CN1972604B - Hiv患者中屏障完整性的提高 - Google Patents
Hiv患者中屏障完整性的提高 Download PDFInfo
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- CN1972604B CN1972604B CN2005800208954A CN200580020895A CN1972604B CN 1972604 B CN1972604 B CN 1972604B CN 2005800208954 A CN2005800208954 A CN 2005800208954A CN 200580020895 A CN200580020895 A CN 200580020895A CN 1972604 B CN1972604 B CN 1972604B
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Abstract
本发明涉及一种刺激感染HIV的患者中肠内屏障性的方法,该方法通过向所述患者包括(EPA)、(DHA)和(ARA)以及至少两种明显不同的低聚糖。
Description
技术领域
本申请涉及一种提高HIV患者中肠内屏障完整性的方法和适合应用于该方法的组合物。
背景技术
肠胃上皮细胞功能通常起到选择性屏障的作用,允许养分、电解液和水的吸收并且阻止包括食品过敏源在内的膳食和微生物抗原的暴露。肠胃上皮细胞限定了通往体循环的抗原通道,其可能引起炎症反应,例如,过敏反应。由于过敏特别是食品过敏发病率的增加,许多研究小组寻找这些疾病的(预防)治疗方法。
EP1272058公开了一种含有不消化的低聚糖的组合物,其中低聚糖用于提高紧密连接以降低肠内渗透性并减少过敏反应。该组合物可以包括LC-PUFA`s(长链多不饱和脂肪酸)。
EP745001公开了一种用于治疗溃疡性结肠炎的不消化低聚糖n-3和n-6脂肪酸的组合物。
Usami et al(临床营养学2001,20(4):351-359)公开了二十碳五烯酸(EPA)对肠内单层细胞中紧密连接渗透性的影响。其中发现EPA提高了渗透性,这表明EPA不适于提高肠内的屏障完整性。
现有技术没有理想的适于提高屏障完整性的配方。
发明内容
本发明提供了一种特选长链不饱和脂肪酸(LC-PUFA`s)和特选低聚糖的并用药物(combination)。LC-PUFA`s和低聚糖的这种并用药物通过协同地提高肠内渗透性、粘液生成、并减少可能损害肠内屏障完整性的发炎介质的粘膜生成来有效地提高屏障完整性。营养或药物配方中的这些化合物的组合特别适合于提高HIV和AIDS患者的肠内完整性。
令人惊奇的是,特选LC-PUFA`s有效地减少了上皮细胞侧(paracellular)的渗透性。与Usami et al(临床营养学2001,20(4):351-359)中报道的形成对比的是,发明人发现C18和C20多不饱和脂肪酸,特别是二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)和花生四烯酸(ARA),能够有效地减少肠内紧密连接的渗透性。
除了LC-PUFA`s之外,本发明组合物包含低聚糖。该特选低聚糖通过刺激粘液的产生来提高屏障完整性,这导致粘液层厚度增加。应当相信,这种影响是由截然不同的低聚糖对短链脂肪酸(SCFA)的产生所造成的影响引起的。因此,当对哺乳动物肠内用药时,LC-PUFA和不消化低聚糖的化合物通过同时降低紧密连接渗透性和刺激粘液生成来协同地提高屏障完整性和/或协同地减少肠内渗透性。
进一步的方面,该组合物提高了肠内粘液层的质量。该粘液层包括粘液素。粘液素是杯状细胞合成和分泌的高分子量糖蛋白。它们在粘膜表面形成一个类凝胶层,以此提高屏障完整性。该粘液层包括不同类型的粘液素,例如,酸性、中性和磺化粘液素。粘液层的增强异质据信以提高屏障功能性。
本组合物优选包括至少两种不同的低聚糖,其直接地或通过改变肠内菌类来影响粘膜构造并有利地影响粘液层中粘膜素异质。每个不同的特选低聚糖据信对粘液数量和质量具有不同影响。此外,两种截然不同的低聚糖还能刺激粘液的质量,其质量由通过低聚糖对SCFA产生的协同刺激的硫化程度来反应。本发明人令人惊奇地发现,根据本发明的两种不同低聚糖的混合物协同地刺激了醋酸酯的产生。本发明人还发现粘液产生以来于醋酸酯产生。
进一步发现ARA的前体,γ-亚麻酸(GLA)可以有利地结合在用于治疗HIV患者的本组合物中。HIV患者经常承受肠内发炎的病痛,这导致不希望的ARA高吸收,因为ARA增加了发炎反应。还发现部分ARA可以由GLA代替,而不对脂肪混合的效果造成负面影响。因此,进一个方面,本发明提供一种包括低聚糖、EPA、DHA、ARA和GLA的组合物,及其在HIV或AIDS的治疗和/或预防上的应用。
本组合物优选通过提供长链和短链的低聚糖而进一步提高。提供不同链长导致在回肠和结肠的不同部分中粘液产生的刺激。短链低聚糖(通常是聚合度(DP)为2、3、4或5)刺激近侧结肠和/或回肠末端中的粘液素产生,而较长链长(优选聚合度(DP)大于5直至60)的低聚糖据信在结肠更末端部分刺激粘液素产生。
通过提供都作为短链和长链低聚糖的至少两种不同的低聚糖,可以获得甚至更进一步的屏障完整性。这些优选的实施例都有助于进一步提高整个回肠和/或结肠中的屏障完整性。
此外,令人惊奇地发现EPA、DHA和ARA能减少白细胞介素4(IL-4)对肠内渗透性的有害影响。IL-4是一种特定患者中由粘膜T-细胞的增加数量所分泌并降低肠内渗透性的细胞因子。因此,本发明还提供一种用来治疗和/或预防肠内IL-4浓度增加的疾病的方法,如过敏,特别是遗传性过敏性皮炎。
具体实施方式
本发明涉及一种营养组合物,包括:
a)EPA、DHA和ARA,其中20和22个碳原子的长链多不饱和脂肪酸的含量不超过总脂肪含量的85wt.%;和
b)至少两种截然不同的低聚糖,其中该两种截然不同的低聚糖具有单糖元中低于90wt.%的同源性。
这种组合物可以有利地用于刺激肠内屏障完整性的方法中,所述方法包括将所述组合物用药于哺乳动物。
本发明进一方面提供了多不饱和脂肪酸的用途,该多不饱和脂肪酸用于制造在治疗感染有人类免疫缺陷病毒(HIV)的患者的方法中所采用的组合物,所述方法包括对所述感染人类免疫缺陷病毒(HIV)的患者给予一种组合物,包括:
a).二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)和花生四烯酸(ARA),其中20和22个碳原子的长链多不饱和脂肪酸含量不超过脂肪总含量的85wt.%;和
b).至少两种截然不同的低聚糖(OL1和OL2),其中这两种截然不同的低聚糖具有单体中低于90wt.%的同源性。
治疗感染HIV的患者的特别实施例是营养治疗。本发明的其他实施例是向感染HIV的患者提供营养的方法中上述所限定组合物的使用,所述方法包括给予所述HIV感染患者所述组合物和上述用于刺激HIV感染患者肠内屏障完整性的方法中所限定组合物的使用,所述方法包括给予所述HIV感染患者所述组合物。
