小鼠,雄性,7-9周龄;C57BL/6正常小鼠6只作为正常对照组(Control)。检疫3-5天,检疫合格后在标准照明条件下(12小时光/暗循环)饲养。经过1周的适应性喂养,db/db小鼠按照体重分层随机分为4组,模型对照组(Model,n=6),给药溶剂体积质量比为0.5%的CMCNa;茄尼醇低剂量组(L-Solanesol,n=6),茄尼醇高剂量组(H-Solanesol,n=6),分别给药15,30mg/kg/day;阳性对照组(Positive,n=6),给药二甲双胍250mg/kg/day。C57BL/6正常小鼠给对照溶剂体积质量比为0.5% CMCNa。各组小鼠按照给药剂量(根据体重计算给药剂量)进行灌胃相应的受试样品,每天灌胃一次,连续六周。
小鼠给药期间,所有小鼠自由饮水正常饮食,每周一早上给足够的饮食和饮水,并分别用天平称量添食的饲料重量和用量筒检测给水的量,每周三晚上称量剩余的饲料和水量。给药第五周的周四进行糖耐量检测,给药第六周的周四进行胰岛素耐受测试。恢复三天后,小鼠禁食不禁水6h后解剖取样。肝脏组织和腹部白色脂肪组织用预冷的生理盐水清洗后,尽量吸干称重。
2、葡萄糖耐量实验(Glucose Tolerance Test,GTT)
给药满五周后小鼠禁食16h后检测空腹血糖,腹腔注射葡萄糖2g/kg,于注射后第30、60、120min取尾静脉血测其血糖水平记录并计算血糖曲线下面积(area under thecurve,AUC)。
3、胰岛素耐受测试(Insulin Tolerance Test,ITT)
给药满六周后小鼠禁食6h后检测空腹血糖,腹腔注射人胰岛素(Eli Lilly&Company,Indianapolis,IN)0.75U/kg后30min、60min和120min取尾静脉血测其血糖水平记录并计算血糖曲线下面积(area under the curve,AUC)。
二、结果分析
1、茄尼醇对db/db小鼠形态的影响
从图1中A可以看出,小鼠体重在早期变化并不明显,各组都呈现出随周龄稳步增长的趋势;在后期,从给药四周后开始,小鼠体重开始出现较为明显的分组变化,阳性药组体重开始下降,给药五周后,茄尼醇组体重也有下降,这在糖尿病早期对于伴随的肥胖的干预是具有积极的作用的。从图1中B的外部形态(整个试验过程都对外部形态进行了观察,其中图1中B给出的是处死前的整体外部形态图,解剖取样后观察肝脏组织)可以看出,模型组小鼠容易掉毛,毛发凌乱粗糙,对照组和用药组小鼠毛发较为顺滑,尤其是高浓度茄尼醇组,从拍照来看,毛发边缘更加整齐顺滑,说明茄尼醇在整体形态外观上对糖尿病小鼠具有保护作用;同时从下方的肝脏图中可以观察到用药茄尼醇组小鼠肝脏病变情况明显改善,db/db小鼠具有明显的脂肪肝,肝脏体积和重量变大,肝脏色泽变浅发黄,茄尼醇高剂量组肝脏色泽红润,体积比模型组小。从图1中C可以看出,茄尼醇高剂量组和茄尼醇低剂量组肝脏系数都明显下降,尤其是茄尼醇高剂量组,其小鼠肝脏更趋近于正常对照组,肝脏系数(肝脏重量/体重*100%)与模型相比有着显著性差异(其中茄尼醇高剂量组与模型组相比p<0.01,茄尼醇低剂量与模型组相比p<0.05);即说明茄尼醇对糖尿病小鼠的脂肪肝具有较好的缓解作用,有助于保护肝脏保持循环中的血糖水平和其它能量物质水平稳定。从图1中D可以观察到,在腹部脂肪的检测中,虽然目测体型似乎没有大的变化,但是茄尼醇高剂量组和茄尼醇低剂量组腹部白色脂肪含量都显著减少,体现在腹部白色脂肪系数(腹部白色脂肪/体重*100%)与模型组相比有显著差异(其中茄尼醇高剂量组与模型组相比p<0.05,茄尼醇低剂量与模型组相比p<0.01);说明茄尼醇对危害极大的腹型肥胖具有抵抗作用,这对于由肥胖引起的2型糖尿病而言具有重要意义,且对于糖尿病小鼠内脏的保护具有重要作用。
2、茄尼醇对糖尿病小鼠空腹血糖的影响
小鼠分组给药前进行空腹血糖的检测记录,给药后第一周、第二周、第三周、第六周采尾静脉血进行空腹血糖的检测,得到的结果如图2所示。从图2中可以看出,模型组小鼠空腹血糖持续上升,最高达33mmol/L;二甲双胍组、茄尼醇高剂量组和茄尼醇低剂量组的空腹血糖值具有显著性下降的趋势;且茄尼醇高剂量组数据更为均一,即使用药浓度比二甲双胍组低约20倍,仍然具有与其近似的效果,甚至在前三周有着比二甲双胍更显著的降低空腹血糖的能力;治疗六周后茄尼醇高剂量组和茄尼醇低剂量组的高血糖症状均发生了明显的改善;从结果中可以看出,本发明利用的烟草提取物茄尼醇具有较好的降低高血糖并维持血糖稳定的积极作用,尤其是在早期,可能具有更优于阳性药二甲双胍的效果。
3、茄尼醇对糖尿病小鼠摄食量和饮水量的影响
