CN107854511B - 关刀豆在制备用于保护膀胱避免损伤的药物中的用途 - Google Patents
关刀豆在制备用于保护膀胱避免损伤的药物中的用途 Download PDFInfo
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Abstract
本发明公开了关刀豆(Canavalia ensiformis)或其萃取物在制备用于保护膀胱避免损伤或预防频尿的药物中的用途。
Description
技术领域
本发明涉及关刀豆(Canavalia ensiformis)或其萃取物在制备用于保护膀胱避免损伤或预防频尿的药物中的用途。
背景技术
化学性膀胱炎可能是由药物如环磷酰胺、硫酸鱼精蛋白、丙酮等的口服治疗所引起,亦可能是由各种其他化学药剂的膀胱灌注所引起。关于各种形式的膀胱炎的病因的一个假设与膀胱尿道上皮表面的去功能化及损伤有关,且与尿液中的物质随后渗入膀胱壁,引起发炎并增加渗透性有关。硫酸鱼精蛋白已经被用于有效地破坏膀胱诱导性膀胱炎的黏蛋白层及尿道上皮。添加尿酸则增强了膀胱炎的严重程度。
在膀胱炎的化学诱导模型中对尿道上皮的损害的主要病因之一为氧化压力。在几种类型的化学性膀胱炎的治疗中,已被证明抗氧化活性的天然产物是有效的。据报告,在盐酸诱导的膀胱炎的大鼠模型中,氧化压力的降低可能在新型草药制剂的抗炎作用中具有作用(Bae,W.J.等人,Neurourology and urodynamics 34,86-91,2015年)。此外,报告也公开了在部分膀胱出口阻塞的大鼠模型中,植物治疗剂可以抑制膀胱氧化压力与发炎(Oka,M.等人,Suppression of bladder oxidative stress and inflammation by aphytotherapeutic agent in a rat model of partial bladder outlet obstruction,The Journal of urology 182,382-390,2009年)。
通过测定在动物膀胱中预防由鱼精蛋白-尿酸诱导的膀胱炎的能力,可以开发一些保护剂或治疗剂。
发明内容
在本发明中意外地发现,一些草药补充剂或萃取物对于保护膀胱以及预防频尿具有良好的效果。
据此,本发明的一方面提供了一种保护膀胱避免损伤的方法。该方法包含对一有需要的个体施用一有效量的关刀豆(Canavalia ensiformis)或其萃取物。
于另一方面,本发明提供了一种预防频尿的方法,包含对一有需要的个体施用一有效量的关刀豆(Canavalia ensiformis)或其萃取物。
于本发明的一实例中,该关刀豆或其萃取物可与一有效保护膀胱避免损伤或预防频尿的治疗剂或物质组合使用。
于再一方面,本发明提供了关刀豆(Canavalia ensiformis)或其萃取物在制备用于保护膀胱避免损伤的药物中的用途。
又再一方面,本发明提供了关刀豆(Canavalia ensiformis)或其萃取物用于在制备用于预防频尿的药物中的用途。
于本发明的一实例中,该关刀豆或其萃取物可与一有效保护膀胱避免损伤或预防频尿的治疗剂或物质组合使用。
于又一方面,本发明提供了一种用于保护膀胱避免损伤或预防频尿的医药或饮食组合物,包含一关刀豆或其萃取物。
于本发明的一实例中,本发明用于保护膀胱避免损伤或预防频尿的医药或饮食组合物,又包含一种有效保护膀胱避免损伤或预防频尿的治疗剂或物质。
