CN114340630A - 用于预防和治疗乳糜泻的瑞巴派特 - Google Patents
用于预防和治疗乳糜泻的瑞巴派特 Download PDFInfo
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- CN114340630A CN114340630A CN202080061731.0A CN202080061731A CN114340630A CN 114340630 A CN114340630 A CN 114340630A CN 202080061731 A CN202080061731 A CN 202080061731A CN 114340630 A CN114340630 A CN 114340630A
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
本发明提供用于预防和/或治疗乳糜泻，尤其是用于患有增加的肠通透性的人或处于增加的肠通透性风险中的人中的瑞巴派特。进一步，本发明提供用于抑制谷蛋白诱导肠通透性增加的方法中的瑞巴派特。
Description
发明领域
本发明涉及用于预防和/或治疗乳糜泻，尤其是用于患有增加的肠通透性的人或处于增加的肠通透性风险中的人中的瑞巴派特。进一步，本发明涉及用于抑制谷蛋白诱导肠通透性增加的方法中的瑞巴派特。
背景技术
乳糜泻(CD)，也称为谷蛋白敏感性肠病，是一种多因素自身免疫病症，其发生在遗传易感个体中，尤其是表达HLA-DQ2/-DQ8单倍型(haplotype)的那些个体中。其是由对谷蛋白不耐受引起的，谷蛋白是小麦、黑麦、大麦和相关谷物中天然存在的蛋白质。如果人患有乳糜泻，食用谷蛋白触发肠粘膜的自身免疫性炎症。随时间推移，这种反应破坏绒毛，绒毛是小肠内壁(lining)的小的指状突出物，其促进营养吸收。当绒毛受损时，营养物不能被适当地吸收到体内。肠损伤经常引起腹泻、疲劳、体重减轻、腹胀(bloating)和贫血，并且可导致严重的并发症。
该病症可以在任何年龄出现，估计影响全世界1/100的人。儿童经常在第一次暴露于谷蛋白之后不久就出现症状，但是在安全地食用谷蛋白产品数年后也可能出现症状。在后一种情况下，病症可能在触发事件例如疾病、怀孕或紧张的现场事件(live event)之后出现。
谷蛋白是种子贮藏蛋白的混合物，其包含高达80％的小麦种子中所含的蛋白。膳食谷蛋白由许多同源蛋白组成，所述同源蛋白在小麦中称为麦醇溶蛋白和麦谷蛋白，在大麦中称为大麦醇溶蛋白，和在黑麦中称为裸麦醇溶蛋白。这些蛋白中的每一种都含有多个疾病特异性T细胞表位。谷蛋白具有相似的氨基酸序列，并且通常含有由脯氨酸和谷氨酰胺残基占主导的重复区段。在谷蛋白进入消化系统之后，其被胃肠道中存在的蛋白酶部分水解。然而，脯氨酸的高含量使得谷蛋白特别耐受肠细胞的腔内蛋白酶(intraluminalproteases)和刷状缘膜酶(brush-border membrane enzymes)的广泛蛋白水解，这导致未消化的谷蛋白的长片段存活在小肠上部，在那里它们可以作为允许T细胞和B细胞应答的免疫原性肽暴露于肠免疫系统的诱导部分。从饮食中除去这些蛋白质引起完全缓解。
人肠道排列单层上皮细胞，其通过紧密连接、粘附连接和桥粒结合在一起。肽可以经由细胞旁途径或经由跨细胞途径穿过肠上皮。在正常生理条件下，穿过肠上皮的大部分(～90％)抗原通过跨细胞途径行进。跨细胞途径受到调节，并导致抗原溶酶体降解成小的非免疫原性肽。剩余的～10％的蛋白呈完整蛋白或部分消化的肽，通过肠紧密连接调节的紧密调节的抗原运送(antigen trafficking)通过细胞旁途径穿过上皮，其导致抗原耐受性。
