CN102791263A - 用于预防或治疗慢性静脉功能不全的包含l-肉碱或丙酰基l-肉碱作为活性成分的联合组合物 - Google Patents
用于预防或治疗慢性静脉功能不全的包含l-肉碱或丙酰基l-肉碱作为活性成分的联合组合物 Download PDFInfo
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- CN102791263A CN102791263A CN2011800080208A CN201180008020A CN102791263A CN 102791263 A CN102791263 A CN 102791263A CN 2011800080208 A CN2011800080208 A CN 2011800080208A CN 201180008020 A CN201180008020 A CN 201180008020A CN 102791263 A CN102791263 A CN 102791263A
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Abstract
本发明描述了一种可用于预防和/或治疗慢性静脉疾病的联合组合物，其包含L-肉碱或丙酰基L-肉碱、曲克芦丁、香叶木苷和橙皮碱作为活性成分。
Description
技术领域
本发明涉及包含L-肉碱或其衍生物或其盐、曲克芦丁、香叶木苷（diosmine）和橙皮碱（hesperidine）作为活性成分的联合组合物（combinationcomposition），其可用于预防和/或治疗慢性静脉功能不全（CVI）。
背景技术
在人体中，动脉将富氧血从心脏运输至身体的其它部位，静脉将缺氧血返回心脏。当人腿静脉不能将足够的血液泵回心脏时，发生慢性静脉功能不全（CVI）。CVI有时也称作慢性静脉疾病或CVD。
人体具有3类静脉：浅静脉（其位于皮肤附近）、深静脉（其位于肌肉群中）和穿静脉（其连接浅静脉和深静脉）。深静脉通向大静脉（即人体的最大静脉），所述大静脉直接通向心脏。
当人体处于直立位置时，他们的腿静脉中的血液必须克服重力才能返回心脏。为了实现该目的，腿肌肉挤压他们的腿和脚的深静脉，以帮助将血液运输回心脏。在静脉中的单向皮瓣（称作瓣膜）保持血液沿正确的方向流动。当腿肌肉松弛时，在静脉内的瓣膜关闭。这会防止血液反向向下流回腿。向心脏送回血液的整个过程称作静脉泵。
当人行走和腿肌肉挤压时，静脉泵良好地工作。但是，当患者（特别是长时间）坐着或站立时，腿静脉中的血液可以合并（pool），并增加静脉血压。深静脉和穿静脉通常能够耐受短时间的高压。但是，长时间坐着或站立可以拉伸静脉壁，因为它们是弹性的。在易感的个体中，这可以随着时间而弱化静脉壁并损伤静脉瓣膜，从而造成CVI。
在CVI过程中，踝可能肿胀，小腿可能感觉绷紧。腿还可能感觉沉重、疲累、不安或疼痛。当行走时或在停止后不久，患者可能感觉疼痛。
CVI可能与静脉曲张相关。静脉曲张是我们透过皮肤可以看见的肿胀的静脉。它们经常呈蓝色、鼓胀和扭曲。大的静脉曲张可以导致皮肤变化，如疹、发红和疮。
CVI也可以造成腿肿胀问题，这是因为在静脉中合并的血液的压力。淋巴系统也可能产生液体（称作淋巴液）来补偿CVI。人腿组织然后可以吸收一些该液体，这可以增加腿的肿胀趋势。在严重的情况下，CVI和腿肿胀可以造成溃疡在腿的下部形成。
在长时间以后，高于腿静脉内的正常压的血压会造成CVI。CVI的其它原因包括深静脉血栓形成（DVT）和静脉炎，它们二者都会通过阻塞血液穿过静脉的自由流动而造成升高的静脉压力。
当血块（确切地称作血栓）堵塞血液流向心脏、流出深静脉或穿静脉时，发生DVT。尝试穿过堵塞的静脉的血液可以增加静脉血压，后者又使瓣膜超载。不能适当地工作的静脉瓣膜称作机能不全的，因为它们伸长且不再有效地工作，机能不全的瓣膜会促成CVI。DVT是一种潜在严重的病症，其会造成腿肿胀，并需要立即的医学注意，因为有时静脉中的血块可以断开并移动至肺。该病症称作肺栓塞。
当浅静脉或深静脉变得肿胀和发炎时，发生静脉炎。该炎症会造成血块形成，这也可以导致DVT。
可以增加CVI的风险的因素包括：静脉曲张的家族史、超重、妊娠、缺乏锻炼、吸烟和长时间站立或坐着。尽管CVI可以影响任何人，年龄和性别也可以是可能增加发展CVI的趋势的因素；超过50岁的女性最经常患上CVI。
对于CVI的轻病例，医师可能推荐加压袜子。加压袜子是挤压静脉并阻止过多的血液回流的弹力长袜。以此方式，加压袜子经常也可以辅助治愈皮肤疮，并防止它们复发。患者可能在余生中需要每天穿着加压袜子。
可能使用注射（称作硬化疗法）或使用外科手术来治疗更严重的CVI病例。少于10%的CVI患者需要外科手术来纠正该问题。外科手术治疗包括：消融、静脉剥离、心脏搭桥手术、瓣膜修复和静脉的血管成形术或搭支架。