通过参考以下描述、附图及申请专利范围,本发明的目的以及本文所公开的本发明的具体实施例的优点及特征将变得更加明显。此外,应当理解的是,这里描述的各种具体实施例的特征不是相互排斥的,且可以各种组合及排列存在。
附图说明
当结合附图阅读时,将更好地理解上述概述以及本发明以下的详细描述。在图式中:
图1显示了各组的膀胱重量,其中各组之间没有显著差异;
图2显示了在膀胱炎之前两组的膀胱压检查,其中该两组具有相似的膀胱容量,且以JB处理的组别被发现提供比没有以JB处理的组别显著更低的顺应性;
图3显示了无膀胱炎,以及在膀胱炎后1周及2周(无JB处理)的膀胱压检查。在膀胱炎后1周及2周后,发现顺应性与膀胱容量没有显著降低;
图4显示了不同组别的膀胱容量,其中在膀胱炎后1周及2周后皆发现所有组别中膀胱容量的无显著且相似的降低;
图5显示了所有组别的顺应性,其中在顺应性数目中发现增加,其代表膀胱僵硬度的增加,从而降低了真实的顺应性。对于没有以JB处理的组别,在膀胱炎后1周及2周后均未观察到显著降低。对于JB处理组,相较于膀胱发炎前及膀胱发炎后未以JB处理的组别,顺应性显著降低。虽然在膀胱发炎后以JP处理的组别有轻微的增加,但这些增加没有达到统计学上的意义;
图6显示了对所有形式的刺激的收缩反应。相较于没有JB处理的组别,没有JB的膀胱炎导致所有形式的刺激显著降低。然而,JB的预处理完全保护膀胱避免收缩功能障碍;
图7显示了抗坏血酸标准品与JB组的总抗氧化活性。曲线是线性的,该标准品的抗氧化剂值为每个mOD光密度27±1.7mg抗坏血酸,JB组则为104±19g AA单位/mg JB。
具体实施方式
除非另有定义,本文使用的所有技术及科学术语具有与本发明所属领域的技术人员通常理解的相同的含义。
于本发明中发现,关刀豆(Jack Bean)对于兔膀胱中由鱼精蛋白-尿酸引起的膀胱炎具有良好的预防效果,同时对于所有形式的刺激,可避免膀胱炎诱发的所有收缩功能,因而证实其可用于预防频尿。
如本文所用,「关刀豆」或「杰克豆(Jack Bean)」等词是指关刀豆(Canavaliaensiformis)的植物,其为一种长期用于人类营养的豆科植物。关刀豆(C.ensiformis)为高度达1米(3.3英尺)的缠绕植物。其具有深根,而使其可抗旱,且可经由长匍匐茎传播。其花朵为粉紫色,豆荚可长达36厘米(14英寸),并具有大白种子。其幼叶也可食用。
关刀豆的两个主要成分为脲酶及刀豆球蛋白A(concanavalin A)。刀豆球蛋白A(ConA)为一种凝集素(糖结合蛋白)且为豆科植物凝集素家族的成员。它特异性地与在各种糖、糖蛋白,以及糖脂中发现的某些结构结合。ConA是一种以刺激小鼠T细胞的能力而闻名的植物有丝分裂促进剂。其亦被发现在治疗肝癌及其他肿瘤方面是有效的。在功能上,脲酶属于酰胺水解酶与磷酸三酯酶的超家族。其为一种催化尿素水解为二氧化碳及氨的酶。这些毒性已被专有方法完全消除。
根据本发明,关刀豆或其萃取物是指关刀豆,或以关刀豆制成的产品,或关刀豆萃取物,或以关刀豆萃取物制成的产品,下文中统称为关刀豆补充剂或简称「JB」。可依医药或食品相关加工技术中已有的方法制成。
实施例关刀豆补充剂对兔子体内化学性膀胱炎的功效
方法
所有方法均由纽约州奥尔巴尼的Stratton VA医疗中心的IACUC委员会批准。
将18只成年雄性NZW兔分为3组,每组6只。
第1组为对照兔组。每只兔子在进入研究之前,以及在1周及2周时(研究结束时)均接受了膀胱压检查。
第2组为在诱导膀胱炎之前二周以及膀胱炎后二周以胃管灌食法每日给予安慰剂的兔子。在进入本研究之前,立即在诱导膀胱炎之前,以及在膀胱炎后1周及2周(研究结束时),每只兔子接受均膀胱压检查。