多不饱和脂肪酸
本发明人惊奇地发现二十碳五烯酸(EPA,n-3)、二十二碳六烯酸(DHA,n-3)和花生四烯酸(ARA,n-6)有效地降低肠内紧密连接渗透性。GLA(n-6)也有效地减少屏障渗透性。因此,特别适合提高肠内屏障完整性的本组合物包括EPA、DHA和ARA,任选地组合有GLA。
本发明人发现,特选LC-PUFA`s有效地减少紧密连接渗透性(见对比Usami et al的实施例)。本发明组合物中20和22个碳原子的LC-PUFA的含量优选不超过总脂肪含量的85wt.%,优选不超过总脂肪含量的35wt.%,更优选不超过总脂肪含量的15wt.%。本发明组合物优选包括总脂肪含量的至少0.1wt.%的20和22个碳原子LC-PUFA,优选至少0.25wt.%,更优选至少0.5wt.%,更优选至少0.75wt.%,更进一步优选至少5wt.%,更进一步优选至少15wt.%和最优选至少25wt.%。因为相同的原因,EPA含量优选不超过总脂肪含量的55wt.%,优选不超过总脂肪含量的35wt.%,更优选不超过总脂肪含量的25wt.%,但优选占总脂肪含量的至少0.05wt.%,更优选至少0.1wt.%,最优选至少1%。DHA含量优选不超过总脂肪含量的15wt.%,更优选不超过总脂肪含量的10wt.%,但占总脂肪含量的至少0.1wt.%。由于发现ARA对降低紧密连接渗透性特别有效,本组合物包含相对高的数量,优选占总脂肪的至少0.1wt.%,甚至更优选至少0.25wt.%,最优选至少0.5wt.%。ARA含量优选不超过总脂肪的15wt.%,优选不超过5wt.%,更优选不超过1wt.%。本发明中,有利地添加包含肠内组合物EPA和DHA的ARA以平衡ARA的作用,如减少ARA代谢物的潜在促炎性作用。来自ARA的过量新陈代谢可能引起发炎。本发明营养组合物优选还包含γ-亚麻酸(GLA,C18)。GLA作为ARA的前体至少部分代替组合物中ARA含量,以进一步降低ARA的促炎性作用。
因此,本发明组合物优选包括ARA、GLA、EPA和DHA,其中(ARA+GLA)/DHA重量比优选高于0.10,优选高于0.25,更优选高于0.5。该比值优选低于25,最优选低于3。
本发明组合物优选包括基于脂肪总量5至75wt.%的多不饱和脂肪酸,优选10至50wt.%。
可以提供20和22个碳原子的LC-PUFA作为游离脂肪酸,以甘油三酸酯的形式、以磷脂的形式,或上述一种以上的混合物。本组合物优选包括磷脂形式的ARA和DHA的至少一种。
本发明营养组合物优选还具有Ω-9(n-9)脂肪酸(优选为油酸,18∶1),以提供足够的营养。本发明组合物优选提供基于总脂肪重量至少1wt.%的n-9脂肪酸,更优选至少5wt.%。n-9脂肪酸的含量优选低于80wt.%。
合适的每日量可以是至少0.1克EPA和0.05克ARA或ARA+GLA,或0.1至5克EPA和0.05至2.5克ARA或ARA+GLA,或0.5至2.5克EPA和0.25至1.25克ARA或ARA+GLA,或0.75至1.5克EPA和0.37至0.75克ARA或ARA+GLA。DHA合适的每日量根据以上给出的比值(ARA+GLA)/DHA得出。
低聚糖
根据本发明合适的低聚糖是具有至少2个单糖元聚合度(DP)的糖类,其在肠内未消化或通过人体上消化道(小肠和胃)中存在的酸或消化酶作用仅部分地消化,但是可以通过人体肠内菌类发酵。术语单糖元指的是具有闭环状结构的单元,优选为己糖,如吡喃糖或呋喃糖形式。该低聚糖的聚合度通常低于60单糖元,优选低于40,更优选低于20。
本发明组合物包括至少两种不同的低聚糖,其中,低聚糖具有单糖元中低于大约90%的同源性,优选低于50%,更优选低于25%,甚至更优选低于5%。本发明中使用的术语“同源性”是不同低聚糖中相同单糖元百分数的累积。例如,低聚糖1(OL1)具有fruc-fruct-glu-gal的结构,由此包括50%的fruc,25%的gal和25%的glu。低聚糖2(OL2)具有fruc-fruc-glu的结构,由此包括66%的fruc,33%的glu。因此不同的低聚糖具有75%(50%fruc+25%glu)的同源性。
在优选实施例中,本发明组合物包括半乳糖低聚糖和选自由果糖低聚糖和菊粉组成的组中的至少一种。
每个本发明低聚糖优选包括至少66%、更优选至少90%的单糖元,该单糖元选自由甘露糖、树胶醛糖、果糖、海藻糖、鼠李糖、半乳糖、β-D-吡喃型半乳糖、核糖、葡萄糖、木糖、糖醛酸及其衍生物组成的组中,以包含其中的单糖元总数来计算。
根据本发明另一个实施例,本组合物低聚糖中至少一个选自由果聚糖、果糖寡聚体、不消化的糊精半乳糖低聚糖(包括反式半乳糖低聚糖)、木低聚糖、***低聚糖、葡萄糖低聚糖、甘露糖低聚糖、海藻糖低聚糖、酸性低聚糖(见下,如糖醛酸低聚糖,如果胶水解产物)及其混合物组成的组中。本组合物优选包括选自由果糖低聚糖(fructooligosaccharides)或菊粉、半乳糖低聚糖和果胶水解产物组成的组中的至少一种、优选至少两种低聚糖。
为了好的粘液数量和质量,本组合物优选包括至少一种低聚糖,其包括至少66%的半乳糖或果糖作为单糖元。在优选实施例中,组合物包括至少一种低聚糖,其包括至少66%的半乳糖作为单糖元和包括至少66%的果糖作为单糖元的至少一种低聚糖。在特别优选的实施例中,本组合物包括半乳糖低聚糖和一种选自果糖低聚糖和菊粉中的低聚糖。果糖低聚糖刺激人体菌类联合鼠(flora-associated rats)结肠末端中硫粘蛋白的产生(Kleessen et al,(2003)Brit J Nutr 89:597-606),半乳糖低聚糖刺激酸性粘液素的产生(Meslin et al.Brit.J.Nutr(1993),69:903-912)。
为了进一步提高整个结肠区域中粘液层的厚度,本发明组合物中至少10wt.%的低聚糖具有2至5(即,2、3、4和/或5)的DP值,至少5wt.%具有10至60的DP值。优选至少50wt.%,更优选至少75wt.%的低聚糖具有2至9(即,2、3、4、5、6、7、8和/或9)的DP值,因为据信其在整个回肠和结肠的近端及中间部份起作用,并因为需要合并到组合物中以获得理想效果的低聚糖重量百分比得到降低。
优选重量比:
a.(DP值为2至5的低聚糖):(DP值为6、7、8和/或9的低聚糖)>1;且
b.(DP值为10到60的低聚糖):(DP值为6、7、8和/或9的低聚糖)>1,a和b两者都大于1。
优选两个重量比都大于2,更优选大于5。
为了进一步提高整个结肠区域内的粘液层厚度和质量,优选至少两种不同低聚糖的每个具有不同的链长,优选基于各自低聚糖总重量的每个低聚糖的至少10wt.%具有2到5(即,2、3、4和/或5)的DP值和至少5wt.%具有10到60的DP值。优选基于该低聚糖总重量的至少50wt.%,更优选至少75wt.%的低聚糖具有2到10的DP值,因为据信其在回肠内和结肠的近体部分及中间部份始终起作用。