黄酮类、曲克芦丁、香叶木苷和橙皮碱（也称作芦丁、oxerutins或芸香苷（rutosides））因为它们的抗氧化剂性质而众所周知，另外，它们还表现出影响循环系统（即血液和微血管内皮细胞）的其它性质（G.I.O.T.2009;35:23-33）。
许多流行病学研究提示，这些黄酮类与循环的改善和普遍减少的心血管疾病风险相关。这些保护作用的基础机制包括：抗血栓形成性质、抗缺血性质、抗氧化性质和血管松弛性质。具体地，这些黄酮类具有通过如下而改善循环的作用：血管扩张，减少血小板凝固和防止低密度脂蛋白（LDL）被氧化（Journal of Agricultural and Food Chemistry 200856（15），第6185-6205页）。
这些黄酮类也表现出强抗炎性质，认为这是抑制不同的促炎症介质（主要是花生四烯酸衍生物、前列腺素E2、F2和血栓烷A2）的合成和生物活性的结果。这些过程会改善静脉压（venous tone）和淋巴排出，并减少毛细血管高渗透性，这通过保护微循环免于炎性过程来实现。
在临床研究中也已经证实了该效应。Belcaro等人（Angiology,59;5S）的研究证实，这些黄酮类可以有效地控制和治疗水肿和静脉高压中的增加的毛细管过滤以及糖尿病性微血管病。
Belcaro等人的另一项研究（Angiology,March 1,2008;59(1)suppl.7S-13S）也聚焦于这些黄酮类在治疗慢性静脉疾病以及慢性静脉功能不全（CVI）、静脉曲张和深静脉疾病的征象和症状中的用途。
在Rev Fr Gynecol Obstet.1991 Feb 25;86(2Pt 2)：209-12中，报道了曲克芦丁在女性（一半在经前期综合征的背景下，一半在妊娠中）中可用于治疗外阴静脉曲张和下肢静脉功能不全。
在Br.J.Surg.2000,87;868-872中，报道了香叶木苷具有抗炎作用，其在保护血管方面起作用，并促进良好血液循环的维持以及维持静脉压。
在Farmaco,40(11);709-712中，报道了橙皮碱具有抗氧化作用，并与曲克芦丁和香叶木苷一起促进健康的血管功能。
在US 4255449中，报道了L-肉碱可用于增加HDL胆固醇和用于治疗与高胆固醇水平有关的疾病。
在WO 040916029中，报道了L-肉碱可用于治疗心血管疾病。
在US 5811457中，报道了丙酰基L-肉碱可用于治疗慢性闭塞性动脉硬化。
在WO 2007045639中，报道了丙酰基L-肉碱可用于治疗透析患者的左心室肥厚。
在US 4343816中，报道了丙酰基L-肉碱可用于治疗外周血管疾病。
此外，尽管有其它出版物证实了本发明的化合物可用于治疗静脉疾病，它们都没有提及、也没有暗示本发明的组合物所表现出的意外的协同效应。
发明内容
现在已经发现，包含L-肉碱或其衍生物（例如丙酰基L-肉碱）或其盐、曲克芦丁、香叶木苷和橙皮碱作为活性成分的联合组合物，当用于预防和/或治疗选自下述的静脉疾病时具有令人惊讶的协同效应：慢性静脉功能不全（CVI）和慢性静脉疾病（CVD）或它们的并发症。
静脉的并发症或疾病（归因于CVI或CVD）的实例记载如下：直肠、肛门和外阴中的静脉的肿胀和炎症；静脉高压；增加的渗透性；水肿；毛细管损伤；皮肤变化；静脉腿溃疡；踝肿胀；腿沉重；静脉曲张；腿肿胀；溃疡；静脉血栓形成；静脉炎；血栓性静脉炎；肺栓塞；痔疮。
因此，本发明的一个目的是，包含L-肉碱或其盐、曲克芦丁、香叶木苷和橙皮碱作为活性成分的联合组合物。
本发明的另一个目的是，包含丙酰基L-肉碱或其盐、曲克芦丁、香叶木苷和橙皮碱作为活性成分的联合组合物。
上述组合物可以另外包含可用于治疗静脉疾病的其它活性成分。
本发明的另一个目的是，一种组合物，其包含：
（a）L-肉碱或丙酰基L-肉碱，其剂量为10至3000mg，优选的剂量为50mg至400mg，最优选的剂量为136mg。
（b）曲克芦丁，其剂量为900mg至50mg，优选的剂量为400mg至200mg，最优选的剂量为300mg；
（c）香叶木苷，其剂量为900mg至50mg，优选的剂量为400mg至200mg，最优选的剂量为300mg；和
（d）橙皮碱，其剂量为10mg至500mg，优选的剂量为50mg至200mg，最优选的剂量为100mg。
本发明的另一个目的是，上述的组合物，其用于抗-慢性静脉功能不全及其并发症。
本发明的另一个目的是，上述的组合物，其用于抗-慢性静脉疾病及其并发症。
本发明的另一个目的是，上述的组合物用于制备药剂的用途，所述药剂用于预防或治疗慢性静脉功能不全、慢性静脉疾病及其并发症，其中所述并发症选自：直肠、肛门和外阴中的静脉的肿胀和炎症；静脉高压；增加的渗透性；水肿；毛细管损伤；皮肤变化；静脉腿溃疡；踝肿胀；腿沉重；静脉曲张；腿肿胀；溃疡；静脉血栓形成；静脉炎；血栓性静脉炎；肺栓塞或痔疮。