第3组为在诱导化学性膀胱炎之前二周以及化学性膀胱炎后二周以胃管灌食法每日给予1ml/kg关刀豆制剂(100mg/ml)的悬浮液的兔子。在进入本研究之前,立即在诱导膀胱炎之前,以及在膀胱炎后1周及2周(研究结束时),每只兔子均接受膀胱压检查。
基于其在动物研究中的用途而选择剂量。通过使用各种体内及体外技术已经显示JB具有显著的抗氧化活性。传统中药利用JB制剂来治疗癌症及氧化压力相关疾病等多种病症,而显示无副作用产生。
在最后的膀胱压检查之后立即将每只兔子的膀胱快速切除并称重。从膀胱中腹侧获得四条纵行肌条(1×0.5cm)。这些膀胱肌条包括肌肉及黏膜层。将每条肌条置于15ml含有葡萄糖(1mg/ml)的Tyrode溶液的单独水浴中,保持在37℃,并以95%氧气及5%二氧化碳的混合物平衡。施加2g的初始静止张力30分钟,并使用力位移传感器以等距方式记录收缩反应。
在2、8及32Hz,80V以及1ms持续时间下,以电场刺激(FS)刺激每条肌条。电场刺激(FS)后,依次测定碳酰胆碱(20mM)、KCl(120mM)以及ATP(1mM)的最大反应。以15分钟的间隔进行一系列三次洗涤,在每种药理学刺激以Tyrode溶液洗涤。
将膀胱的平衡以钝性解剖分离为肌肉及黏膜,在液态氮下冷冻并储存于-80℃下,以进行生物化学分析。
膀胱压检查:
在诱导化学性膀胱炎之前,以及在诱导化学性膀胱炎后1周及2周,每只兔子以氯胺酮/甲苯噻嗪(25mg/10mg,im)麻醉。然后将膀胱在无菌条件下以8F Foley导管导尿,使膀胱排空。使用加热的盐水以2ml/分钟的填充速率进行填充性膀胱内压图,直到发生排尿收缩或溢流失禁。一般而言,每个膀胱压检查需时约30分钟。每个膀胱压检查设置为在排尿为100%的体积,以便使顺应性针对体积的差异进行标准化。以高原区域曲线的20%以上的膀胱内压力升高计算顺应性。
膀胱炎:
立即在膀胱压检查后,将每只兔子以氯胺酮/甲苯噻嗪(25mg/10mg,im)麻醉。在无菌条件下,将膀胱以8F Foley导管导尿排空,然后装入25ml含有硫酸鱼精蛋白(10mg/ml)+尿酸(100mg/ml)的盐水溶液。将该溶液保留在膀胱中30分钟后,排出膀胱,然后以50ml盐水洗涤3次。使兔子恢复二周。
收缩研究:
经过2周的膀胱炎之后,每只兔子在麻醉下接受最后一次膀胱压检查。然后将每只兔子安乐死,并完整切除膀胱。然后将四条全厚度的纵行肌条自膀胱中切开并置于含有15ml的含有1mg/ml葡萄糖的含氧Tyrodes生理溶液的单独隔离水浴中。在30分钟平衡期间,将2克的张力放置在每条肌条上,然后以如下的方式刺激:以2、8及32Hz的电场刺激(FS)、碳酰胆碱、ATP,以及KCl。每次药物刺激后,膀胱肌条以氧化加热的Tyrodes 3倍溶液以15分钟间隔冲洗。记录最大收缩反应。
将膀胱的平衡分离为平滑肌及黏膜组织,在液态氮下冷冻并储存于-80℃,以用于随后的生物化学研究。
总抗氧化剂的CUPRAC测定:
使用CUPRAC测定以确定总抗氧化能力。该测定取决于抗氧化剂用于减少铜离子的电子捐赠能力。CUPRAC工作溶液由10mM氯化二铜二水合物、1M乙酸铵以及7.5mM新偶氮所组成。将0.15mL的上述三种溶液加入至0.15mL的各样品中,使其在室温下反应30分钟,然后在日立U-2001分光亮度计中于450nm波长下读取吸亮度。
统计分析:
分别分析每组数据。使用单因素方差分析,然后进行TUKEY检验各组之间的个体差异;统计学上的意义需达p<0.05。针对所有研究,N=6。
