CN1348368A - 含原花色素作为活性成分的adp-核糖基化抑制剂和治疗肠毒素型细菌感染性疾病的组合物 - Google Patents
含原花色素作为活性成分的adp-核糖基化抑制剂和治疗肠毒素型细菌感染性疾病的组合物 Download PDFInfo
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- CN1348368A CN1348368A CN99816554A CN99816554A CN1348368A CN 1348368 A CN1348368 A CN 1348368A CN 99816554 A CN99816554 A CN 99816554A CN 99816554 A CN99816554 A CN 99816554A CN 1348368 A CN1348368 A CN 1348368A
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Abstract
本发明涉及用于肠毒素型细菌感染性疾病的药物,它含有由天然存在的物质得到的含原花色素的物质如苹果或葡萄提取物作为活性成分,该药物可抑制由肠毒素型肠道感染病原菌,如病原性弧菌(霍乱弧菌、副溶血弧菌)产生的毒素,因此该药物对于感染的治疗与预防是基本有效的;基于原花色素的ADP-核糖基化抑制活性的治疗和/或预防白喉等的药物组合物;用于预防和治疗上述疾病的食品添加剂;以及含有这些添加剂的食品。
Description
治疗肠毒素型细菌感染性疾病的组合物
发明领域
本发明涉及含有原花色素(proanthocyanidin)作为活性成分的腺苷-5’-二磷酸(ADP)-核糖基化抑制剂。更具体地说,本发明涉及用于治疗和/或预防肠毒素型细菌感染性疾病的组合物以及原花色素作为食品添加剂和/或作为食品的用途。
发明背景
WHO 1998年的数据表明全世界由细菌感染引起的死亡人数达到2000万。该报告尤其指出,每年全世界死于霍乱的人数高达数百万。即使在包括抗生素或疫苗等的医疗技术不断改善的今天,患者的人数也没有减少。此外,即使是在发达国家,由于这些年来伴随着国际运输业的显著发展,人员交流与物质流通也逐步增多,由霍乱弧菌(Vibrio cholerae)、痢疾杆菌、产毒性大肠杆菌(Escherichiacoli)、沙门氏菌等细菌引起的旅行者的腹泻有增高的趋势。
霍乱是一种死亡率很高的感染性疾病,它由霍乱弧菌引起,特征是以大量水样腹泻为主要症状。霍乱发生于全世界,特别是亚洲和非洲。霍乱的发病机理是霍乱弧菌经口进入体内,引起小肠内腔粘膜感染并繁殖以产生霍乱毒素。霍乱毒素的结构由两种蛋白亚基组成,它们已知是A和B亚基,正如痢疾杆菌、产毒性大肠杆菌、小肠出血性大肠杆菌等产生的毒素中具有的。B亚基与肠腔上皮细胞的神经节苷脂GM1受体位点结合。已知具有ADP-核糖基化酶活性的霍乱毒素的A亚基催化ADP-核糖基化作用,该作用活化腺苷酰环化酶系统中刺激性GTP-结合蛋白,已知称为GSα,增高肠道上皮细胞中的cAMP水平,大量分泌水和电解质,导致水性腹泻(Med.Immunol.,21,359-365(1994);Masatoshi Noda,SHONI-NAIKA(Children InternalMedicine),28(9),1186-1193(1996))。
目前霍乱通过输液进行治疗,输液是一种系统性疗法。实际上,至今未发现霍乱的基本治疗方法和药物。经过广泛的研究,本发明者之一Masatoshi Noda已经开发出一种抑制引起肠道感染的细菌,如霍乱弧菌等产生的毒素的药物,所述药物使毒素不产生危害,参见“治疗肠毒素型细菌感染的药物”(日本专利申请号6-505177,Masatoshi Noda,Hajime Nishiya和Morimichi Yamaguchi)和“没食子酸酯衍生物和含有它们作为活性成分的药物”(日本专利申请公开10-273495,Masamichi Ueno,Izumi Takai,Hiroshi Ohi,Masakazu Adachi和Masatoshi Noda)。但是,前者由于使用草药作为主要成分涉及生产成本等问题。后者需要进一步的研究,如安全性试验(由于有效成分是合成化合物)。因此,后者要付诸实际使用将花费至少数年的时间。本领域目前的状况是,仍没有低价格的具有高度安全性的从天然存在的物质衍生的药物可用于治疗肠毒素型细菌感染性疾病。因此,非常需要提供一种满足上述要求的药物。
