CN104940181B - β‑羟丁酸或其药学上可接受的盐的用途 - Google Patents
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Abstract
本发明公开了一种β‑羟丁酸或其药学上可接受的盐的用途,具体为β‑羟丁酸或其药学上可接受的盐在制备用于防治糖尿病及其慢性并发症的药物方面的应用,属于医药技术领域。本发明利用链脲佐菌素(STZ)诱导糖尿病大鼠模型,应用β‑羟丁酸皮下注射观察其对大鼠糖尿病及其慢性并发症的防治作用,结果表明,β‑羟丁酸可抑制大鼠体重下降,改善大鼠慢性胰腺、大血管、肾脏、心脏、肝脏等病理学功能变化。本发明以β‑羟丁酸或其药学上可接受的盐作为药物活性成分,与医药领域中常规添加剂组合制成药物,可用于改善糖尿病及其慢性并发症,针对抗氧化应激和硝基化损伤所致疾病进行临床治疗。
Description
技术领域
本发明具体涉及β-羟丁酸或其药学上可接受的盐在制备用于防治糖尿病及其慢性并发症的药物方面的应用,属于医药技术领域。
背景技术
糖尿病为内分泌疾病,以持续性高血糖为基本生化特征,其危害已成为仅次于心脑血管病和恶性肿瘤的非传染性疾病。氧化应激被认为是糖尿病及其慢性并发症发生发展的中心环节(Sudhahar V,et al.2013;Hernandez-Mijares A,et al.2013)。糖尿病时,氧化应激反应的关键酶诱导型一氧化氮合酶(inducible nitric oxide synthase,iNOS)被诱导,合成过量的一氧化氮(nitric oxide,NO)。NO与O2 .-可迅速发生反应生成过氧亚硝基阴离子ONOO-(peroxynitrite),ONOO-可变构转化为高能态,是目前已知的氧化作用最强的一类物质。ONOO-可造成蛋白质、脂质和DNA等生物大分子结构修饰或功能障碍,参与糖尿病血管并发症的发生与进展(El-Remessy AB,et al.2010;Xu J,et al.2012)。Li等(2010)的研究表明ONOO-清除剂Urate可显著延缓糖尿病血管病变的发生与进展,进一步证实ONOO-的关键作用。
然而,抗氧化剂维生素E、C等在大规模临床实验中的疗效却不尽如人意,这可能与它们缺乏特异性,不能有效抑制氧化应激有关(Rahangdale S,et al.2009)。有研究表明,高糖可引起转录因子、组蛋白等的翻译后修饰,导致病理性基因持续表达,在控制血糖后仍会产生并发症(Villeneuve LM,et al.2008;Zhong Q,Kowluru RA.2013,)。糖尿病时,ONOO-最显著的作用是引起蛋白质中酪氨酸残基硝基化,而硝基酪氨酸(Nitrotyrosine,NT)也被认为是ONOO-生成的标志。蛋白质被硝基化后,其结构和功能改变,且很难逆转,导致酶活性、细胞信号转导等的持续改变,引发病理损伤(Khan MA,et al.2014)。
目前,全球已有3.82亿人患有DM,预计到2035年将达到5.92亿。我国有近1亿人患有DM,约占全球患病人数的四分之一,患病率位居世界第一位。糖尿病的主要危害是各种慢性并发症,不管是I型还是II型糖尿病,慢性并发症是致死的主要原因之一。目前,临床上治疗用于糖尿病的口服降糖药甚至胰岛素,虽可控制血糖,但不能阻断糖尿病慢性并发症的发生发展,而针对糖尿病慢性并发症当前尚无特效治疗药物。因此,急需研制一种有效的用于治疗糖尿病及其慢性并发症的药物。