酸性低聚糖
为了进一步提高屏障完整性,本组合物优选包括DP值为2到60的酸性低聚糖。术语酸性低聚糖表示包括至少一个酸性基团的低聚糖,该酸性基团选自由n-乙酰神经氨(糖)酸,、N-glyoloylneuraminic acid、游离或酯化羧酸、硫磺酸基团和磷酸基团组成的组。酸性低聚糖优选包括糖醛酸单元(即,糖醛酸聚合物),更优选半乳糖醛酸单元。酸性低聚糖可以是同质(homogeneous)或异质(heterogeneous)的糖类。合适的实施例是果胶和/或藻酸盐的水解产物。在肠道中,糖醛酸聚合物水解成糖醛酸单体,其刺激肠内醋酸盐的产生,该醋酸盐依次刺激肠内粘液分泌物(Barcelo et al.Gut 2000;46:218-224)。
优选地,酸性低聚糖具有以下结构I,其中,末位己糖(左)优选包括一个双键。除末位己糖单元之外的其它己糖单元优选为糖醛酸单元,甚至更优选为半乳糖醛酸单元。基于这些单元的羧酸基团可以是游离的或(部分)酯化的,优选至少10wt%是甲基化的(见下)。
结构I:聚合酸性低聚糖
其中:
R优选选自氢、羟基或酸基,优选为羟基;
R2、R3、R4和R5中的至少一个代表N-乙酰神经氨(糖)酸、N-glyoloylneuraminic acid、游离或酯化羧酸、硫磺酸基团和磷酸基团,其余代表氢和/或羟基。优选R2、R3、R4和R5中的一个代表N-乙酰神经氨(糖)酸、N-glyoloylneuraminic acid、游离或酯化羧酸、硫磺酸基团和磷酸基团,R2、R3、R4和R5中的其余代表氢和/或羟基。更优选R2、R3、R4和R5中的一个代表游离或酯化羧酸,且其余代表氢和/或羟基。
n为整数,表示己糖单元的数目(也参见下面的聚合度),该己糖可以是任何己糖单元。适合地,n为1~5000的整数。优选己糖单元(多个)为糖醛酸单元。最优选地,R1、R2和R3代表羟基,R4代表氢,R5代表羧酸,n为1~250优选1~10间的任何数字,且己糖单元为半乳糖醛酸。
用于本发明方法中的优选酸性低聚糖的检测、测量和分析已经在与酸性低聚糖相关的较早专利申请即WO0/160378中给出。
为了在整个结肠区域中刺激性提高粘膜层厚度,本组合物优选包括至少10wt%的DP值为2到5(即2、3、4和/或5)的酸性低聚糖和至少5wt%的DP值为10到60的酸性低聚糖,所述wt%是基于低聚糖的总重量。
用于本发明中的酸性低聚糖优选由胶质、果胶酸盐(pectate)、藻酸盐、chondroitine、透明质酸、肝素、肝磷脂(heparane)、细菌性碳水化合物(bacterial carbohydrate)、sialoglycan、岩藻依聚糖(fucoidan)、海藻糖低聚糖(fucooligosaccharides)或角叉菜聚糖制备,更优选由果胶和/或藻酸盐制备。
低聚糖含量
当为可以喂给的流体形态时,本发明组合物优选包括0.1~100克每升的不消化低聚糖,更优选为0.5~50克每升,更优选1~25克每升。低聚糖的过高含量可能由于过度发酵而引起不舒服,而过低含量也可能导致不足的粘膜层。
至少两种不同低聚糖的重量比优选为1~10,更优选为1~5。最优地,这些重量比刺激肠内不同位置处不同类型的粘膜产生。
包括在根据本发明的组合物中的低聚糖的数量超过基于组合物总干重的0.1wt%,优选超过0.2wt%,更优选超过0.5wt%,甚至更优选超过1wt%。本发明组合物优选具有低于20-wt%的低聚糖含量,更优选低于10-wt%,甚至更优选低于5-wt%。
向本组合物中加入核苷酸和/或核苷进一步提高肠粘膜的屏障作用,特别是由于其抑制和/或降低了细菌移动的发生并减少肠内损伤。因此,本组合物还优选包括1~500mg核苷酸和/或核苷/100g干配方,甚至更优选5~100mg。
应用
本组合物可以有利地用于提高哺乳动物尤其是人类的屏障完整性的方法中。本组合物还可以有利地用于与屏障完整性降低有关的疾病治疗或预防的方法中,所述方法包括将本组合物用药于哺乳动物。本组合物优选口服。
对于病人和婴儿来说,本组合物优选配伍完全的营养素,包括蛋白质、碳水化合物和脂肪。本组合物有利地对0~2岁的婴幼儿用药。该组合物可以对屏障完整性削弱的患者和无症状患者用药。本组合物有利地用于对早产儿(在妊娠37周前出生的婴儿)提供必需营养的方法中。
通过在可能导致肠内损伤的医疗之前或之后将本组合物用药于患者,本组合物还可以有利地用于肠内损伤的治疗和/或预防方法中。这种医疗可以是如外科手术或肠内药物治疗(enteral medicine treatment)(如抗生素、止痛剂、NSAID、化疗剂等)。
本组合物还可以有利地用来治疗或预防疾病,其中肠内屏障的瓦解为病程发展的基础,如在治疗或预防慢性炎症的方法中,尤其是肠炎(IBD)、过敏性肠综合征(IBS)、脂泻病、胰腺炎、肝炎、关节炎或糖尿病。此外,本发明还可用于对已经经受或正在经受腹部外科手术的患者和术后内脏功能紊乱的患者和/或营养不良的患者提供营养的方法中。
在本发明的进一步实施例中,本组合物有利地对遭受获得性免疫缺损综合症(AIDS)的患者和/或感染有人体免疫缺损病毒(HIV)的患者用药,如在治疗AIDS和/或HIV感染的方法中。所述方法包括口服本组合物,优选配伍选自碳水化合物、蛋白质或脂肪中的营养素。根据本发明的组合物对低于约700细胞/μl血液的临界水平的CD4+T细胞计数患者特别有用,此时通常高度活性抗逆转录病毒治疗(HAART)尚不需要,但患者确实已经经受病情发展或甚至经历着与肠内屏障完整性有关的一个或多个问题,特别是肠内屏障完整性的功能紊乱。因此,本发明进一方面提供了一种停止或减缓CD4+T细胞计数降低或提高HIV和/或AIDS患者体内CD4+T细胞计数的方法,所述方法包括对患者给药。在一个实施例中,该方法包括对患者给药,所述患者为CD4+T-淋巴细胞细胞计数在200~700细胞/μl血液之间。在另一个实施例中,该方法包括将本组合物用药于患者,所述患者没有接受高度活性抗逆转录病毒治疗(HAART)。在一个特殊实施例中,患者具有200~700细胞/μl血液之间的CD4+T-淋巴细胞细胞计数且未接受高度活性抗逆转录病毒治疗(HAART)。
此外,本发明还可以用来治疗或预防由屏障完整性降低引起的并发症,特别是治疗和/或预防痢疾的方法中,特别是婴儿痢疾。由于婴儿痢疾的发病减少,本组合物还可以有利地用来减少尿疹。
本组合物的给药减少了饮食和微生物抗原特别是食物过敏原从肠道内腔进入粘膜或体循环的途径,因此可以有利地用于治疗或预防过敏和/或过敏反应的方法中,特别用于治疗或预防食物过敏的方法中,如由食物吸收引起的过敏反应。
本发明人还发现,EPA、DHA和/或ARA能够减小IL-4对肠内渗透性的影响。因此,本发明一方面提供用于治疗和/或预防疾病的方法,所述疾病中的肠内IL-4浓度被提高(如过敏性疾病),所述方法包括LC-PUFA的给药,LC-PUFA优选选自EPA、DHA或ARA,优选配伍本发明特选低聚糖。因此,本组合物还可以有利地用于治疗特异性皮炎的方法中。