在健康的个体中，被肠细胞内吞的谷蛋白肽在跨细胞转运期间几乎完全被溶酶体系统降解(Matysiak-Budnik T,Candalh C,Dugave C,Namane A,Cellier C,Cerf-Bensussan N,Heyman M:Alterations of the intestinal transport and processingof gliadin peptides in celiac disease.Gastroenterology 2003；125:696-707)，因此可能避免局部免疫系统的过度活化。相反，在活动性CD中，更多的肽穿过肠粘膜，并且显著部分以完整形式到达固有层。该机制涉及谷蛋白肽结合肠顶膜的分泌型IgA，然后结合肠细胞(enterocyte)上的转铁蛋白受体CD71。然后，其被胞转(transcytosed)，将谷蛋白肽递送至固有层(Matysiak-Budnik T et al.Secretory IgA mediates retrotranscytosis ofintact gliadin peptides via the transferrin receptor in celiac disease.J ExpMed.2008；205(1):143-54)。
有趣的是，谷蛋白肽也通过细胞旁途径穿过上皮层，其包括分解细胞间紧密连接。在到达肠腔时，谷蛋白肽片段与趋化因子C-X-C受体3(CXCR3)结合，从而招募髓样分化初级反应蛋白88(MyD88)，其诱导连蛋白(zonulin)释放到腔中(Lammers KM et al.Gliadininduces an increase in intestinal permeability and zonulin release by bindingto the chemokine receptor CXCR3,Gastroenterology 2008；135(l):194-204)。连蛋白是唯一描述的细胞间紧密连接的生理学调节剂。其结合肠上皮中的表皮生长因子受体(EGFR)和蛋白酶激活受体2(PAR2)。该复合物启动信号传导途径，引起外周膜蛋白(zonulaoccludens proteins)的磷酸化，并导致小肠紧密连接的分解，导致对大分子的肠渗透性增加，从而使谷蛋白肽细胞外泄(paracellular leakage)。
与许多其它自身免疫疾病类似，CD涉及先天和适应性免疫应答。首先，谷蛋白肽通过上述机制进入固有层。在此，它们可以激活树突细胞和巨噬细胞以产生白细胞介素15(IL-15)，其反过来上调肠细胞(intestinal enterocytes)上应激蛋白MICA/B和HLA-E的表达。这些蛋白被存在于上皮内淋巴细胞(IEL)上的自然杀伤受体NKG2D和NKG2C识别，其表达也被IL-15上调(