本发明的另一个目的是，上述的组合物用于制备饮食添加物的用途，所述饮食添加物用于预防或治疗慢性静脉功能不全、慢性静脉疾病及其并发症。
本发明的组合物可以另外包含辅酶、矿物质、抗氧化剂、维生素、抗凝固剂和可用于治疗静脉疾病的药剂。
L-肉碱的盐是L-肉碱与不会产生毒副作用的酸形成的任意盐。
这样的盐的非限制性实例是：氯化物、溴化物、乳清酸盐、天冬氨酸盐、酸性天冬氨酸盐、酸性柠檬酸盐、柠檬酸镁、磷酸盐、酸性磷酸盐、富马酸盐和酸性富马酸盐、富马酸镁、乳酸盐、马来酸盐和酸性马来酸盐、草酸盐、酸性草酸盐、扑酸盐、酸性扑酸盐、硫酸盐、酸性硫酸盐、磷酸葡萄糖、酒石酸盐和酸性酒石酸盐、甘油磷酸盐、粘酸盐、酒石酸镁、2-氨基-乙磺酸盐、2-氨基-乙磺酸镁、甲磺酸盐、酒石酸胆碱、三氯乙酸盐和三氟乙酸盐。
在出版物Int.J.of Pharm.33(1986),201-217中，给出了FDA批准的药学上可接受的盐的列表。
根据本发明的L-肉碱、丙酰基L-肉碱、曲克芦丁、香叶木苷和橙皮碱可以以“共协调方式”施用。前述化合物的“共协调方式”无差别地表示，共同施用（即基本上并行地或相继地补充）L-肉碱或丙酰基L-肉碱和至少一种曲克芦丁、香叶木苷、橙皮碱，或者，联合地和在混合物中施用包含前述活性成分的组合物，所述混合物任选地另外包含一种或多种药学上可接受的赋形剂或稀释剂。
本发明的组合物可以以任意合适的形式口服地、肠胃外地、静脉内地、局部地和/或透皮地给药。口服给药是优选的。
给药形式的一个实例是：在药囊、丸剂、管形瓶、膏剂、凝胶或脂质体中的液体、半液体或固体形式。
L-肉碱和丙酰基L-肉碱是已知的化合物，它们的制备方法描述在US4,254,053中。
曲克芦丁、香叶木苷和橙皮碱在市场上广泛地销售，它们的CAS-No.分别是：7085-55-4、520-27-4和520-26-3。
根据本发明的药物组合物由医学领域的从业人员熟悉的且已经在使用中的活性成分组成。
它们的获得因此是非常容易的，因为这些是目前已经长时间面市的产品，且具有适合人类施用的等级。
对于任意化合物，最初可以在细胞培养试验中或在动物模型（通常是小鼠或大鼠）中估测治疗有效剂量。
所述动物模型也可以用于确定适当的浓度范围和给药途径。这样的信息然后可以用于确定对于在人类中施用而言有用的剂量和途径。
对于人受试者而言，精确有效剂量取决于：疾病状态的严重性，受试者的一般健康，受试者的年龄、体重和性别，饮食，给药时间和频率，联合用药，对治疗的反应敏感性和耐受性/应答。该量可以通过例行试验来确定，且由临床医师判断。
具体实施方式
下面的非限制性实施例进一步例证了本发明。
实施例1
在巴豆油诱导的大鼠痔模型中，直肠-肛门肿胀的减轻。
从Harlan Sprague Dawley购买雄性SD大鼠（6周龄，大约140g），并允许适应1周。根据实验动物国家研究委员会（National Research Council ofLaboratory Animal）护理和使用指南，在没有病原体的设施中维持大鼠。使用7-8周龄的年龄匹配的大鼠，进行每个实验。根据Nishiki公开的方法（Nishiki等人(1988)Folia Pharmacology Japan 92:215-225;Nishiki等人(1988)Folia Pharmacol.Japan 92:227-240），制备巴豆油诱导的大鼠痔模型。简而言之，将被0.16mL诱导物（去离子水:吡啶:乙醚:6%巴豆油/乙醚（1:4:5:10））浸泡的直径4mm的棉签施用于大鼠的肛门12秒。巴豆油的终浓度是3%。水肿线性地发展，直到施用后7-8小时，水肿的严重性持续超过24小时。24小时后，将大鼠安乐死，然后分离出直肠-肛门组织（约10mm长）。测量大鼠体重和直肠-肛门的重量。使用下式计算直肠-肛门系数（RAC）：直肠-肛门的重量（mg）/体重（g）。
将本发明的化合物悬浮于盐水（1mL）中口服地施用，每天1次，持续5天。在用巴豆油诱导水肿的当天，进行本发明的化合物的最后一次治疗。
以下述剂量，单独地或组合地施用本发明的化合物：20mg/kg的丙酰基L-肉碱或L-肉碱；30mg/kg的曲克芦丁、香叶木苷或橙皮碱。
在用巴豆油诱导痔以后24小时，测定大鼠的RAC。
得到的结果记载在下面的表1中。
表1
n=5只大鼠/组；自由度=8。
在表1中报告的结果表明，使用本发明的组合物，会得到统计上显著地更有效的结果（相对于使用单一组分）。
实际上，在表1中报告的结果表明，本发明的组合物会完全抑制巴豆油诱导的直肠-肛门的肿胀。
实施例2
测试的化合物对主动脉环的松弛作用。
该研究的目的是，使用从自发性高血压大鼠分离出的大动脉，研究本发明的组合物的血管松弛作用。
材料和方法
以表示为器官室中的终浓度的浓度，使用测试化合物。
动物