结果
在该实施例中,评估了关刀豆补充剂减少或预防由实验性膀胱炎引起的功能障碍的能力。如前所述,我们通过8F导管将25ml含有硫酸鱼精蛋白(10mg/ml)+尿酸(100mg/ml)的生理盐水置于膀胱中30分钟以诱导膀胱炎。使用了三组兔子。如图1所示,第1组为无膀胱炎治疗的对照兔(无JB处理);第2组为在二周内接受诱导膀胱炎,并使其额外存活二周的兔子(JB+膀胱炎);第3组为在诱导膀胱炎之前2周以及在诱导膀胱炎后二周内以JB处理的兔子(JB)。对照组无任何处理。如图1所示,发现这三组的膀胱重量无明显差异。
如图2所示,虽然这三组之间的膀胱容量没有显著差异,但JB曲线的顺应性明显低于无JB的曲线(较不僵硬)。如图3所示,在膀胱炎后1周及2周,发现顺应性与膀胱容量显著降低。如图4所示,膀胱炎导致该二组膀胱容量相似的显著降低,且膀胱压检查显示膀胱炎+/-JB导致膀胱容量下降。如图5所示,JB组在膀胱炎之前以及在膀胱炎后1周或2周的顺应性明显低于JB组,而在膀胱炎1周及2周时,在对照膀胱炎组中膀胱炎诱导顺应性明显降低,而在膀胱炎后1周或2周时,以JB处理组(JB)的顺应性则无变化。如图7所示,相较于抗坏血酸标准品,JB组的总抗氧化活性显示出显著的抗氧化活性。
关于收缩性的研究,对照膀胱炎在所有形式的刺激反应中都引起显著的下降。如图6所示,膀胱炎后2周,对照组JB对所有形式刺激的收缩反应均显著降低。电场刺激需要以下事件的顺序:1)刺激突触后膜释放乙酰胆碱与ATP。2)跨突触间隙的扩散与突触后蕈毒胆碱类受体及嘌呤受体的刺激。3)通过钙通道将自肌质网(针对蕈毒碱刺激)以及自细胞外部位(针对蕈毒碱以及嘌呤刺激)的Ca++刺激释放至平滑肌细胞内。4)活化平滑肌组分以收缩。5)蕈毒碱与嘌呤受体活化及平滑肌收缩都需要从ATP分解为ADP+Pi的能量。干扰这5个因素中的任何一个都会导致收缩力下降。
关于药物反应:对于碳酰胆碱,没有神经传导物质的释放或扩散,也没有嘌呤神经传递的参与。但是步骤2-5都是必需的。关于ATP,没有神经传导物质的释放或扩散,也没有胆碱神经传递的参与或自SR释放钙。但步骤2-5都是必需的。响应KCl,针对步骤3,没有Ca++从肌质网释出,但步骤4及5是必需的。
对于所有形式的刺激,施用JB避免膀胱炎诱发的所有收缩功能障碍。这表示上面列出的机制(1-5)都受到保护。
摘述结果
在排尿时观察到膀胱体积的减少可能是由各种过程所引起。首先,膀胱炎会损害糖胺聚糖层,这将使尿液溶质进入膀胱。这些可使尿道上皮中的感觉受体变得敏感,在较少的膀胱内体积的情况下就会刺激排尿反射,而非在受控制的膀胱中刺激排尿所需的体积。其次,膀胱炎可能会导致肌质网的损伤,这将导致增加Ca++的释放,其会导致膀胱胀满的平滑肌张力增加(增加膀胱僵硬度以及降低顺应性),因此达到在相对低的膀胱内容积开始排尿的膀胱内压力。在人类体内,膀胱炎通常导致排尿时体积减少,以及膀胱顺应性降低。膀胱炎的另一个结果将是以ATP的形式向细胞提供代谢能量的线粒体损伤。ATP的减少将导致收缩功能障碍,导致收缩力下降,如同在没有JB处理的膀胱炎组中所见的情形。
实验中诱发的膀胱炎导致顺应性降低,排尿时的体积减少,以及对所有形式的刺激减少收缩反应。这些结果表示膀胱炎导致膀胱黏膜、肌浆网、线粒体,以及平滑肌纤维的病理损伤,在引发膀胱炎后二周内保持不变。观察到排尿量的减少可能是上述一个或几个因素的结果,并非所有的这些因素都与病理学有关。膀胱炎无治疗组别的顺应性明显降低,显示出对上述膀胱炎的病理反应。JB对顺应性的保护作用强有力地显示,该预处理保护膀胱避免了肌质网的损伤。