β-羟丁酸是酮体的主要组分,除供能外β-羟丁酸还被报道作为信号分子参与基因表达调控(Newman JC,Verdin E.2014)。还有报道称β-羟丁酸具有抗氧化应激、抗硝基化损伤作用,但内在分子机制尚不清楚(Cheng B,et al.2013;Kabiraj P,et al.2012)。最近有研究表明,β-羟丁酸作为内源性HDAC抑制剂,可选择性升高抗氧化等保护性基因启动子部位的组蛋白乙酰化水平,起到保护作用(Shimazu T,et al.2013;Lim S,et al.2011)。但是,在糖尿病时β-羟丁酸能否影响起关键作用的ONOO-,从而发挥心血管保护作用尚未有研究。亦有报道,低β-羟丁酸水平伴随着过量的纤维化(Joseloff E,et al.2013)。
发明内容
本发明的目的是提供一种β-羟丁酸或其药学上可接受的盐的用途。
为了实现以上目的,本发明所采用的技术方案是:
β-羟丁酸或其药学上可接受的盐的用途,具体为β-羟丁酸或其药学上可接受的盐在制备用于防治糖尿病及其慢性并发症的药物方面的应用。
β-羟丁酸药学上可接受的盐包括β-羟丁酸钠盐、β-羟丁酸钾盐等,均为市售商品。
所述糖尿病为I型糖尿病。
所述药物中β-羟丁酸或其药学上可接受的盐为药学活性成分(或主药),在药物中的质量百分比含量可为0.01~99.9%。除上述组分外,药物中还可包含制药领域常规添加的赋形剂(如作为填充剂的乳糖、淀粉等糖醇类)、润滑剂(如硬脂酸镁、硬脂酸钙)、增塑剂、崩解剂和防腐剂等,具体选择可根据主药性质及制备剂型等确定。本发明中,药物的剂型不限,可以为片剂(如分散片)、散剂(如冻干粉)、胶囊剂(如微囊、软胶囊)、颗粒剂、丸剂(如微丸、滴丸)、口服液、注射液等任意药剂学剂型。对于液态药剂(如口服液、注射剂等),其pH值范围没有特别限制,通常为4~8.5。
应当注意的是,β-羟丁酸或其药学上可接受的盐对糖尿病及其慢性并发症的防治作用,是指对糖尿病及其慢性并发症的形态与功能的改善作用,包括增加体重,降低硝基化水平,改善胰脏、主动脉、肾脏、心脏、肝脏等的病理形态学改变等。
β-羟丁酸的分子结构式如下式所示:
更具体的,β-羟丁酸或其药学上可接受的盐在制备拮抗(或抑制)由糖尿病及其慢性并发症所致氧化应激及硝基化的药物方面的应用。例如,在糖尿病及其慢性并发症的发生发展时期,β-羟丁酸或其药学上可接受的盐作为药物活性成分,与医药领域中常规添加剂组合制成药物,施用于病患针对抗氧化应激和硝基化损伤所致疾病的临床治疗。治疗过程中,β-羟丁酸或其药学上可接受的盐取药用量,可酌情增减,其质量百分比含量在0.01~99.9%范围。
更具体的,β-羟丁酸或其药学上可接受的盐在制备抑制由糖尿病及其慢性并发症所致体重下降的药物方面的应用。
本发明的有益效果:
本发明利用链脲佐菌素(STZ)诱导糖尿病大鼠模型,应用β-羟丁酸皮下注射观察其对大鼠糖尿病及其慢性并发症的防治作用,结果表明,β-羟丁酸可抑制大鼠体重下降,改善大鼠慢性胰脏、主动脉(或大血管)、肾脏、心脏、肝脏等病理学功能变化。
本发明以β-羟丁酸或其药学上可接受的盐作为药物活性成分,与医药领域中常规添加剂组合制成药物,可用于改善糖尿病及其慢性并发症,针对抗氧化应激和硝基化损伤所致疾病进行临床治疗。
附图说明
图1为本发明试验例中各试验组大鼠的体重变化结果;
图2为各试验组大鼠的胰腺病理学变化结果;
图3为各试验组大鼠的大血管病理学变化结果;
图4为各试验组大鼠的肾脏病理学变化结果;
图5为各试验组大鼠的心脏病理学变化结果;
图6为各试验组大鼠的肝脏病理学变化结果。