S et al.A direct role for NKG2D/MICA interaction invillous atrophy during celiac disease.Immunity.2004；21(3):367-7；Kinoshita Net al.Autocrine IL-15mediates intestinal epithelial cell death via theactivation of neighboring intraepithelial NK cells.J Immunol.2002；169(11):6187-92)。该过程经由穿孔素/粒酶和/或Fas/FasL途径引起IEL的细胞毒性和细胞凋亡诱导活性及上皮细胞损伤(Ciccocioppo R et al.Cytolytic mechanisms ofintraepithelial lymphocytes in coeliac disease(CoD).Clin Exp Immunol.2000；120:235-40)。
适应性免疫应答包括肠固有层中存在的谷蛋白肽与抗原呈递细胞(APC)，特别是与DC的结合。这些细胞将谷蛋白肽呈递给T细胞受体，这导致能够诱导淋巴细胞B分化成浆细胞的CD4+T细胞的强烈活化，产生针对谷蛋白的特异性抗体。进一步，谷蛋白肽通过组织转谷氨酰胺酶(tTG或TG2)进行脱酰胺作用，其增强了它们对APC上展示的MHC II分子(如HLA-DQ2或DQ8)的亲和力。这种脱酰胺过程使APC不仅能够摄取免疫原性肽，而且能够摄取tTG-肽复合物。因此，产生了不仅针对谷蛋白肽而且针对tTG的抗体(Di Sabatino A etal.The function of tissue transglutaminase in celiac disease.AutoimmunRev.2012；11(10):746-53)。CD4+T细胞也分泌促炎细胞因子，其中干扰素(IFN-γ)是主要的，其刺激细胞毒性T细胞和成纤维细胞以产生负责降解细胞外基质和基底膜两者的基质金属蛋白酶(MMP)。
上述炎症过程导致破坏了小肠粘膜内壁的结构和功能，导致绒毛变平和隐窝增生。目前，对乳糜泻唯一已知的有效治疗是严格终身无谷蛋白饮食，其引起肠粘膜恢复，改善症状并降低在大多数人中发展并发症的风险。如果不治疗，其可能导致癌症，例如肠淋巴瘤。因此，存在对替代疗法增加的需求。
瑞巴派特，化学名是2-[(4-氯苯甲酰基)氨基]-3-(2-氧代-1H-喹啉-4-基)丙酸，用于治疗急性和/或慢性胃炎和胃十二指肠溃疡。其作用机制涉及粘膜防御、清除自由基和暂时激活编码环氧合酶-2的基因。
发明简述
已经出人意料地发现，当向患有乳糜泻的患者施用瑞巴派特时，其能够抑制疾病症状并且甚至可以导致完全缓解。这是非常令人惊讶的，因为还没有报道临床上用于治疗胃部疾病的瑞巴派特可以有效地抗主要影响小肠的乳糜泻。尽管瑞巴派特自从1990年就已经上市，但是关于其在肠中的行为知之甚少。该分子在胃肠道中吸收差，这表明在口服给药之后，其可以以足够高的浓度到达肠粘膜以发挥治疗作用。从这个观点来看，瑞巴派特针对CD的推测作用机制可能是基于诱导肠中粘蛋白产生、抑制炎症和降低肠壁通透性的能力。
因此，本发明提供用于预防和/或治疗乳糜泻(特别地，通过降低肠通透性)的瑞巴派特或其药物组合物。优选地，瑞巴派特用于预防和/或治疗坚持无谷蛋白饮食的人的乳糜泻。
如本文使用的“瑞巴派特”应当包括该活性成分的所有形式，例如无水形式、水合或溶剂化形式(例如，半水合物形式)、结晶形式；及其可药用盐。
“预防”或“预防性使用”在本文中应当理解为预防或延迟乳糜泻的发病，包括在完全或部分缓解的患者中，例如在无谷蛋白饮食或任何其它先前治疗之后，其症状的复发。其还包括在以其他方式坚持无谷蛋白饮食的人中谷蛋白溢出(transgression)之后疾病症状不恶化(non-worsening)。