在24±2℃，在60±20%相对湿度，以12-h亮-暗周期，圈养体重为250-300g的10-12周龄的雄性自发性高血压大鼠（SHR）。大鼠自由地接近标准食物和水的饮食。根据欧盟动物伦理处理的指南，进行所有实验。通过颈椎脱位处死大鼠，并快速地解剖主动脉。
主动脉环制备
将胸降主动脉置于改进的克-汉二氏溶液（PSS）中，该溶液含有（mM）：NaCl 118、KC1 4.75、NaHCO325、MgSO4 1.2、CaC12 1.8、KH2PO4 1.2和葡萄糖11。
在去除多余的脂肪和结缔组织以后，将主动脉切成2-3-mm环。在2g的基本张力下，在20mL含有PSS的器官浴槽中，固定主动脉环，并连接至等长传感器（Harvard UF-1）；用Powerlab数据获取系统（AD-Instruments）记录信号。将组织浴液维持在37℃，并用95%O2和5%CO2气体混合物鼓泡。
测试的化合物的松弛作用。
通过将所述化合物加给用去氧肾上腺素（1微摩尔）预收缩的主动脉环，评估测试的化合物的松弛作用。
在用去氧肾上腺素收缩主动脉以后，当达到收缩反应时，将所述测试化合物加入槽液中。将所有结果表示为去氧肾上腺素诱导的反应的最大收缩的百分比。
统计分析
将结果表示为最初预收缩水平的百分比。
基于实际收缩值平均值±SE（n=8个主动脉制品/组），计算显著性。研究了来自单个主动脉的8个制品。使用Student t-检验，作为统计分析的比较检验。
认为p<0.05值代表显著差异。
得到的结果记载在下面的表2中。
表2
在表2中报告的结果表明，将本发明的组合物加给用去氧肾上腺素预收缩的主动脉环，会引起内皮依赖性的松弛，与单一组分相比，这是统计上显著地更有效的。
在下面记载了本发明的组合物的一些非限制性实施例。
组合物1
组合物2
组合物3
组合物4
Claims (14)
1.联合组合物，其包含作为活性成分的L-肉碱或其衍生物或盐、曲克芦丁、香叶木苷、橙皮碱和任选的一种或多种药学上可接受的赋形剂。
2.根据权利要求1所述的联合组合物，其中所述L-肉碱的衍生物是丙酰基L-肉碱。
3.根据权利要求1或2所述的联合组合物，其包含：
-L-肉碱或丙酰基L-肉碱，其剂量为10至3000mg，优选的剂量为50mg至400mg，最优选的剂量为136mg；
-曲克芦丁，其剂量为900mg至50mg，优选的剂量为400mg至200mg，最优选的剂量为300mg；
-香叶木苷，其剂量为900mg至50mg，优选的剂量为400mg至200mg，最优选的剂量为300mg；和
-橙皮碱，其剂量为10mg至500mg，优选的剂量为50mg至200mg，最优选的剂量为100mg。
4.根据权利要求1所述的联合组合物，其作为饮食添加物。
5.根据权利要求1所述的联合组合物，其作为药剂。
6.根据权利要求1所述的联合组合物，其另外包含辅酶、矿物质、抗氧化剂、维生素、抗凝固剂和可用于治疗静脉疾病的药剂。
7.根据权利要求1或2所述的联合组合物，其用于预防或治疗静脉疾病。
8.包含L-肉碱或其衍生物或盐、曲克芦丁、香叶木苷和橙皮碱作为活性成分的联合组合物用于制备药剂的用途，所述药剂用于预防或治疗静脉疾病。
9.根据权利要求8所述的用途，其中所述L-肉碱的衍生物是丙酰基L-肉碱。
10.根据权利要求8或9所述的用途，其中所述静脉疾病选自：慢性静脉功能不全、慢性静脉疾病和它们的并发症。
11.根据权利要求10所述的用途，其中所述并发症选自：直肠、肛门和外阴中的静脉的肿胀和炎症；静脉高压；增加的渗透性；水肿；毛细管损伤；皮肤变化；静脉腿溃疡；踝肿胀；腿沉重；静脉曲张；腿肿胀；溃疡；静脉血栓形成；静脉炎；血栓性静脉炎；肺栓塞或痔疮。
12.根据权利要求8或9所述的用途，其中所述L-肉碱或丙酰基L-肉碱的盐选自：氯化物、溴化物、乳清酸盐、天冬氨酸盐、酸性天冬氨酸盐、酸性柠檬酸盐、柠檬酸镁、磷酸盐、酸性磷酸盐、富马酸盐和酸性富马酸盐、富马酸镁、乳酸盐、马来酸盐和酸性马来酸盐、草酸盐、酸性草酸盐、扑酸盐、酸性扑酸盐、硫酸盐、酸性硫酸盐、磷酸葡萄糖、酒石酸盐和酸性酒石酸盐、甘油磷酸盐、粘酸盐、酒石酸镁、2-氨基-乙磺酸盐、2-氨基-乙磺酸镁、甲磺酸盐、酒石酸胆碱、三氯乙酸盐或三氟乙酸盐。
13.根据权利要求8或9所述的用途，其用于口服的、肠胃外的、静脉内的、局部的和/或透皮的给药。
14.根据权利要求8或9所述的用途，其用于口服给药。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103877108A (zh) * | 2012-12-21 | 2014-06-25 | 瑟维尔实验室 | 口服混悬液形式的包含黄酮类组分和黄原胶的药物组合物 |