对药理学试剂(碳酰胆碱、ATP,以及KCl)的收缩反应则强有力地显示JB预处理保护膀胱避免损伤线粒体以及平滑肌纤维。对于电场刺激收缩,JB完全保护对所有刺激频率的反应,表示JB完全预防突触前神经与突触后蕈毒碱与嘌呤受体之间的突触连接的损伤,显示其可用于预防频尿。
结论
膀胱炎导致顺应性降低,排尿时体积减少,以及减少对所有形式刺激的收缩反应。这些结果显示,硫酸鱼精蛋白-尿酸性膀胱炎对膀胱黏膜、肌浆网、线粒体,以及平滑肌纤维的病理生理损伤在发生膀胱炎后二周保持不变。JB对顺应性的保护作用强有力地显示,这种预处理可保护膀胱避免对肌质网膜、线粒体,以及细胞膜的损伤,并可用于预防频尿。
虽然本说明书包含许多细节,但这些说明不应被解释为对本发明的范围或可以申请专利保护的内容的限制,而应被解释为对本发明的特定具体实施例特有的特征的描述。在本说明书中在单独具体实施例的上下文中描述的某些特征也可以在单个具体实施例中的组合实现。反之,在单个具体实施例的上下文中描述的各种特征也可以分开地或以任何适当的合适的子组合在多个具体实施例中实现。此外,尽管上述功能可以某些组合的形式进行,而且甚至最初请求专利保护,但请求保护的组合的一个或多个特征在某些情况下可以从组合中被切除,且可以针对子组合或子组合的变化请求保护的组合。
Claims (2)
1.关刀豆(Canavalia ensiformis)或其萃取物在制备用于预防频尿的药物中的用途。
2.如权利要求1所述的用途,其中该关刀豆(Canavalia ensiformis)或其萃取物是与一种有效保护膀胱避免膀胱炎引起的损伤或预防频尿的治疗剂或物质组合使用。
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DE19722264A1 (de) * | 1997-05-28 | 1998-12-03 | Inst Pflanzengenetik & Kultur | Neue Chitinase |
JP2005500257A (ja) * | 2001-03-14 | 2005-01-06 | ダコサイトメーション・デンマーク・アクティーゼルスカブ | 新規なmhc分子構築物、ならびに診断および処置のためにこれらの構築物を用いる方法、ならびにmhc分子の使用 |
CN1622806A (zh) * | 2001-11-02 | 2005-06-01 | 阿斯特拉曾尼卡有限公司 | 用于治疗膀胱活动过度的方法 |
US7727560B2 (en) * | 2004-05-18 | 2010-06-01 | Sou Yi Lu | Treating cancer, liver, kidney, platelet and hemopoietic disorder or complication |
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US10441620B2 (en) | 2019-10-15 |
US20180078596A1 (en) | 2018-03-22 |
TW201813655A (zh) | 2018-04-16 |
TWI667034B (zh) | 2019-08-01 |
CN107854511A (zh) | 2018-03-30 |
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