“治疗”本文中应当理解为能够消除、抑制、减缓或逆转乳糜泻进展的疗法，包括抑制小肠的慢性炎症、减少绒毛萎缩和/或隐窝增生、减少肠通透性异常和自身抗体的逐渐消失。其还意味着涵盖改善或减轻疾病的临床症状，例如腹泻、腹、疲劳、腹痛、恶心和呕吐、便秘、体重减轻、口腔溃疡、缺铁性贫血、抑郁或焦虑、疱疹样皮炎、头痛、骨密度损失、关节炎等。
如本文使用的“谷蛋白”应当包括存在于小麦或相关谷物物种，包括大麦、黑麦和燕麦中的蛋白质，其对某些个体有潜在的危害。谷蛋白特别包括α、β、γ和ω麦醇溶蛋白，以及小麦中低和高分子量(LMW和HMW)麦谷蛋白；大麦中的B、C和D大麦醇溶蛋白；黑麦中的β、γ和ω黑麦醇溶蛋白；和燕麦中的燕麦蛋白。
目前的证据主体(body of evidence)表明，多种因素，例如遗传构成和环境触发，在乳糜泻的发展中起作用。已经表明，增加的肠通透性是CD发病机制的另一个关键因素，因为它使得谷蛋白肽能够进入谷蛋白反应性T细胞位于其中的固有层。对爱尔兰塞特犬(Irish Setter dogs)(天然存在的谷蛋白敏感性模型)的研究表明，肠通透性增加甚至可能在其自身免疫病发病之前就存在(Hall EJ,Batt RM.Abnormal permeability precedesthe development of a gluten sensitive enteropathy in Irish setterdogs.Gut.1991；32；749-753)。在本发明的框架中，令人惊奇地发现瑞巴派特还能够帮助CD患者的肠通透性正常化。这可能是由于其恢复上皮细胞紧密连接的功能的能力，从而降低肠壁的通透性并防止谷蛋白进入固有层中。这有助于抑制慢性炎症并防止由自身免疫反应引起的进一步组织损伤。
在一个方面，本发明提供用于预防和/或治疗患有增加的肠通透性的人或处于增加的肠通透性风险中的人的乳糜泻的方法中的瑞巴派特，所述增加的肠通透性为例如由于家族既往病史引起的或由于暴露于诱导增加的肠通透性的条件或物质引起的。在一个优选的实施方案中，瑞巴派特用于预防乳糜泻的方法中。
“增加的肠通透性”在本文中用作指小的肠壁缺陷的术语，包括由肠壁的亚临床慢性炎症(轻度炎症)引起的那些。这些肠壁缺陷可表现为乳糜泻，也可表现为其它医学病症，例如慢性便秘或胃轻瘫。增加的肠通透性可以使用特殊试验例如乳果糖-甘露醇试验(La/Ma test；例如Uil JJ et al.Sensitivity of a hyperosmolar or low-osmolar testsolution for sugar absorption in recognizing small intestinal mucosal damagein coeliac disease.Digest Liver Dis 2000；32:195-200)，A-1-AT试验或zonulin试验来诊断。通常，增加的肠通透性是肠壁对半径尺寸大于4埃的颗粒的通透性。
诱导增加的肠通透性的物质包括非甾体抗炎药(NSAID)，例如乙酰水杨酸、布洛芬、萘普生、酮洛芬、非诺洛芬、氟比洛芬、双氯芬酸、酮咯酸、依托度酸、吲哚美辛、托美丁、吡罗昔康、美洛昔康和选择性COX-2抑制剂例如塞来考昔和艾托考昔；酒精；尼古丁；食品添加剂；抗生素；和化疗剂。因此，同时或连续共同施用瑞巴派特与非甾体抗炎药、化疗药或抗生素预防肠壁损伤，且因此预防和延迟与增加的肠通透性相关的乳糜泻的发病。预防性使用瑞巴派特还可以用于滥用酒精、尼古丁或已知损伤肠壁其它药物的人。如本文使用的术语“滥用”指包括不是由于医学原因必须的并导致依赖性和/或健康损害(包括轻度肠壁炎症)的任何消耗。