| CN104605451A (zh) * | 2015-01-31 | 2015-05-13 | 丁年生 | 一种防止毛细血管出血的玫瑰花饮料及其制备方法 |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2656288T3 (es) * | 2013-12-05 | 2018-02-26 | Alfasigma S.P.A. | Composición útil para favorecer la fertilidad femenina |
| FR3019820B1 (fr) * | 2014-04-15 | 2017-07-21 | Peter Weyts | Composes de type flavonoides pour leur utilisation dans le traitement d'une pathologie du pied d'un mammifere ongule-composition pharmaceutique associee |
| RU2704976C2 (ru) * | 2017-05-10 | 2019-11-01 | Общество с ограниченной ответственностью "Трейдсервис" | Флеботропная комбинированная фармацевтическая композиция |
| RU2705794C1 (ru) * | 2018-09-26 | 2019-11-12 | Общество с ограниченной ответственностью "Трейдсервис" | Комбинированная мягкая лекарственная форма для лечения геморроидальных заболеваний |
| RU2689409C1 (ru) * | 2018-11-21 | 2019-05-28 | Общество с ограниченной ответственностью "Трейдсервис" | Комбинированная мягкая лекарственная форма диосмина и троксерутина |
| IT202000003122A1 (it) * | 2020-02-17 | 2021-08-17 | Apharm Srl | Associazione di principi attivi e loro uso nel trattamento e/o nella prevenzione della insufficienza venosa |
| HUP2100299A1 (hu) | 2021-08-19 | 2023-02-28 | Keri Pharma Hungary Kft | Új gyógyászati kombináció alkalmazása krónikus vénás elégtelenség kezelésére |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4415589A (en) * | 1981-11-06 | 1983-11-15 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Use of carnitine and of lower acyl-carnitines in the therapeutic treatment of the pathology of the veins |
| US5949786A (en) * | 1996-08-15 | 1999-09-07 | 3Com Corporation | Stochastic circuit identification in a multi-protocol network switch |
| WO2000028986A1 (en) * | 1998-11-13 | 2000-05-25 | Sigma-Tau Healthscience S.P.A. | Antioxidant composition comprising propionyl l-carnitine and a flavonoid against thrombosis and atherosclerosis |
| WO2003066573A1 (en) * | 2002-02-04 | 2003-08-14 | Aldo Fassi | Metal salts of carnitines, dietary supplements containing same and dietary kits for counteracing sexual disorders in male subjects |