本组合物优选用包装的粉末或包装的可喂给形态来提供。为了防止成品损坏,可喂给形态的包装尺寸优选不超过一份剂量,如优选不超过500ml;粉末状形式的本组合物包装尺寸优选不超过250份剂量。粉末的合适包装尺寸为2000g或更少,优选每(per)1000g或更少。
该具有标签的包装产品由本发明完成,其标签向消费者明确或隐含指出根据一个或多个上述或下述目的所述产品的使用。这种标签可以是如表示本方法中用来预防对食物过敏原的过敏反应时用包括如“降低食物敏感性”、“提高肠内耐受力”、“提高食品耐受性”或类似文字来表示。类似地,表示本方法用于治疗和/或预防过敏时可以通过合并与“提高抵抗力”或“降低敏感性”等同的术语来表示。
配方
已经发现,本组合物可以有利地用于食品如幼(婴)儿食品和临床产品。这种食品优选包括脂类、蛋白质和碳水化合物,并优选以液体形式用药。本发明使用的术语“液体食品”包括干食(如粉末的),其带有说明书以便指导适量液体(如水)混合所述干食。
因此,本发明还涉及一种营养组合物,其优选包括5~50en%的脂类、5~50en%的蛋白质、15~90en%的碳水化合物和低聚糖和LC-PUFA’s的本组合物。优选地,本营养组合物优选包括10~30en%的脂类、7.5~40en%的蛋白质和25~75en%的碳水化合物(en%是能量百分比的缩写,表示构成制剂的总卡值中各组分的相对数量)。
优选地,使用植物脂类和选自鱼油和Ω-3植物、藻类或细菌性油中至少一种油的组合物。
用于营业性制剂的蛋白质优选选自非人类的动物性蛋白质(如牛乳蛋白质、肉蛋白质和蛋类蛋白质)、植物蛋白质(如大豆蛋白质、小麦蛋白质、大米蛋白质和花生蛋白质)、游离氨基酸及其混合物。牛乳是氮源,特别是牛乳蛋白质如干酪素和乳清蛋白质为特别优选。
排便不规律(如大便秘结、大便不足、腹泻)是许多婴儿和接受流体食物病人的主要问题。已经发现,大便问题可以通过在流体食物中加入本发明低聚糖来减少,其中重量克分子渗透压浓度为50~500mOsm/kg,更优选为100~400mOsm/kg。
鉴于上述内容,还有一个重要的是,液体食物不具有过量卡值密度,然而仍能向喂给对象提供充足的热量。因此,液体食物优选具有0.1~2.5kcal/ml的热量密度,更优选具有0.5~1.5kcal/ml的热量密度,最优选为0.6~0.8kcal/ml。
具体实施方式
实施例1:LC-PUFA对屏障完整性的影响
在transwell过滤器(Corning,Costar BV,荷兰)中培养肠内上皮细胞系T84(美国典型培养物(ATTC),Manassas,USA)的单细胞层(MC),供给粘膜和浆膜两种样品,并刺激人类肠内上皮细胞。两周后融合(confluency),单细胞层潜伏在具有多不饱和脂肪酸ARA(花生四烯酸;5,8,11,14-二十碳四烯酸)、DHA(顺式-4,7,10,13,16,19二十二碳六烯酸)、EPA(二十碳四烯酸)或对照棕榈(C 16:0)酸(Palm)(Sigma,St.Louis,USA)的腔室。选择后一个过程来模仿活体内食物化合物的给药路径。细胞与不同浓度的(10μM和100μM)ARA、DHA、EPA、GLA或棕榈酸孵育0、24、48和72小时。实施实验来评估基础的屏障完整性。通过测量透过上皮的抵抗力(TER,Ω.cm2)、对4kD FITC右旋糖酐(旁细胞渗透性标记(paracellular permeabilitymarker),Sigma,USA)的渗透性、抵抗力来确定上皮屏障功能,该透过上皮的抵抗力是由上皮电压-电阻表(EVOM;World PrecisionInstruments,德国)来测定。对4kDa FITC-右旋糖酐的上皮渗透性按如下确定。在右旋糖酐加入培养基之前,该培养基采用不含酚红的培养基更新一小时,然后向内腔代谢区添加5μl(原料100mg/ml)4kDaFITC-右旋糖酐。30分钟孵育之后,100μl样品从浆膜区收集起来,并在485nm激发波长和520nm发射波长(FLUOstarBMGLabtechnologies,USA)下测量荧光信号。FITC-右旋糖酐的流量(fluxes)以每mol的FITC-右旋糖酐/cm2/h来计算。使用ANOVA(10版本的SPSS)来进行统计学分析。
表1中给出了孵育72小时后脂肪酸(100μM)的对天然屏障完整性的影响结果。表1示出LC-PUFA’sARA、EPA、GLA和DHA减少了分子流量,提高了上皮抵抗力。相反对照实验表明棕榈酸具有相反作用,即损害屏障完整性。这些结果对于有利地使用根据本发明的组合物中的EPA、DHA、GLA和ARA、特别是ARA和根据本发明的方法如提高屏障完整性方法的使用给出了指示。这些结果进一步支持了脂肪酸和不消化低聚糖的本发明组合物的增强效应。
图1示出了根据各种脂肪酸(棕榈酸、DHA、GLA和AA)对基本屏障完整性(TER)影响的时间和剂量(10μM和100μM)。图1示出LC-PUFA’sAA、DHA和GLA提高了上皮屏障完整性,由提高的抵抗力(TER)反应。这些结果表明,EPA、DHA、GLA和ARA、特别是ARA有利地用于根据本发明的组合物中,并指示了用于根据本发明的方法即提高屏障完整性的方法中。这些结果进一步支持了脂肪酸和不消化低聚糖的本发明组合物的增强效应。
表1
成分(LC-PUFA) | 流量 | 抵抗力(TER) |
对照 | 79 | 1090 |
棕榈酸 | 161 | 831 |
DHA | 72 | 1574 |
ARA | 28 | 1816 |
EPA | 65 | 1493 |
实施例2:LC-PUFA对IL-4介导(mediated)屏障完整性的影响
在transwell过滤器(Corning,Costar BV,荷兰)中培养肠内上皮细胞系T84(ATTC,USA)的单细胞层(MC),补充粘膜和浆膜两种样品,并刺激人类肠内上皮细胞。两周后融合(confluency),单细胞层孵育在IL-4(2ng/ml,浆膜区,Sigma,USA)中,具有或不具有多不饱和脂肪酸ARA、DHA、GLA、EPA或对照棕榈酸(10μM或100μM,粘膜区,Sigma,St.Louis USA)。在IL-4孵育之前,细胞与GLA、ARA、DHA、EPA或棕榈酸预孵育48小时。PUFA’s和具有IL-4的棕榈酸的共同孵育再继续48小时;同时,培养基和添加物每24小时更换一次。上皮屏障功能通过测量如实施例1所述的透过上皮的抵抗力(TER)和渗透性来确定。按实施例1所述来进行统计学评价。
表2中给出了GLA、ARA、DHA、EPA和棕榈酸(100μM)对IL-4介导屏障破坏的影响的结果。表2示出,LC-PUFA’sGLA、ARA、DHA和EPA抑制了由IL-4引起的流量增加。相反,棕榈酸具有不利的影响,与对照相比,降低了屏障破坏性。这些结果指示了,GLA、ARA、DHA和EPA在临床和婴幼儿营养配方以防止或减少IL-4介导屏障破坏上有利的使用,如在食物或牛奶中发生过敏。这些结果进一步支持了脂肪酸和不消化低聚糖的本发明组合物的增强效应。