发明描述
本发明的目的是提供一种由天然存在的物质得到的和/或用于基础治疗的高度安全的成分和/或预防肠毒素型细菌感染性疾病的ADP-核糖基化抑制剂,该抑制剂可抑制由经由肠毒素型细菌,如弧菌属病原菌(霍乱弧菌、副溶血弧菌)的引起肠道感染的细菌产生的毒素的活性并使这些毒素不产生危害。
本发明者对天然存在的物质,尤其是由食用植物得到的具有下列性质的那些物质进行了广泛的研究:能抑制体内毒素,如霍乱毒素催化的ADP-核糖基化作用,能抑制水性腹泻,但对人体没有副作用。结果,在食用植物提取物,如苹果提取物、葡萄提取物等中发现了对ADP-核糖基化作用具有特别有效的抑制作用和对肠毒素型细菌感染性疾病具有治疗活性的物质。由此完成了本发明。
附图概述
附图1是表示试验实施例1中苹果提取物的浓度与其抑制活性之间的关系的图。
发明的最佳实施方式
本发明中使用的有效成分之一的苹果提取物基本上由多酚组成。本发明者已对这些多酚进行了组成特性、安全性、制备方法进行了广泛的研究,以证实它们的功能和实用性,这些研究记载于日本专利申请号7-285876中。由其申请者制备的这些多酚已作为食品原料、食品添加剂、化妆品原料等在市场上销售。实际上,这些市售产品被应用于各种食品、加工食品、化妆品等。作为进一步广泛研究的结果,本发明者发现这些多酚物质显示出ADP-核糖基化抑制作用,可有效地治疗肠毒素型细菌感染性疾病;本发明者已鉴别出该物质是一种多酚——原花色素。
原花色素是一种至少为二聚物物质,它由具有类黄酮骨架的黄烷-3-醇或黄烷-3,4-二醇缩合或聚合而成(Hemingway,R.W.等人,Chemistry and Significance of Condensed Tannins,83-107)。已经证实,例如苹果提取物含有2-至15-聚原花色素(Ohnishi-Kameyana M.等人,Rapid Comm.Mass Spectrom.,11,31-36(1997))。
任何提取物均可用作本发明的活性成分,只要植物提取物含有2-至15-聚原花色素。可使用任何无关的植物原料,只要可以从植物原料获得含有足量2-至15-聚原花色素的提取物。这些植物提取物可以是粗提物,但需含有至少一定量的2-至15-聚原花色素。提取物也可在分离为2-至15-聚原花色素或者进一步纯化为4-至15-聚原花色素,更优选分离为至少6聚体的原花色素(6-聚体)后使用。这些2-至15-聚原花色素,优选4-至15-聚原花色素,更优选至少6-聚的原花色素可按照日本专利10-184143中描述的方法进行分离和提取,该文献引入本文以供参考。
含原花色素的食用植物的实例除苹果外,还包括蔷薇科植物:草莓和覆盆子。除蔷薇科以外的食用植物的实例是葡萄科的葡萄、猕猴桃属的猕猴桃、杜鹃花科的乌饭树和越橘、豆科的赤豆和罗望子、柿科的柿子树、芭蕉科的香蕉、漆树科的腰果、梧桐科的可可、日本橡树、常绿橡树、崖椒属的栗子和pasanias以及大麻科的啤酒花。鉴于资源的有效利用和提取体积量大,其中,尤其可使用由于过剩而筛除的小苹果和压榨葡萄的残渣中包含的葡萄籽。
本发明提供了一种ADP-核糖基化抑制剂,它含有由食用植物得到的原花色素作为有效成分;以及一种用于治疗肠毒素型细菌性感染疾病的含有所述抑制剂的组合物。除原花色素外,本发明的抑制剂和组合物可进一步含有其它多酚、与有机酸或糖结合的原花色素及其溶剂化物,如水合物。本发明的抑制剂和组合物中也可含有从同种原料中获得的其它成分。