| US20040053860A1 (en) * | 2002-09-02 | 2004-03-18 | Merck Patent Gmbh | Flavonoid derivatives for the treatment of eczema |
| WO2006089317A1 (de) * | 2005-01-14 | 2006-08-31 | Hermine Engl | Pharmazeutische mikrozirkulatorisch wirksame darreichungsform mindestens ein flavonoid enthaltend |
| EP2208498A1 (en) * | 2007-09-07 | 2010-07-21 | World Trade Import-Export, WTIE A.G. | Pharmaceutical composition combining various venotonic and vasoprotective agents for the treatment of chronic venous insufficiency |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2903558C2 (de) | 1978-02-03 | 1994-09-01 | Sigma Tau Ind Farmaceuti | Verwendung von L-Carnitin |
| IT1156852B (it) | 1978-07-10 | 1987-02-04 | Sigma Tau Ind Farmaceuti | Procedimento industriale per la preparazione del d'canforato della l carnitinammide e del d canforato della d carnitinammide e sue applicazioni |
| IT1206954B (it) | 1979-02-12 | 1989-05-17 | Sigma Tau Ind Farmaceuti | Agenti terapeutici a base di un acil derivato della carnitina per la cura di vasculopatie periferiche |
| CH662505A5 (it) * | 1985-04-30 | 1987-10-15 | Seuref Ag | Composizioni farmaceutiche ad azione protettiva vascolare. |
| JP2669146B2 (ja) | 1990-11-26 | 1997-10-27 | 富士電機株式会社 | 半導体素子の保護用ヒューズ |
| FR2710844B1 (fr) * | 1993-10-07 | 1995-12-29 | Bidel Christian Georges | Composition pour le traitement ou la prévention de l'herpès. |
| DE69605531T2 (de) | 1996-03-04 | 2000-05-31 | Sigma Tau Ind Farmaceuti | Carnitinderivat als Arzneimittel zur Behandlung von Arteriosklerose obliterans |
| ITRM20030178A1 (it) | 2003-04-17 | 2004-10-18 | Sigma Tau Ind Farmaceuti | Uso della l-carnitina per il trattamento di patologie cardiovascolari. |
| US20070087975A1 (en) | 2005-10-17 | 2007-04-19 | Sigma-Tau Industrie Farmaceutiche Riunite Spa | Compound useful for the prevention and treatment of left ventricular hypertrophy in dialysed patients |
-
2010
- 2010-02-02 EP EP10152363A patent/EP2353596A1/en not_active Withdrawn
-
2011
- 2011-02-07 UA UAA201207518A patent/UA107687C2/ru unknown