诱导增加的肠通透性的条件与应激、不平衡膳食、过敏、细菌、病毒或寄生虫感染和各种医学治疗有关。这样的条件特别地包括应激诱导的胃炎，食物中毒，胆酸、胃HCl和胃蛋白酶分泌失衡，非感染性腹泻，放疗，化疗，GIT粘膜的感染性或感染后损伤，微生物障碍(例如由抗生素治疗诱发的)。
患有增加的肠通透性的人通常患有至少一种选自轻度肠壁炎症、慢性便秘或胃轻瘫的病症。
在一个方面，本发明提供通过向需要这种治疗的受试者施用药学有效剂量的瑞巴派特或其药物组合物来预防和/或治疗乳糜泻的方法。受试者优选是人类受试者，特别是患有增加的肠通透性的人或处于增加的肠通透性风险中的人。进一步，本发明还包括瑞巴派特在制备用于预防和/或治疗乳糜泻的药物中的用途，特别是在患有增加的肠通透性的人中或在处于增加的肠通透性的风险中的人中。
在一个方面，本发明提供用于抑制谷蛋白诱导的肠通透性增加的方法中的瑞巴派特。所述方法包括以足以抑制所述肠通透性增加的量向需要其的受试者施用瑞巴派特或其组合物。进一步，本发明还包括瑞巴派特在制备用于抑制谷蛋白诱导的肠通透性增加的组合物中的用途。
在本发明所述的治疗适应症中，瑞巴派特可以优选地以口服药物形式使用，例如片剂、胶囊、锭剂、颗粒、微粒(小药囊)、口腔分散片或膜剂、舌下片、压碎片剂(crushedtablets)、口服溶液、口服混悬液、糖浆、漱口水、漱口液。或者，其可以以直肠药物形式使用，例如栓剂和灌肠剂。优选地，口服药物形式如片剂、胶囊、锭剂和颗粒是具有肠释放的形式，例如肠缓释释放或肠控制释放形式。
药物形式可以含有至少一种可药用赋形剂，选自填充剂、粘合剂、润滑剂、助流剂、崩解剂/溶胀剂、增溶剂、肠释放剂、粘膜粘附组分、缓释剂、防腐剂、包衣和着色剂。这样的赋形剂是药物制剂领域中已知的，并且本领域技术人员能够选择用于相关药物形式的合适赋形剂。
用于制备药物形式和组合物的合适方法包括活性成分与辅助物质和组分的湿法制粒或干法制粒，或活性成分与辅助物质和组分的直接均质化的过程。
填充剂可以优选地选自糖醇(例如，甘露醇、山梨醇、木糖醇)、乳糖、淀粉、预胶化淀粉、纤维素、硅化纤维素、磷酸氢钙、磷酸钙、蔗糖和硫酸钙。相对于组合物的总重量计，填充剂可以优选以5-90wt％的量存在。
粘合剂可以优选地选自淀粉、预胶化淀粉、聚维酮、共聚维酮、羟丙基甲基纤维素、羟丙基纤维素、乙基纤维素、纤维素。相对于组合物的总重量计，粘合剂可以优选以1-20重量％的量存在。
润滑剂可以优选选自硬脂酸镁、硬脂酸钙、硬脂酸、聚乙二醇和硬脂酰富马酸钠。相对于组合物的总重量计，润滑剂可以优选以至多5wt％的量存在。
助流剂可以优选选自二氧化硅、滑石和月桂基硫酸钠。相对于组合物的总重量计，助流剂可以优选以0.5-10wt％的量存在。
溶胀剂和/或崩解剂可以优选选自交聚维酮、共聚维酮、聚维酮、交联羧甲基纤维素、羟丙基甲基纤维素、淀粉、预胶化淀粉、低取代羟丙基纤维素、羧甲基淀粉钠。相对于组合物的总重量计，溶胀剂/崩解剂可以优选以1-50wt％的量存在。
增溶剂可以优选选自泊洛沙姆、月桂基硫酸钠、聚山梨酯、聚氧乙烯化油酸甘油酯、单硬脂酸甘油酯和环糊精。相对于组合物的总重量计，增溶剂可以优选以至多30wt％的量存在。
肠释放剂可以优选选自羟丙基甲基纤维素邻苯二甲酸酯、聚(甲基丙烯酸-共-甲基丙烯酸甲酯)、邻苯二甲酸乙酸纤维素、聚(乙酸乙烯邻苯二甲酸酯)、油桐酸酯。相对于组合物的总重量计，肠释放剂可以优选以2-40wt.％的量存在。
粘膜粘附成分可以优选选自藻酸丙二醇酯、藻酸钠、藻酸钙、藻酸钾、羟丙基甲基纤维素、羧甲基纤维素钠、聚丙烯酸、聚环氧乙烷、聚维酮和共聚维酮。相对于组合物的总重量计，粘膜粘附组分可以优选以5-70wt.％的量存在。