含有从食用植物得到的原花色素作为有效成分的本发明药物组合物可用于治疗和/或预防肠毒素型细菌感染性疾病,如由霍乱或肉毒杆菌引起的旅行者腹泻。此外,由于本发明的药物组合物具有特别有效的ADP-核糖基化抑制剂作用,因此也可有效地治疗和/或预防其它感染性疾病,如白喉、百日咳、破伤风、机遇性感染等,据知这些疾病的暴发与ADP-核糖基酶密切相关。
含有从食用植物得到原花色素作为有效成分的本发明药物组合物可使用制备药物制剂常用的载体、赋形剂和其它添加剂制备。固体或液体载体和赋形剂都可用于制备药物制剂。这类载体和赋形剂的实例包括乳糖、蔗糖、脂肪酸酯、糊精、硬脂酸镁、淀粉、滑石、明胶、琼脂、果胶、阿拉伯胶、橄榄油、芝麻油、可可脂、乙二醇等。
本发明的药物组合物一般以片剂、丸剂、胶囊、颗粒、粉末、液体等形式口服给药。对于每个具体病例,口服剂量可根据患者的适应症、年龄、性别等适当决定,然而对于成年人,当以原花色素计算时,本发明组合物的日剂量一般为100mg-10g,优选200mg-1g。该组合物可以大丸剂形式给药,或者口服日剂量可分次给药。当然,日剂量可根据各种情况进行改变,在某些情况下,小于上面给出的剂量就足够了。
对于本发明组合物的口服给药,可利用如片剂、粉末或颗粒形式的固体组合物。在这类固体组合物中,将由食用植物得到的原花色素与至少一种对活性成分惰性的稀释剂混合。稀释剂的实例包括乳糖、甘露糖醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、正硅酸和铝酸镁。如果需要,组合物还可含有除惰性稀释剂外的其它添加剂。这类添加剂的实例包括润滑剂,如硬脂酸镁;崩解剂,如乙醇酸纤维素钙;稳定剂,如乳糖;且溶剂,如谷氨酸或天门冬氨酸。如果需要,片剂或丸剂可用蔗糖、明胶-羟丙基纤维素、邻苯二甲酸羟丙基甲基纤维素、还原palatinose、玉米醇溶蛋白等肠溶或胃溶涂膜包衣。
含由食用植物得到的原花色素作为有效成分的可用于口服的液体组合物呈可药用乳液、溶液、悬浮液、糖浆、酏剂等形式。这些口服液体制剂还可含有常用的惰性稀释剂,如纯水或乙醇。除上述惰性稀释剂外,该液体制剂还可含有润湿剂、悬浮剂、乳化剂、分散剂、稳定剂(如乳糖)、辅助剂,如溶解助剂(如谷氨酸或天门冬氨酸)、甜味剂、着色剂、赋形剂和防腐剂。
本发明的由食用植物得到的原花色素还可用作食品添加剂。在这种情况下,原花色素可作为抗菌剂使用。当所应用的食品是液体,如牛奶、饮料、果汁等时,可在邻饮用前将原花色素直接加到这些液体食品中。原花色素的用量为约50mg-1000mg/100ml液体。当将原花色素掺入主食,如意大利面、面包或稻米中时,在烹制或加工主食时,原花色素可以50mg-500mg/100g食品的量加到主食中。
实施例
下面将以实施例更具体地描述本发明,但不应认为是对本发明的限制。制备实施例1:苹果提取物的制备
将10kg小苹果洗净、压碎后榨汁,将所得的果汁离心并过滤,得到8.5kg澄明果汁。使该果汁通过体积为1升的苯乙烯吸附树脂柱。该柱用水洗涤后,用65%乙醇水溶液进行洗脱。将得到的洗脱液真空浓缩。浓缩物进行喷雾干燥,得到59.7g苹果提取物。制备实施例2:葡萄提取物的制备
去茎后,压榨葡萄并使压榨过的葡萄残渣过筛以收集葡萄籽。1kg的葡萄籽用水洗涤后,用50%乙醇提取。将提取液真空浓缩。将浓缩物过滤,得到提取物。然后使该提取物通过体积为1升的苯乙烯吸附树脂柱。该柱用水洗涤后,用65%乙醇水溶液进行洗脱。将得到的洗脱液真空浓缩并进行喷雾干燥,得到40.7g葡萄提取物。制备实施例3:苹果提取物的分离
使制备实施例1得到的苹果提取物的水溶液通过苯乙烯吸附树脂柱,得到含89%原花色素的原花色素总馏分。对原花色素总馏分进行高压液相色谱,分别分离单体(儿茶素)、二聚体、三聚体、四聚体和五聚体以及六聚体或更高聚合度的馏分。将这些馏分分别真空浓缩并冻干,得到相应的干燥产物。药物制备例1
将制备实施例1获得的50g苹果提取物与30g玉米淀粉、10g结晶纤维素、4g羧甲基纤维素钙和1g硬脂酸镁混合。将该混合物用压片机压片得到片剂。药物制备例2