- 2011-02-07 SI SI201130232T patent/SI2531189T1/sl unknown
- 2011-02-07 BR BR112012019351A patent/BR112012019351A2/pt active Search and Examination
- 2011-02-07 US US13/576,780 patent/US20130005670A1/en not_active Abandoned
- 2011-02-07 MX MX2012008890A patent/MX2012008890A/es active IP Right Grant
- 2011-02-07 AU AU2011212153A patent/AU2011212153B2/en not_active Ceased
- 2011-02-07 DK DK11709464.9T patent/DK2531189T3/da active
- 2011-02-07 PL PL11709464T patent/PL2531189T3/pl unknown
- 2011-02-07 US US13/022,102 patent/US20110189152A1/en not_active Abandoned
- 2011-02-07 PE PE2012001096A patent/PE20121700A1/es active IP Right Grant
- 2011-02-07 RS RSP20140448 patent/RS53515B1/en unknown
- 2011-02-07 PT PT117094649T patent/PT2531189E/pt unknown
- 2011-02-07 EA EA201200786A patent/EA021107B1/ru not_active IP Right Cessation
- 2011-02-07 ES ES11709464.9T patent/ES2487647T3/es active Active
- 2011-02-07 CN CN201180008020.8A patent/CN102791263B/zh active Active
- 2011-02-07 NZ NZ600695A patent/NZ600695A/en not_active IP Right Cessation
- 2011-02-07 WO PCT/IB2011/000200 patent/WO2011095882A1/en active Application Filing
- 2011-02-07 SG SG2012049011A patent/SG182323A1/en unknown
- 2011-02-07 EP EP11709464.9A patent/EP2531189B1/en active Active
-
2012
- 2012-06-20 CO CO12103267A patent/CO6551731A2/es not_active Application Discontinuation
- 2012-08-02 IL IL221273A patent/IL221273A/en not_active IP Right Cessation
-
2013
- 2013-09-19 US US14/031,555 patent/US9457037B2/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4415589A (en) * | 1981-11-06 | 1983-11-15 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Use of carnitine and of lower acyl-carnitines in the therapeutic treatment of the pathology of the veins |
| US5949786A (en) * | 1996-08-15 | 1999-09-07 | 3Com Corporation | Stochastic circuit identification in a multi-protocol network switch |
| WO2000028986A1 (en) * | 1998-11-13 | 2000-05-25 | Sigma-Tau Healthscience S.P.A. | Antioxidant composition comprising propionyl l-carnitine and a flavonoid against thrombosis and atherosclerosis |