图2示出了根据各种FA’s(棕榈酸、DHA、GLA和ARA)对IL-4介导屏障破坏性(流量)影响的时间和剂量(10μM和100μM)。图2示出ARA、DHA和GLA保护不受IL-4介导屏障破坏,由降低的4kD右旋糖苷反应。这些结果表明,GLA、ARA、DHA和EPA在临床和婴幼儿营养配方以防止或减少IL-4介导屏障破坏上有利的使用,如在食物或牛奶中发生过敏。这些结果进一步支持了脂肪酸和不消化低聚糖的本发明组合物的增强效应。
表2
成分(PUFA) | 渗透性(IL-4流量) | 抵抗力(IL-4TER) |
对照 | 573 | 281 |
GLA | 360↓ | 331↑ |
成分(PUFA) | 渗透性(IL-4流量) | 抵抗力(IL-4TER) |
ARA | 273↓ | 337↑ |
EPA | 236↓ | 375↑ |
DHA | 304↓ | 328↑ |
↓=由PUFA降低的渗透性;↑=由PUFA提高的抵抗力。
实施例3:低聚糖对醋酸盐产物的影响
从奶瓶喂养的婴儿的新鲜粪便中获取微生物。1~4个月大婴儿的新鲜排屑物收集并放入防腐介质中2小时。由于培养基或者是益生元(prebiotics)(TOS;TOS/菊粉(HP)混合物为9/1(w/w)比值、菊粉;低聚糖(OS)/菊粉混合物为1/1(w/w)比值,或者一个(空)也不使用。转乳低聚糖(transgalactooligosaccharides)(TOS)从VivinalGOS,Borculo Domo Ingredients,Zwolle,荷兰中获得,并包括不消化低聚糖:33wt%二糖、39wt%三糖、18wt%四糖、7wt%五糖、3wt%六糖、七糖和八糖(en octasaccharides)。菊粉(HP)Orafti活性食品成分、Tienen、Belgium即Raftiline平均DP为23;培养基:McBain&MacFarlane培养基:含有缓冲剂的蛋白胨水为3.0g/l,酵母抽提物为2.5g/l,粘液素(细胞刷状缘)为0.8g/l,胰蛋白胨为3.0g/l,L-半胱氨酸-HCL为0.4g/l,胆汁盐为0.05g/l,K2HPO4·3H2O为2.6g/l,NaHCO3为0.2g/l,NaCl为4.5g/l,MgSO4·7H2O为0.5g/l,CaCl2为0.228g/l,FeSO4·7H2O为0.005g/l。用培养基填充500ml斯科特瓶并在121℃下杀菌15分钟。含有缓冲剂的培养基:K2HPO4·3H2O为2.6g/l,NaHCO3为0.2g/l,NaCl为4.5g/l,MgSO4·7H2O为0.5g/l,CaCl2为0.228g/l,FeSO4·7H2O为0.005g/l。用K2HPO4或NaHCO3调节pH值为6.3±0.1。用培养基填充500ml斯科特瓶并在121℃下杀菌15分钟。防腐培养基:含有缓冲剂蛋白胨为20.0g/l,L-半胱氨酸-HCL为0.5g/l,巯基乙酸钠为0.5g/l,每升刃天青(resazurine)药片1个,用1M的NaOH或HCl调节pH值为6.7±0.1。在微波炉中沸腾。血清瓶用25ml培养基填充,并在121℃下杀菌15分钟。
新鲜的粪便样品与防腐培养基混合,在4℃下保存几个小时。粪便的保存溶液以13000rpm离心处理15分钟,去除上清液,粪便以1∶5的重量比与McBain&Mac Farlane培养基混合。3ml粪便悬浮液与85mg葡萄糖或益生元或无添加剂(空)的结合放入瓶子,充分混合。t=0的样品被收回(0.5ml),得到悬浮液的2.5ml被引入在填充有60ml含缓冲剂培养基的60ml瓶中的渗析管中。该瓶密封好,并在37℃下培养。3、24和48小时后,样品用皮下注射器从渗析管(0.2ml)或透析缓冲液(1.0ml)取出,并立即放入冰中以停止发酵。该实验使用如下样品来实施:
1)85mgTOS
2)85mg菊粉
3)85mg比值为9/1(w/w)的TOS/菊粉
4)85mg比值为1/1(w/w)的OS/菊粉
使用装配有火焰电离探测器的Varian 3800气相色谱仪(GC)(Varian Inc.,Walnut Creek,USA)测定SCFA(醋酸盐、丙酸盐、丁酸盐)的数量。0.5μl的样品使用氦作为载气(3.0psi)在80℃注射到柱中(Stabilwax,15×0.53mm,薄膜厚度1.00μm,Restek,Co.,USA)中。注射样品之后,以16℃/min的速度将烤箱加热至160℃,随后以20℃/min的速度加热至220℃,最后在220℃下保温1.5分钟。注射器和探测器的温度为200℃。2-ethylbytyric酸作为内标物。
图3示出了不同低聚糖发酵引起的的绝对(图3A)和相对SCFA剖面(profile)(图3B)。图3A示出了两种不同低聚糖的混合物(TOS/菊粉),其中这两种截然不同的低聚糖具有低于90的单糖单元同源性,不同链长导致每克纤维比单一成分更显著且增强数量的SCFA(特别是醋酸盐)。图3B示出了TOS/菊粉组合物的添加有利于有益醋酸盐(B)的更高比例。体内的醋酸盐产生通过杯形细胞和用于肠内粘液层厚度的测量转换成提高的粘液产生(参见实施例4)。这些结果表明本发明组合物有利的使用。
实施例4:SCFA对粘液产生的影响
在24或96孔(well)组织培养皿(Corning B.V.)中培养肠内上皮细胞T84细胞(ATCC,USA)的单细胞层。T84用短链脂肪酸醋酸盐、丙酸盐和丁酸盐(SFCA,Merck,USA)在0.025~4.0mM浓度下培养24小时。收集上清液和/或细胞,确定MUC-2(粘液素)的表达。点印迹技术被用来确定细胞培养中的MUC-2表达,因为粘液素是非常大的糖蛋白质(超过500kDa),这使得它们难以在western印迹技术中进行处理。该方法使用预先免疫的血清(T84污损的负性)、CCD-18Co(ATCC,USA)负性对照细胞和牛血清白蛋白(BSA)来实现。细胞样品收集在Laemmli(蛋白质分离缓冲剂)中,使用根据制造方法的微生物蛋白化验(Biorad,USA)实施蛋白质的确定。样品(0.3-0.7-1.0μg/2μl)点迹在硝酸纤维膜(Schleicher&Schuell,德国)上。薄膜在TBST/5%Protivar(Nutricia,荷兰)中封闭,随后用抗-MUC-2抗体(由荷兰Rotterdam的Erasmus大学Einerhand博士友善捐赠)培养1小时。洗涤之后,印迹用山羊的抗-兔-HRP(SantacruzBiotechnology,USA)培养,为了探测底物,使用ECL(RocheDiagnostics,荷兰)。使用Lumi-Imager(Boehringer Mannheim B.V.,荷兰)来实施密度计量学,用光单元(BLU)来表达信号。BLU’s还相对于对照培养(%BLU)来表达。为了比较SCFA对MUC-2表达的刺激效果,减去了基本的MUC-2表达水平。