将制备实施例1获得的50g苹果提取物与7g羧甲基纤维素钙、2g硬脂酸镁和1g硅酸酐混合。将足量的无菌水加到该混合物中。将该混合物挤出制粒并干燥,得到颗粒剂。药物制备例3
将制备实施例1获得的45g苹果提取物与5g蔗糖脂肪酸酯混合。将该混合物用压片机压片得到片剂。该片用25g还原palatinose包衣并进一步用2g玉米醇溶蛋白包衣,得到糖衣片。试验实施例1:通过胍丁胺分析的评价
已知霍乱毒素ADP-核糖基化物Gsα是胞内蛋白质G,并且还对作为胍丁胺底物的NAD~ADP-核糖还具有ADP-核糖基化转化酶抑制剂活性。基于这种机理,按照Noda等人报道的胍丁胺分析法(Noda M.等人,Biochemistry,28,7936(1989)),评价原花色素抑制霍乱毒素的活性。
即,将1μg霍乱毒素和一定量的表1所示的样品与下列组成的反应混合物混合:50mM磷酸钾缓冲液(pH7.5),5mM MgCl2,100μMGTP,100μM[腺嘌呤-14C]NAD(6000cpm),20mM DTT,20mM胍丁胺和0.1mg/ml卵清蛋白(总计300μl)。使该混合物在30℃反应3小时。使50μl反应混合物通过Dowex AG1-X2填充柱(Φ5×20mm,Bio Rad,Inc.制造)。除去未反应的[腺嘌呤-14C]NAD,测定霍乱毒素的ADP-核糖基化作用产生的[腺嘌呤-14C]ADP-核糖基化胍丁胺的放射活性。测定用作该[腺嘌呤-14C]ADP-核糖基化胍丁胺形成指示的每份样品中霍乱毒素的ADP-核糖基化转移酶活性的抑制。结果示于表1。附图1还给出了苹果提取物的浓度与ADP-核糖基化抑制活性之间的关系。
表1
霍乱毒素抑制率(%)
*1:苹果提取物IC 50<10μg/ml*2:对霍乱毒素具有阳性反应的患者:日本专利申请号6-505177。
试验样品 | 浓度(μg/ml) | 抑制率(%) |
苹果提取物(小苹果)* | 25 | 95.4 |
葡萄提取物(种子) | 63 | 96.1 |
向日葵提取物(种子) | 167 | 4.0 |
大黄提取物(草药)* | 10 | 99.3 |
原花色素总馏分单体(儿茶素)二聚体馏分三聚体馏分四聚体馏分五聚体馏分≤六聚体的馏分 | 25252525252525 | 97.80.07.09.551.896.797.6 |
在该试验中,当按照Porter方法以原花色素B2计算时,苹果提取物和葡萄提取物分别含51%和63%原花色素。试验实施例2:通过结扎兔小肠回路方法的分析
据知霍乱毒素ADP-核糖基化物Gsα(也称为胞内蛋白质G)致使肠袢上皮细胞中腺苷酰基环化酶持续活化、cAMP水平增高以及水和电解质的大量分泌,导致水样腹泻。为测定抑制由霍乱毒素引起的腹泻的活性,通过De等人报道的结扎兔回路的方法(De S.N.和D.N.Chatterje,J.Pathol.Bacteriol.,66,559(1953))测定水样腹泻中,苹果提取物的体液累积活性。即,每隔15cm结扎兔的回肠以形成数个封闭的肠系统回路。在给予每个回路1μg霍乱毒素和一定量的样品后,将小肠回路放入兔体内。使兔保持尽可能的舒适,18小时后,测定霍乱毒素引起的体液积累。
结果表明苹果提取物在50μg/回路剂量下几乎完全抑制由1μg霍乱毒素引起的体液积累。这些结果证实了本发明描述的食用植物提取物及其有效成分原花色素作用于霍乱毒素,抑制ADP-核糖基化转移酶活性,因此与草药“大黄”的提取物一样,表现出抗霍乱毒素的活性。
工业实用性
含原花色素作为活性成分的本发明ADP-核糖基化抑制剂可有效地治疗和/或预防肠毒素型细菌感染性疾病。上述的这类食用植物提取物中含有的原花色素作为活性成分的安全性已经得到肯定,因为在长期的人类历史中,产生原花色素的植物都被用作食用植物。即便如此,在原花色素被用作食品添加剂前,通过急性毒性试验等也再次证实了原花色素的安全性。原花色素已经以试验植物的提取物、抗氧剂或食品原料形式被广泛地使用。未见对人类具有任何副作用的报道。因此,原花色素极其安全,可非常有效地治疗和/或预防肠毒素型细菌感染性疾病。因此原花色素是一种特别有用的药物。