| WO2003066573A1 (en) * | 2002-02-04 | 2003-08-14 | Aldo Fassi | Metal salts of carnitines, dietary supplements containing same and dietary kits for counteracing sexual disorders in male subjects |
| US20040053860A1 (en) * | 2002-09-02 | 2004-03-18 | Merck Patent Gmbh | Flavonoid derivatives for the treatment of eczema |
| WO2006089317A1 (de) * | 2005-01-14 | 2006-08-31 | Hermine Engl | Pharmazeutische mikrozirkulatorisch wirksame darreichungsform mindestens ein flavonoid enthaltend |
| EP2208498A1 (en) * | 2007-09-07 | 2010-07-21 | World Trade Import-Export, WTIE A.G. | Pharmaceutical composition combining various venotonic and vasoprotective agents for the treatment of chronic venous insufficiency |
Non-Patent Citations (3)
| Title |
|---|
| 张冬松等: "橙皮苷的药理活性研究进展", 《中国现代中药》 * |
| 李玉山: "橙皮苷研究新进展", 《科技导报》 * |
| 陆伟根等: "曲克芦丁颗粒剂的特性及临床效果", 《中国新药杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103877108A (zh) * | 2012-12-21 | 2014-06-25 | 瑟维尔实验室 | 口服混悬液形式的包含黄酮类组分和黄原胶的药物组合物 |
| CN104605451A (zh) * | 2015-01-31 | 2015-05-13 | 丁年生 | 一种防止毛细血管出血的玫瑰花饮料及其制备方法 |
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| UA107687C2 (ru) | 2015-02-10 |
| ES2487647T3 (es) | 2014-08-22 |
| CN102791263B (zh) | 2016-10-12 |
| EP2353596A1 (en) | 2011-08-10 |
| NZ600695A (en) | 2014-03-28 |
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| EA201200786A1 (ru) | 2013-01-30 |
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| EP2531189A1 (en) | 2012-12-12 |
| PT2531189E (pt) | 2014-08-25 |
| BR112012019351A2 (pt) | 2017-06-27 |
| PE20121700A1 (es) | 2012-12-22 |
| DK2531189T3 (da) | 2014-09-01 |
| AU2011212153B2 (en) | 2016-08-04 |
| RS53515B1 (en) | 2015-02-27 |
| US20140018310A1 (en) | 2014-01-16 |
| SG182323A1 (en) | 2012-08-30 |
| AU2011212153A1 (en) | 2012-07-05 |
| EA021107B1 (ru) | 2015-04-30 |
| PL2531189T3 (pl) | 2014-10-31 |
| US20130005670A1 (en) | 2013-01-03 |
| MX2012008890A (es) | 2012-08-31 |
| WO2011095882A8 (en) | 2012-08-02 |
| SI2531189T1 (sl) | 2014-09-30 |
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