CN1620308A - 含有表皮生长因子的药物组合物在预防糖尿病肢端坏疽截肢中的用途 - Google Patents
含有表皮生长因子的药物组合物在预防糖尿病肢端坏疽截肢中的用途 Download PDFInfo
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Abstract
本发明涉及优选形式为注射用药物组合物的表皮生长因子(EGF)的用途,所述组合物经渗透方式施用于慢性缺血性皮肤病变内部或周围以便预防糖尿病足的截肢。所述组合物可施用于近期外科手术造成的、由于长时间缺血后氧合血急性再灌注作用造成的损伤表面,由此预防进一步的手术步骤并有利于保存肢体。上述的组合物可被用来改善(i)细胞微环境,由此增加组织的修复和保护能力和生存力,和(ii)皮肤缺血性病变的愈合,由此刺激细胞增殖。本发明适用于人类、兽医学和实验医学,特别式脉管血管学和外科学、皮肤病学、烧伤处理和重建外科学和老年医学。所述组合物可用于与大和/或微血管系统病变相关的难治性溃疡,患有淋巴和/或静脉回流不充分和溃疡或其他不容易愈合的病变的病人。
Description
技术领域
本发明涉及一种药物组合物的用途,该组合物包含表皮生长因子(EFG),优选的是注射形式和通过渗透进入和扩散到皮肤慢性缺血性溃疡伤口给予,以便预防糖尿病肢端坏疽(diabetic limb)截肢。也可以通过近期手术的截肢后的表面,或长期缺血后,氧化血急性再灌注过程的损伤部位给予。这可以预防外科再干涉,因此帮助保存肢体。
背景技术
在部分或完全性急性或慢性动脉供血不足后,机体的每个器官和组织均容易遭受不可逆的损伤。慢性静脉回流障碍也可能引起组织损伤(T.D.Lucas y l.L.Szweda,Cardiac reperfusion injury:aging,lipid peroxidationand mitochondrial dysfunction.Proc Natl Acad Sci USA 1998,95(2):510-514)。此类问题常常见于糖尿病患者。由于大和微血管系统的损害导致这些个体中肢体局部循环障碍。此外,外周神经的结构也受到影响,也导致循环障碍恶化。自主或感觉神经系统的糖尿病相关性损伤引发肢体皮肤防御机制如汗腺和皮脂腺分泌的障碍。局部感觉丧失导致足部易于发生局部外伤并可能发展为难治性病变。
多种风险因素与糖尿病患者中见到的难以治愈的症状相关,例如,高水平和持续性的血糖过高、血色素和许多其他循环中的蛋白质和组织蛋白质的糖基化,如,胶原,等(Kurose l,Argenbright LW Wolf,R,LianxiL,Granger DN.Ischemia/reperfusion-induced microvascular dysfunction:role of oxidants and lipid mediators.Am J Physiol 1997,272:H2976-H2982)。伤口不愈合加之合并循环障碍,结果是许多的糖尿病病人不得不进行截肢。患有肢体炎症性或退化性动脉病变的病人在膝关节以下常常仅有可以忽略的或无效的灌注。持续缺氧导致其它的皮肤、微脉管、神经和关节并发症,前者常导致难治性缺血性溃疡。此外,神经,脉管,和其它的皮肤结构可受到严重损害并常常出现坏疽。这更进一步造成溃疡的难治性倾向(McCallon SK,Knight CA,Valiulus JP,Cunningham MW,McCulloch JM,Farinas LP.Vacuum-assisted closureversus saline-moistened gauze in the healing of postoperative diabetic footwounds.Ostomy Wound Manage 2000,46:28-32)。
在此,我们将描述当今医学界用于解决这种痛苦的一些方法。
在当今本领域通常使用的方法中,新陈代谢平衡矫正可减少糖尿病并发症的风险因子。另外,减少受到侵袭的肢体的负荷是促进肢体溃疡愈合的受到重视的解决方案。给予抗生素以及给坏疽和形成窦道的组织频繁进行外科清创手术是本领域的现状。进行这些措施可不考虑被感染的足部的灌注情况。但是,对于严重缺血性和进展性溃疡的重度难治病例,截肢是不可避免的。针对慢性或复发的其它附加的医学干涉措施在本领域中显示出一些益处。