缓释剂可以优选选自纤维素和纤维素醚，例如羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、乙基纤维素、甲基纤维素、聚乙酸乙烯酯、海藻酸、藻酸丙二醇酯、藻酸钠、藻酸钙、藻酸钾、聚甲基丙烯酸酯、瓜尔胶、黄原胶、角叉菜胶、蓖麻油、蜂蜡、巴西棕榈蜡、棕榈酰硬脂酸甘油酯、单硬脂酸甘油酯、山嵛酸甘油酯、硬脂醇、聚丙烯酸。相对于组合物的总重量计，缓释剂可以优选以5-70wt.％的量存在。
在一些实施方案中，口服药物组合物可以进一步包含在与胃液接触时能够形成二氧化碳的可药用组分，这样的组分可以优选选自碱金属和碱土金属的碳酸盐和碳酸氢盐；并且相对于组合物的总重量集，可以优选以1-50wt.％的量存在。
瑞巴派特的典型日剂量可以是对于平均人(70kg体重)1-5000mg，更优选50-2500mg，甚至更优选100-1000mg，最优选300-500mg。
当施用瑞巴派特的立即释放制剂时，日剂量通常分成分开施用的若干剂量。日剂量可以分成二至六个单独的剂量，每日两次或每日三次或每日四次或每日五次或每日六次服用。在一个优选的实施方案中，将日剂量分成每日三次施用的三个单独剂量，例如每日三次施用100mg剂量。或者，整个日剂量可以一次性服用，尤其是如果其为缓释制剂的形式，例如每日一次施用300mg剂量。治疗的持续时间由医师决定。
在下文中，通过实施例更具体地描述本发明。然而，提供以下工作实施例仅用于说明，因此本发明不限于此。
实施例
消除-激发试验
为了研究瑞巴派特对乳糜泻的作用，使用谷蛋白挑战试验。进入试验的成年患者在无谷蛋白饮食(GFD)下稳定，导致疾病症状消失至少12个月。所有参与者先前由医生使用上部内窥镜检查和十二指肠活检诊断乳糜泻。通过高的绒毛高度/隐窝深度比(Vh/Cd＞2-3)和从饮食中排除谷蛋白之后抗-tTG抗体水平的下降(小于10U/mL)证实了无谷蛋白饮食坚持性(adherence)。
将患者分成两组，每天三次服用瑞巴派特100mg，或者在每次主要进餐之前服用安慰剂。两组继续无谷蛋白饮食。在处理开始后的三个月(第90天)进行谷蛋白挑战试验。患者每天食用一片包含约2.7g小麦谷蛋白的白面包，持续6周的时间，但是在别的方面保持他们通常的无谷蛋白饮食。两组继续接受瑞巴派特或安慰剂治疗。
通过胃肠症状评分量表(Gastrointestinal Symptom Rating Scale,GSRS)问卷调查每周评价CD症状，该问卷调查是一种广泛用于乳糜泻和其它胃肠疾病研究的手段(Svedlund J,Sjodin I,Dotevall G.GSRS-a clinical rating scale forgastrointestinal symptoms in patients with irritable bowel syndrome andpeptic ulcer disease.Dig Dis Sci 1988；33:129-134)。其由15个问题组成，这些问题被分组成五个领域(腹泻、腹痛、消化不良、便秘和反流)，其合并成作为所有15个问题的平均值计算的总分数。评分是基于从1到7分的李克特量表(Likert scale)，其中1分表示最小的胃肠道症状，7分表示最严重的症状。