图4显示了SCFA(醋酸盐、丙酸盐和丁酸盐)对肠内上皮细胞(MC T84)和上皮间充质细胞联合培养(CC T84)中MUC-2表达的不同影响。图4还示出,醋酸盐与丙酸盐和丁酸盐在刺激MUC-2表达(粘液的产生)上更有效。因此,本发明低聚糖的组合(其显示出提高醋酸盐的产生(参见实施例3))对于刺激粘液的产生特别有效,并可以有利地应用于刺激屏障完整性的方法中。
实施例5:婴幼儿牛乳配方I
成分(每升),能量672千卡;蛋白质15g;乳清:干酪素的比值为60∶40;脂肪36g;碳水化合物72g;维生素A 750RE;混合的天然颈动脉(carotids)400IU;维生素D 10.6mcg,维生素F 7.4mg;维生素K67.0mcg;维生素B1(硫胺)1000mcg;维生素B2(核黄素)1500mcg;维生素B6(吡哆素)600mvg;维生素B12(cyanacobalmine)2.0mcg;烟酸9.0mcg;叶酸80mcg;泛酸3000mcg;维生素H 90mcg;维生素C(抗坏血酸)90mcg;胆碱100mg;肌醇33mg;钙460Mg;磷333Mg;镁64Mg;铁8.0Mg;锌6.0Mg;锰50mcg;铜560mcg;碘100mcg;钠160mg;钾650mg;氯化物433mg和硒14mcg;其中脂肪含量包括3克鱼油和3克40%的花生四烯酸油(DSM Food Specialties;Delft,荷兰);进一步包括4克转乳低聚糖Elix’orTM(Borculo DomoIngredients,荷兰)和4克Raftiline(Orafti Active Food Ingredients,比利时)。
实施例6:用于改善HIV/AIDS相关症状的营养(bar)的组合物
原材料 g/天 蛋白质 碳水化合物(carbs) 脂肪 g/100
克
牛乳蛋白质 20.00 15.00 2.10 0.80 21.04
蛋类蛋白质 21.09 16.8 70.00 0.00 22.19
玻璃苣油 4.00 0.00 0.00 4.00 4.21
EPA-DHA油 6.00 0.00 0.00 6.00 6.31
半乳糖低聚糖 15.38 0.00 4.78 0.00 16.18
安茴酰牛扁碱 0.79 0.00 0.00 0.00 0.83
果胶玉米糖母液 8.54 0.11 0.09 0.00 8.98
果糖组
(Fructosestroop) 15.40 0.00 11.92 0.00 16.20
甘油 3.85 0.00 3.8 30.00 4.05
总计 95.05 31.98 22.72 10.80 100.00
每天 每100克
千卡 en% 千卡
能量蛋白质 128 40.5 135
能量碳水化合物 91 28.8 96
能量脂肪 97 30.8 102
Claims (12)
1.一种多不饱和脂肪酸的用途,该多不饱和脂肪酸用于制备由感染有人类免疫缺陷病毒(HIV)的患者使用的组合物,所述组合物包括:
a.二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)和花生四烯酸(ARA),其中具有20和22个碳原子的长链多不饱和脂肪酸含量不超过脂肪总含量的85wt.%;和
b.至少两种截然不同的低聚糖,其中截然不同的低聚糖具有同源性低于90%的单糖元。
2.根据权利要求1所述的用途,其中,该组合物进一步包括γ-亚麻酸(GLA)。
3.一种营养组合物,包括:
a.EPA、DHA和ARA,其中具有20和22个碳原子的长链多不饱和脂肪酸的含量不超过总脂肪含量的85wt.%;和
b.至少两种截然不同的低聚糖,其中截然不同的低聚糖具有同源性低于90%的单糖元;
c.一种酸性低聚糖。
4.根据权利要求3的组合物,其中所述酸性低聚糖为DP为2~60的糖醛酸聚合物。
5.根据权利要求3的组合物,其中所述低聚糖包括半乳低聚糖和选自果糖低聚糖、菊粉或其混合物的果聚糖。
6.根据权利要求3或5的组合物,其中低聚糖的至少10wt%具有2~5的聚合度(DP),且至少5wt%具有10~60的DP。
7.根据权利要求3或5的组合物,包括7.5~12.5能量%的蛋白质;40~55能量%的碳水化合物;和35~50能量%的脂肪,其中所述蛋白质包括选自水解的牛乳蛋白质、植物蛋白质和/或氨基酸中的一种。
8.根据权利要求3或5的组合物,所述组合物具有0.6~0.8kcal/ml的含热量;50~500mOsm/kg的重量克分子渗透压浓度;和低于50mPas的粘度。
9.根据权利要求3或5的组合物,其中该组合物进一步包括GLA。
10.根据权利要求3或5的组合物,其用作药物。
11.根据权利要求1的用途,其中患者是遭受CD4+T-淋巴细胞计数在200~700细胞/μl血液的人类,且其中所述患者没有接受高活性抗逆转录病毒治疗。
12.根据权利要求3或5的组合物的用途,该组合物用于制造治疗或预防腹泻的药物,其中所述腹泻由肠内屏障完整性缺陷引起。
Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/NL2004/000444 WO2005122790A1 (en) | 2004-06-22 | 2004-06-22 | Improvement of intestinal barrier integrity |
NLPCT/NL2004/000444 | 2004-06-22 | ||
EP05103260A EP1721611A1 (en) | 2005-04-21 | 2005-04-21 | Nutritional supplement with oligosaccharides for a category of HIV patients |
EP05103257A EP1723951A1 (en) | 2005-04-21 | 2005-04-21 | Nutritional supplement with oligosaccharides for a category of HIV patients |
EP05103257.1 | 2005-04-21 | ||
EP05103260.5 | 2005-04-21 | ||
PCT/NL2005/000451 WO2005122791A2 (en) | 2004-06-22 | 2005-06-22 | Improvement of barrier integrity in hiv patients with fatty acids |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1972604A CN1972604A (zh) | 2007-05-30 |
CN1972604B true CN1972604B (zh) | 2010-06-02 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN2005800208954A Active CN1972604B (zh) | 2004-06-22 | 2005-06-22 | Hiv患者中屏障完整性的提高 |