具体实施方式
下述实施例仅对本发明作进一步详细说明,但不构成对本发明的任何限制。
实施例1
本实施例中β-羟丁酸在制备用于防治糖尿病及其慢性并发症的药物方面的应用,包括:取药用量的β-羟丁酸,与赋形剂淀粉混合制备成粉剂。β-羟丁酸的药用量为1~500mg/kg体重。
实施例2
本实施例中β-羟丁酸药学上可接受的盐在制备拮抗氧化应激及其硝基化的药物方面的应用,包括:取药用量的β-羟丁酸钠盐,与注射用水混合制备成注射液。
实施例3
本实施例中β-羟丁酸在制备抑制由糖尿病所致体重下降的药物方面的应用,包括:取药用量的β-羟丁酸,与注射用水混合制备成注射液。
在本发明的其他实施例中,也可取药用量的β-羟丁酸钠盐,与注射用水混合制备成注射液。药用量均同实施例1。在本领域,粉剂、注射液的制备为现有技术,此处不予赘述。
试验例
β-羟丁酸用于改善糖尿病及其慢性并发症形态与功能的有效性试验:
(1)I型糖尿病大鼠模型的建立
对雄性SD大鼠(3月龄,体重280~320g)腹腔注射链脲佐菌素STZ(40mg/kg体重,新鲜配制),制备糖尿病模型。同样大鼠腹腔注射缓冲液作为正常对照。
(2)β-羟丁酸作用于I型糖尿病大鼠模型
糖尿病大鼠分为4组:正常对照组、糖尿病组、β-羟丁酸组和铁卟啉(FeTPPs)组。治疗组分别给予β-羟丁酸(50mg/kg体重)和铁卟啉(0.5mg/kg体重),两天1次皮下注射;非治疗组两天1次皮下注射等量生理盐水;正常对照组不给予任何治疗。疗程为13周。
在实验开始和结束时,分别给大鼠称重,并计算各组大鼠的体重增量。试验结果见图1。结果表明,在β-羟丁酸治疗试验中,与正常对照组(123±18g)相比,糖尿病组大鼠体重不增(6±33g),有统计意义(p<0.01);与糖尿病组相比,β-羟丁酸组大鼠体重显著增加(153±53g),有统计意义(p<0.01);铁卟啉组大鼠体重显著增加(96±28g),有统计意义(p<0.05)。数据分析均采用两样本均数比较t检验。
实验结束时,分别取大鼠的胰腺、大血管、肾脏、心脏和肝脏,再分别进行HE染色,观察病理改变,试验结果见图2~6。
从图2可以看出,与正常对照组相比,糖尿病组胰腺细胞皱缩,呈条束状而变窄,细胞浆变空;与糖尿病组相比,β-羟丁酸组和铁卟啉组胰腺细胞病理改变明显减轻。
从图3可以看出,与正常对照组相比,糖尿病组血管管壁增厚,内皮细胞脱落;与糖尿病组相比,β-羟丁酸组和铁卟啉组胰腺细胞病理改变明显减轻。
从图4可以看出,与正常对照组相比,糖尿病组肾小球肥大,肾小囊腔增宽;与糖尿病组相比,β-羟丁酸组和铁卟啉组胰腺细胞病理改变明显减轻。
从图5可以看出,与正常对照组相比,糖尿病组心肌纤维排列紊乱,润盘消失;与糖尿病组相比,β-羟丁酸组和铁卟啉组胰腺细胞病理改变明显减轻。
从图6可以看出,与正常对照组相比,糖尿病组肝细胞水肿,间隙增宽;与糖尿病组相比,β-羟丁酸组和铁卟啉组胰腺细胞病理改变明显减轻。
Claims (2)
1.β-羟丁酸或其药学上可接受的盐的用途,其特征在于:β-羟丁酸或其药学上可接受的盐在制备用于防治糖尿病慢性并发症的药物方面的应用;
其中对于糖尿病慢性并发症的防治是指改善胰脏、主动脉、肾脏、心脏、肝脏的病理形态学改变。
2.根据权利要求1所述的用途,其特征在于:β-羟丁酸或其药学上可接受的盐为药物活性成分,在药物中的质量百分比含量为0.01~99.9%。
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