在试验开始时，在挑战6周之前和之后，使用标准的尿乳果糖/甘露醇(La/Ma)排泄分数比测量肠通透性。La/Ma试验是基于对非代谢糖的不同吸收。在健康的肠中，单糖(例如，甘露醇)通过肠粘膜被动吸收，而较大的二糖分子(例如，乳果糖)通常几乎不被吸收。相反，患有乳糜泻的患者由于肠通透性增加而具有乳果糖吸收的一致性增加(经由细胞旁路途径)，并且由于绒毛萎缩导致表面积减少而具有甘露醇吸收的减少(经由跨细胞途径)，从而导致La/Ma比增加。
在研究期的开始(第0天)和结束(第132天)进行十二指肠活检。由病理学家测量相邻绒毛/隐窝的平均高度/平均深度来确定绒毛高度与隐窝深度比(Vh/Cd)。该比值＜2被认为是绒毛萎缩和隐窝增生的指征。
通过酶联免疫吸附测定(ELISA)来测定血清平均抗tTG IgA抗体水平，并比较基线时和挑战6周之后的差异。
结果概述在表1中。
表1
在瑞巴派特预处理过程中，平均总GSRS评分降低，随后在谷蛋白挑战过程中逐渐向基线值增加。相反，在谷蛋白挑战的第一周期间，安慰剂组经历GSRS评分快速增加，并且此后其保持升高。患者报告了广泛的症状，包括腹泻、腹胀、腹痛和疲倦。瑞巴派特与安慰剂相比GSRS评分的差异表明瑞巴派特治疗组的平均GSRS评分显著低于安慰剂组(在研究结束时为0.6单位)。这意味着与安慰剂组相比，在谷蛋白挑战之前和期间接受瑞巴派特的患者组中的症状在统计学显著地不太严重。
尽管已知La/Ma的排泄分数在人与人之间是高度可变的，但是结果表明安慰剂组中每日摄入谷蛋白之后这些糖的比例显著增加，提示肠通透性增加。相反，在谷蛋白挑战结束时，瑞巴派特处理组中La/Ma比率保持接近基线，表明其对抗不期望的肠通透性增加的活性。
从第0天开始，在小肠活组织检查中，所有参与者都具有正常的Vh/Cd比率。然而，在每日摄入谷蛋白6周之后，安慰剂组的大多数患者都观察到组织学变化。平均Vh/Cd比率恶化至1.7，表明活动性乳糜泻。令人惊讶地，在绒毛高度与隐窝深度比方面，瑞巴派特组中的患者从基线到治疗后没有显示出负向变化，表明治疗成功。
在谷蛋白挑战之后平均抗tTG IgA抗体滴度升高，但是在瑞巴派特处理组中保持低于10U/ml阈值。安慰剂组显示更强的平均抗体应答，尽管一些患者在谷蛋白挑战过程中没有出现任何可测量的抗-tTG IgA水平变化。
消除-激发试验的结果表明瑞巴派特提供肠粘膜抗摄入谷蛋白的保护，降低肠通透性并改善了患者报告的乳糜泻症状。该药物允许消耗谷蛋白而不会使疾病恶化，其可显著改善生活质量，因为坚持严格的无谷蛋白饮食是困难且昂贵的。此外，不能完全避免意外的谷蛋白摄入，并且甚至在标记不含谷蛋白的产品中也可能发现痕量的谷蛋白。可以得出结论，瑞巴派特在乳糜泻控制中提供了独特的机会，改善了患者的生活质量，并且可以确保该疾病的长期缓解。
Claims (15)
1.用于预防和/或治疗乳糜泻的方法中的瑞巴派特。
2.根据权利要求1使用的瑞巴派特，其中瑞巴派特用于预防和/或治疗坚持无谷蛋白饮食的人的乳糜泻。
3.用于抑制谷蛋白诱导的增加的肠通透性的方法中的瑞巴派特。
4.根据权利要求1使用的瑞巴派特，其中瑞巴派特用于预防和/或治疗患有增加的肠通透性的人或处于增加的肠通透性的风险中的人的乳糜泻。
5.根据前述权利要求中任一项使用的瑞巴派特，其中瑞巴派特用于预防乳糜泻的方法中。
6.根据权利要求4或5使用的瑞巴派特，其中所述患有增加的肠通透性的人为患有至少一种选自轻度肠壁炎症、慢性便秘或胃轻瘫的病症的人。
7.根据权利要求4或5使用的瑞巴派特，其中所述处于增加的肠通透性的风险中的人为患有应激、不平衡膳食、细菌、病毒或寄生虫感染的人。
8.根据权利要求4或5使用的瑞巴派特，其中所述处于增加的肠通透性风险的人是暴露于选自以下的至少一种物质的人：非甾体抗炎药、酒精、尼古丁、食品添加剂、化疗剂和抗生素。