Country Status (19)
Country | Link |
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US (2) | US20080015166A1 (zh) |
EP (1) | EP1758469B2 (zh) |
JP (1) | JP5301155B2 (zh) |
CN (1) | CN1972604B (zh) |
AT (1) | ATE446686T1 (zh) |
AU (1) | AU2005253898B2 (zh) |
BR (1) | BRPI0512528B8 (zh) |
CA (1) | CA2570208A1 (zh) |
DE (1) | DE602005017389D1 (zh) |
DK (1) | DK1758469T4 (zh) |
ES (1) | ES2336015T5 (zh) |
MX (1) | MXPA06015071A (zh) |
NO (1) | NO332430B1 (zh) |
NZ (1) | NZ552118A (zh) |
PL (1) | PL1758469T5 (zh) |
PT (1) | PT1758469E (zh) |
RU (1) | RU2429718C2 (zh) |
SI (1) | SI1758469T2 (zh) |
WO (1) | WO2005122791A2 (zh) |
Families Citing this family (17)
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DE19836339B4 (de) | 1998-08-11 | 2011-12-22 | N.V. Nutricia | Kohlenhydratmischung |
DK1538924T3 (da) * | 2002-08-30 | 2008-02-04 | Campina Bv | Skummende ingrediens og produkter indeholdende ingrediensen |
EP1597978A1 (en) * | 2004-05-17 | 2005-11-23 | Nutricia N.V. | Synergism of GOS and polyfructose |
US8252769B2 (en) * | 2004-06-22 | 2012-08-28 | N. V. Nutricia | Intestinal barrier integrity |
EP1721611A1 (en) * | 2005-04-21 | 2006-11-15 | N.V. Nutricia | Nutritional supplement with oligosaccharides for a category of HIV patients |
EP1723951A1 (en) * | 2005-04-21 | 2006-11-22 | N.V. Nutricia | Nutritional supplement with oligosaccharides for a category of HIV patients |
CA2605960A1 (en) * | 2005-04-21 | 2006-10-26 | N.V. Nutricia | Nutritional supplement for hiv patients |
AU2007286641B2 (en) * | 2006-08-23 | 2012-12-13 | Kellogg Company | Method for suppression of fishy aromas in food products by proteins |
CA2704371A1 (en) * | 2007-11-01 | 2009-05-07 | Wake Forest University School Of Medicine | Compositions and methods for prevention and treatment of mammalian diseases |
US8343753B2 (en) | 2007-11-01 | 2013-01-01 | Wake Forest University School Of Medicine | Compositions, methods, and kits for polyunsaturated fatty acids from microalgae |
WO2009096772A1 (en) * | 2008-02-01 | 2009-08-06 | N.V. Nutricia | Composition for stimulating natural killer cell activity |
WO2012092156A1 (en) | 2010-12-31 | 2012-07-05 | Abbott Laboratories | Methods for decreasing the incidence of necrotizing enterocolitis in infants, toddlers, or children using human milk oligosaccharides |
CN103379908B (zh) | 2010-12-31 | 2020-02-14 | 雅培制药有限公司 | 使用人乳寡糖、维生素c和抗炎剂减少氧化应激的发病率的方法 |
WO2012177118A1 (en) | 2011-06-22 | 2012-12-27 | N.V. Nutricia | Method for reducing the occurrence of infection in young children |
US11446316B2 (en) | 2011-07-22 | 2022-09-20 | Abbott Laboratories | Galactooligosaccharides for preventing injury and/or promoting healing of the gastrointestinal tract |
CN113662199A (zh) | 2011-08-29 | 2021-11-19 | 雅培制药有限公司 | 用于预防胃肠道损伤和/或促进胃肠道愈合的人乳寡糖 |
BR112019021742A2 (pt) | 2017-04-17 | 2020-05-05 | Univ Chicago | composição, sistema, composição farmacêutica, composição alimentícia ou nutracêutica, método e uso da composição |