由于在给药过程中要进行小鼠葡萄糖耐量和胰岛素抵抗的测试,涉及到小鼠的禁食操作,因此小鼠摄食量和饮水量的称量,为了减少误差,实验设计为统计每周一到周三的量;其中摄食量的统计结果如图3中A所示,饮水量的统计结果如图3中B所示;从图3中可以看出,阳性组、茄尼醇高剂量组和茄尼醇低剂量组的小鼠的摄食量和饮水量均下降,很好的改善了糖尿病小鼠多食多饮的现象。在饲养过程中也观察到阳性组、茄尼醇高剂量组和茄尼醇低剂量组的小鼠垫料较为干爽,多尿现象也有改善;即本发明涉及的茄尼醇对糖尿病的饮食和排泄均有明显的改善,促进了糖尿病小鼠趋近正常的生活规律。另外,从变化趋势来看,与二甲双胍变化幅度比较剧烈相比,茄尼醇高剂量组和茄尼醇低剂量组处理的糖尿病小鼠摄食量和饮水量变化比较平稳,也可能是茄尼醇组糖尿病小鼠情绪更加稳定,食欲相对来说变化幅度小;这对糖尿病发病后期易消瘦的特征而言,具有更好的调节作用。
4、茄尼醇对糖尿病小鼠葡萄糖耐量的调节作用
根据在给药过程中检测到的变化的空腹血糖值为依据,在第五周时进行葡糖糖耐受的检测。为了将小鼠空腹血糖起始值调为一致,将小鼠禁食16h后,检测空腹血糖,各组血糖值均在5左右,之后腹腔注射葡萄糖2g/kg,于注射后第30min、60min和120min取尾静脉血测其血糖水平记录,得到的结果如图4中A所示,并计算血糖曲线下面积(area under thecurve,AUC),得到的结果如图4中B所示。从图4中可以看出,阳性组、茄尼醇高剂量组和茄尼醇低剂量组小鼠葡萄糖耐量明显得到改善,尤其是茄尼醇高剂量组的效果甚至优于二甲双胍阳性药组,说明茄尼醇有助于加强糖尿病小鼠机体对血糖的调节能力。
5、茄尼醇对糖尿病小鼠胰岛素抵抗的调节作用
根据db/db小鼠的发病规律,为了更好的确认糖尿病小鼠的胰岛素抵抗的变化,在第六周在将小鼠禁食6h后检测空腹血糖,再腹腔注射人胰岛素(Eli Lilly&Company,Indianapolis,IN)0.75U/kg后30min、60min和120min取尾静脉血测其血糖水平记录,得到的结果如图5中A所示,进一步计算血糖曲线下面积(area under the curve,AUC),得到的结果如图5中B所示。从图5中可以看出,茄尼醇高剂量组改善胰岛素抵抗的效果与二甲双胍疗效相当。说明茄尼醇有助于增加糖尿病小鼠胰岛素的敏感性,平衡了胰岛素对血糖的调节作用。
最后应当说明的是,以上实施例以说明本发明的技术方案而非对本发明保护范围的限制,尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
Claims (10)
1.烟草提取物在制备预防和/或治疗糖尿病药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述烟草提取物为茄尼醇。
3.根据权利要求1所述的应用,其特征在于,所述糖尿病为2型糖尿病。
4.根据权利要求3所述的应用,其特征在于,所述糖尿病为早期2型糖尿病。
5.一种预防和/或治疗糖尿病的药物制剂,其特征在于,所述药物制剂包括茄尼醇或其药学上可接受的盐、异构体、前药、代谢产物、氮氧化合物、水合物、多晶型物或溶剂化物。
6.根据权利要求5所述的药物制剂,其特征在于,所述药物制剂还包括药学上可接受的载体。
7.根据权利要求5所述的药物制剂,其特征在于,所述药物制剂的剂型为胶囊剂、片剂、粉剂、口服剂、丸剂或注射剂。
8.一种预防和/或治疗糖尿病的药物组合物,其特征在于,所述药物组合物包括茄尼醇或其药学上可接受的盐、异构体、前药、代谢产物、氮氧化合物、水合物、多晶型物或溶剂化物,和常见的预防和/或治疗糖尿病的药物。
9.根据权利要求8所述的药物组合物,其特征在于,所述常见的预防和/或治疗糖尿病的药物为促胰岛素分泌剂。
10.根据权利要求8所述的药物组合物,其特征在于,所述药物组合物还包括药学上可接受的载体。
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CN105884579A (zh) * | 2016-05-13 | 2016-08-24 | 红云红河烟草(集团)有限责任公司 | 一种从废弃烟叶中提取茄尼醇的方法 |
CN116251080A (zh) * | 2023-02-16 | 2023-06-13 | 杭州师范大学 | 茄尼醇在制备预防、治疗或缓解慢性疼痛药物中的应用 |
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CN105884579A (zh) * | 2016-05-13 | 2016-08-24 | 红云红河烟草(集团)有限责任公司 | 一种从废弃烟叶中提取茄尼醇的方法 |
CN116251080A (zh) * | 2023-02-16 | 2023-06-13 | 杭州师范大学 | 茄尼醇在制备预防、治疗或缓解慢性疼痛药物中的应用 |
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KANWAL RAJ等: "Novel class of hybrid natural products as antidiabetic agents.", NATURAL PRODUCT RESEARCH, vol. 23, no. 1, pages 60 - 69 * |
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