9.根据权利要求8使用的瑞巴派特，其中瑞巴派特与非甾体抗炎药、化疗剂或抗生素同时或依次共同施用。
10.根据权利要求8使用的瑞巴派特，其中向滥用酒精、尼古丁或其它药物的人施用瑞巴派特。
11.根据权利要求4或5使用的瑞巴派特，其中所述处于增加的肠通透性风险中的人是患有或暴露于至少一种选自以下的病症的人：应激诱导的胃炎，食物中毒，胆酸、胃HCl和胃蛋白酶分泌失衡，非感染性腹泻，放疗，化疗，GIT粘膜的感染性或感染后损伤，微生物障碍。
12.根据前述权利要求中任一项使用的瑞巴派特，其中瑞巴派特以口服药物形式施用，优选地选自片剂、胶囊、锭剂、颗粒、微粒(小药囊)、口腔分散片或膜剂、舌下片、压碎片剂(crushed tablets)、口服溶液、口服混悬液、糖浆、漱口水、漱口液；或以直肠药物形式施用，优选地选自栓剂和灌肠剂。
13.根据权利要求12使用的瑞巴派特，其中所述口服药物形式是具有肠释放的形式，优选肠缓续释放或肠控制释放形式。
14.根据权利要求13使用的瑞巴派特，其中所述药物形式包含瑞巴派特和至少一种可药用赋形剂，选自填充剂、粘合剂、润滑剂、助流剂、崩解剂/溶胀剂、增溶剂、肠释放剂、粘膜粘附组分、缓释剂、防腐剂、包衣和着色剂。
15.根据前述权利要求中任一项使用的瑞巴派特，其中瑞巴派特以1至5000mg，更优选50至2500mg，甚至更优选100至1000mg，最优选300至500mg的日剂量施用。
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| CN105943534A (zh) * | 2008-04-15 | 2016-09-21 | 萨可德生物科学公司 | 用于局部治疗免疫相关疾病的局部lfa-1拮抗剂 |
| CN106456549A (zh) * | 2014-04-04 | 2017-02-22 | 阿尔巴医疗公司 | 利用拉瑞唑来治疗乳糜泻的方法 |
| CN109562137A (zh) * | 2015-09-01 | 2019-04-02 | 第波生物公司 | 用于治疗与异常炎性反应有关的病况的方法和组合物 |
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| US20050159396A1 (en) * | 2004-01-20 | 2005-07-21 | Harty Richard F. | Compositions and methods of treatment for inflammatory diseases |
| CN105943534A (zh) * | 2008-04-15 | 2016-09-21 | 萨可德生物科学公司 | 用于局部治疗免疫相关疾病的局部lfa-1拮抗剂 |
| CN103429224A (zh) * | 2011-03-24 | 2013-12-04 | 大塚制药株式会社 | 用于治疗口腔疾病的包含瑞巴派特的药物组合物 |
| CN106456549A (zh) * | 2014-04-04 | 2017-02-22 | 阿尔巴医疗公司 | 利用拉瑞唑来治疗乳糜泻的方法 |
| CN109562137A (zh) * | 2015-09-01 | 2019-04-02 | 第波生物公司 | 用于治疗与异常炎性反应有关的病况的方法和组合物 |
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