但是,使用任何这些治疗性干涉要求,预先检测许多在糖尿病患者中可能受损的功能系统,如心血管,肾脏,肝脏等,尤其是,第一和第二个器官。在某些情况下,已经引入其他治疗方法用来预防或纠正血小板聚集,如溶解血栓的药物。
大血管再成形手术对于任何缺血性病人总是危险的,无论是否是糖尿病患者。此外,手术也很昂贵,而且不适用于很多病人。因此,手术范围非常有限。血管内手术也很复杂、昂贵并且仅能用在有限的动脉节段例如髂动脉和股动脉-腘动脉。当病变以片状形式出现时,大部分这些节段常常出现钙化。
当今,腰交感神经阻断手术已例外地应用于糖尿病中。已经存在的自主神经病变妨碍了其有效性。
最近出现了对付糖尿病足部病变(糖尿病肢端坏疽)的希望,即人重组血小板衍生生长因子,商业上是Becaplermin或Regranex,其已经获得美国食品和药品管理局(FDA)批准。这个药物特别用于神经病变引起的足部溃疡。最近发表的大多数文章数据显示,在美国的多中心,对照,和随机临床试验中只有50%的有效率(T.Jeffery Wieman,Janice M.Smiell,Yachin Su.Efficacy and safety of topical gel formulation of recombinanthuman platelet derived growth factor-BB(Becaplermin)in patients withchronic neuropathic diabetic ulcers.Diabetes Care 1998,21:822-827)。值得注意的是,在上述的研究PDGF-BB中,Becaplermin治疗后,伤口变小,变浅并且在形状大小或严重程度上决不能与我们使用本发明的治疗相比较。另一方面,所述临床试验是对具有正常和标准的动脉血供应的神经病性足部溃疡进行的。在我们的病例中,对严重的缺血性溃疡如依据Wagner分类处于IV和V期的溃疡进行了治疗并已经治愈。我们处理的大多数伤口是缺血性的。我们治疗的所有伤口大于20cm2和10到40mm深。在PDGF-BB临床试验中,伤口只有2.7±3.45cm2和0.5±0.49cm深。PDGF-BB治疗所需解决的关键方面是高复发率。在第三个月约达到30%。
最近的另一个关于大面积急性皮肤伤口(例如烧伤,或慢性如静脉溃疡)的发明是制造生物合成的人类皮肤等价物。但是,缺乏治疗糖尿病足部溃疡的临床对照试验,并且看上去,任何人类皮肤等价物均不太可能控制或逆转潜在的缺血性过程(Editorial.New Skin for Old.Developmentsin Biological Skin Substitutes.Arch Dermatol 1998;134:344-348)。
概括而言,目前没有能够有效治愈与局部缺血相关的那些难治性伤口的治疗方法。预防复发可能是一个更复杂的挑战。
发明内容
本发明的目的是一种注射用药物组合物的用途,该药物组合物包含可提高组织的存活和对缺氧的适应性的表皮生长因子(EGF);可治愈皮肤和邻近的软组织的缺血性和慢性溃疡而不发生反复。该组合物可治愈缺血性溃疡性或非典型性伤口或那些皮肤和邻近软组织暴露于动脉血再灌注过程而造成的那些伤口。在本文中的缺血性伤口定义为由于糖尿病患者的大和小血管长期损伤导致外周灌注障碍引起的下肢皮肤和软组织损伤。再灌注过程所累及的伤口大多数是在截肢手术或剧烈清创手术过程中当长时间的区域性血液动力学灌注抑制期后再次引入氧合血液时产生的。或者,在糖尿病患者中,这些过程可出现在血管成形手术之后。
在这些损伤中使用EGF可减慢组织损害的进程,特别是与组织中血流障碍和毒素存留相关的腿部和足部。
本发明的组合物可引发和稳定维持本领域还未能成功治愈的慢性缺血性伤口的愈合过程。当没有其他可获得的治疗缺血性和慢性伤口的医学方法选择时,使用这个组合物后可避免截肢手术。本组合物也可减少外科手术再灌注病变以完全治愈缺血性/感染性/神经病性足部溃疡。采用这个治疗方法,可明显的中断伤口边缘的细胞停滞(cellular arrest)过程和随后的组织退化。这可以避免进一步的剧烈清创手术和部分截肢的需要。依靠常规的细胞保护和援救作用的组合物可增强缺血性/感染性/神经病性糖尿病足部溃疡的愈合。