Claims (11)
1.一种腺苷-5’-二磷酸(ADP)-核糖基化抑制剂,含有原花色素作为有效成分。
2.权利要求1的ADP-核糖基化抑制剂,其中的原花色素由食用植物或由食用植物得到的物质获得。
3.权利要求2的ADP-核糖基化抑制剂,其中所述的食用植物或用食用植物得到的物质是苹果或葡萄提取物。
4.权利要求1-3任一项的ADP-核糖基化抑制剂,其中的原花色素是用至少一种选自下列的溶剂萃取得到的原花色素:水、醇、酯和酮。
5.权利要求1-4任一项的ADP-核糖基化抑制剂,其中的原花色素是采用下列方法纯化得到的原花色素:苯乙烯型吸附树脂、阴离子交换树脂、十八烷基-化学结合型硅胶、辛基-化学结合型硅胶、苯基-化学结合型硅胶和硅胶。
6.一种治疗和/或预防白喉、百日咳、破伤风和机遇性感染的组合物,含有权利要求1-5中任一项的ADP-核糖基化抑制剂作为有效成分。
7.一种治疗和/或预防肠毒素型细菌感染性疾病的组合物,含有原花色素作为有效成分。
8.权利要求7的治疗和/或预防肠毒素型细菌感染性疾病的组合物,用于治疗和/或预防霍乱、肉毒杆菌和旅行者腹泻。
9.权利要求7或8的治疗和/或预防肠毒素型细菌感染性疾病的组合物,其中所述的食用植物或由食用植物得到的物质是苹果或葡萄的提取物。
10.权利要求7-9任一项的治疗和/或预防肠毒素型细菌感染性疾病的组合物,其中的原花色素是用至少一种选自下列的溶剂萃取得到的原花色素:水、醇、酯和酮。
11.权利要求7-10任一项的治疗和/或预防肠毒素型细菌感染性疾病的组合物,其中的原花色素是采用下列方法纯化得到的原花色素:苯乙烯型吸附树脂、阴离子交换树脂、十八烷基-化学结合型硅胶、辛基-化学结合型硅胶、苯基-化学结合型硅胶和硅胶。
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AU2003267079B2 (en) * | 2002-09-10 | 2008-08-14 | Chiba University | Factors that bind intestinal toxins |
US7090856B2 (en) | 2003-06-19 | 2006-08-15 | Hong Kong University Of Science And Technology | Anti-fouling exopolysaccharides isolated from cultures of Vibrio alginolyticus and Vibrio proteolyticus |
CN113827588A (zh) * | 2021-09-23 | 2021-12-24 | 天津国际生物医药联合研究院 | 原花青素在抗结核分枝杆菌感染中的潜在应用 |
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JPH1029947A (ja) * | 1996-07-15 | 1998-02-03 | Nippon Koutai Kenkyusho:Kk | 生体内毒素型細菌性腸管感染症治療剤 |
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IL134904A0 (en) * | 1997-09-09 | 2001-05-20 | Univ Rutgers | Plant proanthocyanidin extract effective at inhibiting adherence of bacteria with p-type fimbriae to surfaces |
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