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2005
- 2005-06-22 WO PCT/NL2005/000451 patent/WO2005122791A2/en active Application Filing
- 2005-06-22 EP EP05755280.4A patent/EP1758469B2/en active Active
- 2005-06-22 US US11/571,118 patent/US20080015166A1/en not_active Abandoned
- 2005-06-22 DE DE602005017389T patent/DE602005017389D1/de active Active
- 2005-06-22 CN CN2005800208954A patent/CN1972604B/zh active Active
- 2005-06-22 NZ NZ552118A patent/NZ552118A/en not_active IP Right Cessation
- 2005-06-22 PT PT05755280T patent/PT1758469E/pt unknown
- 2005-06-22 JP JP2007517984A patent/JP5301155B2/ja not_active Expired - Fee Related
- 2005-06-22 AU AU2005253898A patent/AU2005253898B2/en active Active
- 2005-06-22 SI SI200530880T patent/SI1758469T2/sl unknown
- 2005-06-22 BR BRPI0512528A patent/BRPI0512528B8/pt active IP Right Grant
- 2005-06-22 CA CA002570208A patent/CA2570208A1/en not_active Abandoned
- 2005-06-22 PL PL05755280T patent/PL1758469T5/pl unknown
- 2005-06-22 RU RU2007102053/10A patent/RU2429718C2/ru not_active IP Right Cessation
- 2005-06-22 ES ES05755280.4T patent/ES2336015T5/es active Active
- 2005-06-22 DK DK05755280.4T patent/DK1758469T4/da active
- 2005-06-22 MX MXPA06015071A patent/MXPA06015071A/es active IP Right Grant
- 2005-06-22 AT AT05755280T patent/ATE446686T1/de active
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- 2006-12-19 NO NO20065915A patent/NO332430B1/no not_active IP Right Cessation
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2009
- 2009-12-29 US US12/648,891 patent/US20100167982A1/en not_active Abandoned
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CN1498620A (zh) * | 2002-11-06 | 2004-05-26 | 刘亚平 | 一种含低聚糖组合物 |
Also Published As
Publication number | Publication date |
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AU2005253898A1 (en) | 2005-12-29 |
BRPI0512528B8 (pt) | 2022-11-22 |
BRPI0512528A (pt) | 2008-03-25 |
PL1758469T3 (pl) | 2010-05-31 |
US20100167982A1 (en) | 2010-07-01 |
EP1758469B2 (en) | 2013-09-25 |
DK1758469T4 (da) | 2013-11-04 |
WO2005122791A3 (en) | 2006-04-13 |
EP1758469A2 (en) | 2007-03-07 |
CA2570208A1 (en) | 2005-12-29 |
JP5301155B2 (ja) | 2013-09-25 |
ES2336015T5 (es) | 2014-01-09 |
DK1758469T3 (da) | 2009-12-21 |
NZ552118A (en) | 2010-03-26 |
BRPI0512528B1 (pt) | 2018-02-06 |
RU2429718C2 (ru) | 2011-09-27 |
ES2336015T3 (es) | 2010-04-07 |
AU2005253898B2 (en) | 2010-02-18 |
DE602005017389D1 (de) | 2009-12-10 |
PL1758469T5 (pl) | 2014-01-31 |
ATE446686T1 (de) | 2009-11-15 |
JP2008503570A (ja) | 2008-02-07 |
RU2007102053A (ru) | 2008-07-27 |
NO332430B1 (no) | 2012-09-17 |
SI1758469T1 (sl) | 2010-02-26 |
CN1972604A (zh) | 2007-05-30 |
WO2005122791A2 (en) | 2005-12-29 |
MXPA06015071A (es) | 2007-08-06 |
EP1758469B1 (en) | 2009-10-28 |
US20080015166A1 (en) | 2008-01-17 |
PT1758469E (pt) | 2010-02-03 |
NO20065915L (no) | 2007-03-22 |
SI1758469T2 (sl) | 2013-12-31 |
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