所述组合物通过在伤口边缘和病变的底部局部渗透而施用,而且该组合物可含有天然、重组或合成技术获得的多肽。施用过程类似进行局部麻醉封闭,在损伤周围和不同点插入针头,以便于所有深底部表面和边缘直接接触到该组合物。组合物沉积进入4到20个渗透点,各个点之间的距离不超过1.5cm。点的数量由本领域人员确定。大的伤口将需要大量的灌输点。本领域技术人员在施用时间上将发现几个公认的结果:局部水肿情况和局部对组合物渗开的阻力。伤口边缘和底部剧烈的清创手术将依据本领域技术人员的经验。概括而言,治疗过程中可显著减少剧烈的清创手术和小的截肢手术。如果随着处理过程边缘变得活力下降,可对其适当地清创并随后在表皮下间隙内进行渗透。渗透通常每周隔天进行以便每周渗透三次。每次渗透点的数量依赖于伤口大小,通常范围在4-20个之间。在处于Wagner分类的IV和V期的感染/缺血性伤口中,在第六次渗透后出现肉芽组织。在少数严重的伤口中,有可能在处理的第一周,3次渗透后就看到一些反应。或者,在外周灌注完全缺乏的非常严重的缺血和低于9g/L的贫血中,每天进行治疗。在这些病人中,第9次渗透左右出现的肉芽迹象。在所有的病例中,注射总量大约1ml,所以一个溃疡可获得总量为4-20ml的组合物。优选使用的皮下针头271/2。组合物可含有天然来源的、经化学合成或通过重组DNA技术的EGF多肽。应用在此描述的含有EGF的药物组合物,采用最低限度的创伤性步骤,可使慢性和缺血性病变的组织完全再生。组合物的使用也减少外科手术以及小和大截肢手术的数量。在其他病例中,使用在此描述的本发明可以允许(I)不需要外科步骤,去除缺血性荚膜(ischemic capsule)。这可能是由于从深部区域出现了一个新的重塑肉芽组织,其使得坏死物抬高和分离,(II)连续渗透之后,在将要截肢前(如脚趾)生长出新的皮内血管生成纤维组织,因此存在一个促肉芽生长的环境。这可有助于减少和消除败血症,增强伤口愈合并减轻再灌注病变。
药物组合物的成分如下:
表皮生长因子(EGF):当施用至溃疡内部时,细胞保护药物可激活细胞自我防御机制。EGF促进细胞在应激环境下的适应性和存活。当成纤维细胞损伤和/或老化时,EGF在老化的这些细胞中引发凋亡,对于其他最终被援救的细胞,EFG是一个存活因子。EGF在微环境中作为一个选择性压力,适应的细胞可以繁殖。由于它的细胞保护作用,可预防缺血性/再灌注病变。组合物含有10-1000mg/ml的无菌载体。EGF可以是天然的、合成或重组的。EGF可以是液体、悬浮于水中、溶于缓冲液、冻干并溶解等液体形式。EGF也可以是均质粉末,由高压喷射装置应用。EGF可以在一个适合在瞬时转染的人类细胞中表达的基因构建体中的DNA形式施用。
聚乙烯亚胺(PEI):它是带有很高阳性电荷的-质子化的化合物,其可增强EGF与它受体的相互作用,延长其在胞外基质中的半衰期,预防细胞内降解,所以以这种方法它的生物学作用被放大。在配方中发现摩尔关系比例可以从1∶1达到1(EGF)∶10(PEI)。
磷酸钠缓冲液:化学稳定剂。它的pH约6.5,摩尔浓度范围5-100mM。配方中的最佳范围是10-20mM。
O-棉子糖:冻干过程的稳定剂。使用浓度为5-50mg/ml,但是它的最佳范围是8-20mg/ml。
L-甘氨酸:等渗剂。使用浓度5-50mg/ml,但是它的最佳浓度是10-20mg/ml。
纤连蛋白:促进EGF的生物学功能稳定。其提高了EGF与它的细胞受体的相互作用。使用范围从10-20μg/ml。
果聚糖:当EGF溶于液体的保护剂。它作为EGF的筛选剂。促进它胞外空间的生物分配。在组合物中它的范围是1-20mg/ml。
药物组合物也可将如下有效成分与EGF结合:
芸香苷:静脉滋补剂和静脉营养剂。它在配方中的浓度是20-1000μg/ml。其可被用做游离的芸香苷水合物或作为冻干的芸香苷盐如硫酸盐。
利多卡因:营养剂。利多卡因减弱促炎症细胞因子的局部分泌和血管腔中粘附因子的表达。在配方中,利多卡因被用作一个盐酸盐,并且它的浓度范围5-40mg/ml。
三磷酸腺苷(ATP):它具有促血管舒张和促新陈代谢的作用。它在配方中的浓度范围从0.05-20mg/ml,作为一个钠盐或游离酸。
三磷酸鸟苷(GTP):增强局部血管舒张。它在配方中作为钠盐存在。它的浓度范围从1-100mg/ml。
烟碱(烟酰胺):呈现有用的细胞合成代谢底物。它的浓度范围从1-130mg/ml。
L-精氨酸:调节血管压力。配方中用作盐酸盐结晶。它的浓度范围从1-100ng/ml。
肝素:细胞保护剂,促有丝分裂剂。在配方中用作钠盐,浓度范围从1-10μg/ml(0.1-1U)。
实施例:
总共9个病人接受药物组合物治疗。所有病人均具有如下特征:
1.所有病人均患有II型糖尿病,有10-25年病史,主要采用口服降糖治疗。
2.所有病人均有难愈合困难的情况。一些病人早先曾经进行患侧截肢手术。
3.所有治疗的伤口符合糖尿病肢端慢性溃疡,划分为缺血性/感染性/神经病性糖尿病足或混合形式。在所有伤口中,主要是Wagner的IV期或V期。
4.使用本配方治疗的所有伤口均可被认为是难治性或难愈合的伤口;一些长达一个月或更长的时间。
5.所有伤口均大约20cm2或更大,在大多数病例中,溃疡深度到达骨膜,致使骨组织暴露。其中,一个病人伴随缺血性跟骨。
6.所有治疗的病人均有高度倾向于需要截肢。
7.所有病人经治疗出院后一直随诊,到目前为止没有一个病人复发。没有观察到晚期不良反应或局部缺血性信号。当时没有记录到不良反应。
治疗基于在病变周围对伤口底部和边界至少5个不同及等距的点的深部渗透。注射针头必须导向伤口中心基底区域、边缘和/或存在的窦道(如果有的话)。在每个注射点,沉积1ml溶液。除了正常的局部疼痛,随着治疗或治疗后没有观察到不良反应。配方总是含有EGF作为主要的有效成分,在一些实施例中,配方包含一些以上所述有效成分。在所有治疗的病人中,均预防了足尖、足部或主要的截肢。各个实施例显示各个病人进行渗透的总次数。
实施例1
病人ACDF,49岁,女性。病人患有缺血性/感染性糖尿病足,患有II型糖尿病,具有16年病史,2年半前病人进行了预先的交感神经切除手术和右下肢髁上(supracondilial)截肢手术。当左足第一个脚趾出现溃疡、湿性、活力下降和难愈性损伤时,尽管经许多小的清创手术以去除缺血性荚膜,促进伤口的边缘和底部新生,但最终左足第一个脚趾仍被手术切除。在术后5天,截肢端缺血、边缘出现发绀和活力下降。以组合物进行渗透引发预期的自发的溃疡上皮再次生长。从第四次渗透,注意到伤口方面发生了显著的改变,开始产生肉芽组织,出血,几天后,重新覆盖上皮。病人总共获得9次渗透(3/周,因此,需要3周的治疗)。上皮再次生长后,病人出院。没有复发。
实施例2
病人ERC,66岁,女性。病人具有12年II型糖尿病病史,患有缺血性感染性糖尿病足和缺少末梢动脉搏动。进行了一次小的跖骨横截肢(minor transmetatarsal)手术,具有向下的大窦道。截肢部位的基底部变得发绀、缺血、活力下降和大量黄色成分堆积。组合物渗透开始即产生了预期的肉芽组织和自发愈合倾向。11次渗透后,受伤的足部包括的窦道完全治愈,产生肉芽和重新覆盖上皮。其包括大约4cm深的同侧窦道。首次观察到这个病人的伤疤重塑(remodeling)。
实施例3
病人ECS,63岁,女性。她从41岁开始患II型糖尿病。她患有缺血性感染性足部病变和一个早先的对侧髁下(infracondilial)截肢手术。由于严重的缺血,她被确诊接受了第一个脚趾切除手术。手术中,一个缺血性荚膜被植入邻近脚趾的底部并延伸到后面和下面。在该处的损伤是活力下降的,并且没有观察到愈合过程。足趾和邻近的软组织被除去,打开一个大和深的边缘,类似6cm长的窦道。手术后3天,再次出现缺血性和坏疽迹象。3天后,伤口的轮廓变得发绀和缺血。经组合物渗透后产生预期的治愈反应倾向。11次渗透后,病人伤口被良好的角质化上皮充分再次覆盖,伤口完全愈合。病人出院。也观察到伤疤重塑。
实施例4
病人RNP,69岁,男性。病人具有12年II型糖尿病感染病史,伴有末梢动脉搏动不足,患有缺血性/感染性足部病变。由于溃疡性病变经现有治疗方法难以治愈,病人进行了一个跖骨横截肢手术。在手术创面上,出现缺血性斑块并且愈合过程没有任何进展。病人在床上抱怨自发疼痛。紫绀延伸到手术创面轮廓周围,在清创手术过程中仅有微量出血。手术切除缺血性斑块,在术后4天,开始渗透治疗。在术后第6天观察到组织改善的迹象,所以自发疼痛消失,明显出现一个红色的肉芽组织。12次渗透后,病人伤口完全被上皮再次覆盖,即需要4周的治疗。出院随诊12个月进展良好,没有复发。
实施例5
病人ISV,74岁,女性。病人30年前患糖尿病。她患有缺血性/感染性足部病变。早先进行过跖骨横截肢手术,有难愈合史。她被确诊有第5脚趾的坏疽病变。进行外科手术并在几天后出现缺血性斑块。她接受了更进一步的清创手术,在足部下外侧外表面大面积暴露到骨膜。48小时后,边缘变得缺血,因此,进行渗透治疗尝试以实现包括边缘部分自发治愈。第6次渗透后,出现了一个有益的和出血的肉芽组织。病变对治疗产生有利的反应并且在11次后充分地被上皮覆盖。病人出院后情况良好。
实施例6
病人RDR,44岁,男性。12年前患II型糖尿病。他患有缺血性/感染性糖尿病足,由于二个脚趾的缺血性病变,接受跖骨横截肢手术。病人缺少末梢动脉搏动并显示外周灌流不足的临床迹象。他有对侧胫骨区域愈合障碍史。截肢手术后,在伤口皮肤轮廓上出现发绀病灶。开始渗透治疗,预期产生充分的肉芽组织以进行自体移植,或第二目的是愈合和重塑。在第四次渗透时,肉芽组织第一次出现,伤口边缘再生,其同时伴有正常的颜色和增生。因此不必要进行自体移植。完成15次渗透后(5周),不需要做自身移植。出院后进一步好转。
实施例7
病人RGR,49岁,女性。她是10年的糖尿病患者,行走100米即有疼痛性跛行并有难愈合史。在双侧肢体的胫侧面上有几个抗愈合性溃疡。治疗的损伤是位于左小腿第三脚趾上的缺血性溃疡,其在肢体外侧,直径约6.4cm,0.5cm深。溃疡发展了2个月未能治愈。首先的方法是底部和边缘的保守清创术,在第二天开始渗透治疗。在第三次渗透后,病变处开始出现肉芽,伴有边缘收缩和一个单纯的最终分层和角质化的新上皮增殖。进行12次渗透(治疗4周)。出院后满意。
实施例8
病人GPJ,57岁,患有12年的II型糖尿病病史。他患有缺血性/感染性糖尿病足,没有胫动脉搏动迹象。由于右脚四个脚趾的缺血和坏疽,他接受了跖骨横截肢手术。手术后7天,出现愈合障碍,伤口边缘变得发绀和丧失活力,没有伤口修复的迹象。作为其他外科干涉的替代措施,开始进行渗透治疗。9次(3周)后,病变完全被上皮覆盖。出院后进展顺利,未见并发症。
实施例9
病人DLF,51岁,男性。具有II型糖尿病病史的病人,20年前患有哮喘。病人因穿孔性足底溃疡伴周围组织严重缺血和坏疽入院。左足几乎完全坏死。手术暴露骨膜后出现跟骨坏死。开始渗透治疗以试图替代立即截肢手术。唯一的希望是产生适于进行皮肤移植的多产和血管化的肉芽组织。共进行15次渗透,包括跟骨。第5次渗透后,肉芽组织开始出芽。当完成15渗透(5周),移植物被移植。病人进展顺利,他目前可以自己行走。
表1。给予每个病人的组合物和有效成分
病人名称 | 组合物 |
ACDF | 表皮生长因子(50μg/ml)+芸香苷(50mg/ml) |
ERC | 表皮生长因子(125μg/ml的钠缓冲液,pH6.5+20mgO-棉子糖和10mg的L-甘氨酸/ml缓冲液) |
ECS | 表皮生长因子(125μg/ml)+利多卡因(10mg/ml) |
RNP | 表皮生长因子(10μg/ml)+三磷酸盐腺苷(2.5mg/ml) |
ISV | 表皮生长因子(100μg/ml)+三磷酸鸟苷(5mg/ml) |
RDR | 表皮生长因子(30μg/ml)+NAD(25mg/ml) |
RGR | 表皮生长因子(25μg/ml)+L-精氨酸(10ng/ml) |
GPJ | 表皮生长因子(100μg/ml)+肝素(0.75U/ml) |
DLF | 表皮生长因子(100μg/ml,钠缓冲液,pH6.5+10mg O-棉子糖和10μg纤连蛋白和15mg L-甘氨酸) |
Claims (20)
1.表皮生长因子(EGF)在制备用于通过局部渗透至包括病变部位的边缘和底部的组织而治疗糖尿病患者的缺血性病变或再灌注病变的药物组合物中的应用。
2.权利要求1的表皮生长因子的应用,其中所述缺血性病变或再灌注病变位于下肢如足部、小腿或大腿、或两者均有。
3.前述权利要求中任一项的表皮生长因子的应用,其中所述治疗导致不必进行截肢或再次截肢。
4.前述权利要求中任一项的表皮生长因子的应用,其中所述EGF是人EGF。
5.前述权利要求中任一项的表皮生长因子的应用,其中所述含有EGF的药物组合物是一种液体组合物或一种在使用前用水或水性缓冲液重新配制的干的或冻干的组合物。
6.权利要求5的表皮生长因子的应用,其中所述含有EGF的药物组合物是一种任选地水性缓冲液组合物或一种用水或水性缓冲液重新配制的干的或冻干的组合物。
7.前述权利要求中任一项的表皮生长因子的应用,其中所述含有EGF的药物组合物含有10-1000μg/ml的EGF。
8.前述权利要求中任一项的表皮生长因子的应用,其中所述含有EGF的药物组合物还含有10μg到500mg的选自纤连蛋白、O-棉子糖、果聚糖和聚乙烯亚胺(PEI)中的至少一种成员。
9.前述权利要求中任一项的表皮生长因子的应用,其中所述含有EGF的药物组合物还含有20-1000μg/ml的至少一种天然类黄酮。
10.权利要求9的表皮生长因子的应用,其中所述天然类黄酮是芸香苷。
11.前述权利要求中任一项的表皮生长因子的应用,其中所述含有EGF的药物组合物还含有5-40mg/ml的利多卡因。
12.前述权利要求中任一项的表皮生长因子的应用,其中所述含有EGF的药物组合物还含有0.05-20mg/ml的三磷酸腺苷(ATP)或其盐。
13.前述权利要求中任一项的表皮生长因子的应用,其中所述含有EGF的药物组合物还含有1-100mg/ml的三磷酸鸟苷(GTP)或其盐。
14.前述权利要求中任一项的表皮生长因子的应用,其中所述含有EGF的药物组合物还含有1-130mg/ml的烟碱。
15.前述权利要求中任一项的表皮生长因子的应用,其中所述含有EGF的药物组合物还含有1-100ng/ml的L-精氨酸。
16.前述权利要求中任一项的表皮生长因子的应用,其中所述含有EGF的药物组合物还含有1-10μg/ml的肝素盐。
17.前述权利要求中任一项的表皮生长因子的应用,其中所述的局部渗透的治疗为每天一次、两天一次、三天一次、每周2或3次。
18.前述权利要求中任一项的表皮生长因子的应用,其中所述的局部渗透的治疗进行3次或更多次,优选为4到20次。
19.前述权利要求中任一项的表皮生长因子的应用,其中所述的局部渗透的治疗每次在3个或更多的点、优选为4到20个点上进行,所述的点沿着病变周围分布。
20.一种用于通过局部渗透至包括病变部位的边缘和底部的组织而治疗糖尿病患者的缺血性病变或再灌注病变的药物组合物,其是液体或冻干的组合物,含有10-1000μg/ml的EGF并组合了至少一种选自如下一组的成员:纤连蛋白、O-棉子糖、果聚糖、聚乙烯亚胺、类黄酮如芸香苷、利多卡因、三磷酸腺苷或其盐、三磷酸鸟苷或其盐、烟碱、L-精氨酸和肝素盐。
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CU0308/2001 | 2001-12-20 | ||
CU20010308A CU23043A1 (es) | 2001-12-20 | 2001-12-20 | Composicion farmaceutica que contiene factor de crecimiento epidrmico (egf) para la prevencion de la amputacion de pie diabetico. |
CU0308/01 | 2001-12-20 | ||
PCT/CU2002/000011 WO2003053458A1 (es) | 2001-12-20 | 2002-12-04 | Uso de una composición farmacéutica que contiene factor de crecimiento epidérmico (egf) para la prevención de la amputación del pie diabético |
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EP (1) | EP1466617B1 (zh) |
JP (1) | JP4808378B2 (zh) |
KR (1) | KR100795654B1 (zh) |
CN (1) | CN1306954C (zh) |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103933552A (zh) * | 2006-01-31 | 2014-07-23 | 遗传工程与生物技术中心 | 用于预防糖尿病足截除的微球体药物组合物 |
CN101573130B (zh) * | 2006-10-03 | 2012-10-31 | 遗传工程与生物技术中心 | 表皮生长因子用于在糖尿病性神经病中外周神经的形态功能恢复的用途 |
CN104173366A (zh) * | 2014-09-14 | 2014-12-03 | 陈钏黄 | 一种三磷酸腺苷二钠在制备治疗糖尿病足药物中的应用 |
CN113727727A (zh) * | 2019-03-18 | 2021-11-30 | 遗传工程与生物技术中心 | 表皮生长因子在治疗糖尿病性足溃疡中的用途 |
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MXPA04005831A (es) | 2004-09-13 |
ES2322568T3 (es) | 2009-06-23 |
KR100795654B1 (ko) | 2008-01-21 |
AU2002361923B2 (en) | 2006-02-02 |
US20080312139A1 (en) | 2008-12-18 |
CA2470971C (en) | 2011-02-01 |
EP1466617B1 (en) | 2009-02-18 |
MY139214A (en) | 2009-08-28 |
PT1466617E (pt) | 2009-05-20 |
KR20040094669A (ko) | 2004-11-10 |
US7465704B2 (en) | 2008-12-16 |
BRPI0215214B1 (pt) | 2017-05-30 |
JP2005516024A (ja) | 2005-06-02 |
DE60231248D1 (de) | 2009-04-02 |
BR0215214A (pt) | 2004-12-07 |
US20050107294A1 (en) | 2005-05-19 |
US7799760B2 (en) | 2010-09-21 |
JP4808378B2 (ja) | 2011-11-02 |
CA2470971A1 (en) | 2003-07-03 |
WO2003053458A1 (es) | 2003-07-03 |
CU23043A1 (es) | 2005-05-20 |
ATE422897T1 (de) | 2009-03-15 |
AU2002361923A1 (en) | 2003-07-09 |
UA80813C2 (en) | 2007-11-12 |
RU2289424C2 (ru) | 2006-12-20 |
BRPI0215214B8 (pt) | 2021-05-25 |
DK1466617T3 (da) | 2009-06-15 |
HK1077740A1 (en) | 2006-02-24 |
SI1466617T1 (sl) | 2009-08-31 |
EP1466617A1 (en) | 2004-10-13 |
AR037824A1 (es) | 2004-12-09 |
CN1306954C (zh) | 2007-03-28 |
RU2004122091A (ru) | 2005-04-10 |
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