CN114340628A - 用于预防和治疗克罗恩病的瑞巴派特 - Google Patents
用于预防和治疗克罗恩病的瑞巴派特 Download PDFInfo
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- CN114340628A CN114340628A CN202080061729.3A CN202080061729A CN114340628A CN 114340628 A CN114340628 A CN 114340628A CN 202080061729 A CN202080061729 A CN 202080061729A CN 114340628 A CN114340628 A CN 114340628A
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Abstract
本发明提供用于预防和/或治疗克罗恩病的方法中的瑞巴派特。特别地,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克罗恩病。
Description
发明领域
本发明涉及用于预防和/或治疗克罗恩病的方法,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。
背景技术
克罗恩病(CD)是一种属于炎性肠病(IBD)的疾病。其是一种慢性多因素病症,其中涉及遗传、环境和微生物因素。虽然确切的原因是未知的,但是似乎疾病的发病是由干扰粘膜屏障、改变肠微生物群的健康平衡和异常刺激肠道免疫应答的环境因素触发的。这导致肠的慢性炎症,具有典型症状,例如腹泻、体重减轻、疲劳、直肠出血和腹痛。
该病症可发生在任何年龄,但是其通常开始于青少年和二十多岁。估计在欧洲和北美洲1,000人中有约3人受到影响,在男性和女性中的频率类似。其最常影响小肠末端和结肠始端,但是其也可能影响从口到肛门的胃肠道的任何部分。跳跃性病灶(Skiplesions)和零散性炎症(patchy inflammation)是CD的典型发现。
目前,克罗恩病不能治愈,当前治疗目的在于减少引发症状的炎症。多年来,已经开发了几类药物用于治疗CD。药物的选择取决于炎症的位置、疾病的严重性、并发症和患者对医学治疗的反应。尽管轻度疾病可以用5-氨基水杨酸盐单独或与抗生素联合治疗,但是许多患者最终需要皮质类固醇控制症状。它们可以帮助减少炎症并诱导症状缓解,但是它们的长期使用与众所周知的副作用相关,因此不推荐用于维持疗法。此外,约一半患者不能停止皮质类固醇治疗而无疾病恶化。免疫抑制剂,如硫代嘌呤和甲氨蝶呤,经常被开处方用于对皮质类固醇有抗性或依赖性的患者;然而,这些药物起效慢,副作用严重,并且临床缓解率为约40%。
在对使用皮质类固醇和免疫抑制剂的常规治疗无反应的患者中使用抗TNFα的单克隆抗体,例如英夫利昔单抗(Remicade)和阿达木单抗(Humira)的生物疗法。进一步的选择是抗白细胞介素的抗体,例如起人IL-12和IL-23拮抗剂作用的优特克单抗(Stelara),和结合人整联蛋白的那些抗体,例如靶向整联蛋白α4β7导致肠选择性抗炎活性的维多珠单抗(Entyvio)。单克隆抗体起效相对快速并诱导粘膜愈合,但是高达30%的患者对治疗没有反应(主要无应答者),并且在最初使用这些药物受益的患者中,高达50%的患者可能在十二个月内失去对治疗的反应(次要无应答者),需要剂量递增或改变疗法。尽管单一疗法被认为是相对安全的,但是患者对感染更敏感且具有更高的恶性肿瘤风险。此外,在已经达到持续缓解期的患者中的治疗戒断仍然是一个持续的问题。
尽管上述一些治疗可能导致疾病症状的长期缓解,但是大多数CD患者最终需要手术。因此,对于抑制肠道炎症并导致疾病症状持续完全缓解的治疗仍然存在高度未满足的医学需要。为了满足这种需要,本发明提供一种同时适用于CD的诱导治疗和维持治疗的可负担的治疗方法。
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,当向患有克罗恩病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疾病完全缓解。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肠的克罗恩病。尽管瑞巴派特自从1990年就已经上市,但是关于其在胃肠道中的行为知之甚少。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。然而,就本人所知,口服瑞巴派特从未被报道为克罗恩病的有效治疗方法。
作用机制可能基于瑞巴派特在肠中诱导粘蛋白产生、抑制炎症和恢复上皮细胞紧密连接的功能,从而降低肠壁的通透性并使肠功能正常化的能力(Diao L etal.Rebamipide suppresses diclofenac-induced intestinal permeability viamitochondrial protection in mice.World J Gastroenterol.2012;18(10):1059-1066)。这导致慢性炎症的抑制和肠恢复,防止进一步的组织损伤和疾病症状的减轻。事实上,增加对各种试剂的小肠通透性是克罗恩病患者中常见的观察结果(Katz KD etal.Intestinal permeability in patients with Crohn’s disease and their healthyrelatives.Gastroenterology.1989;97(4):927-931),并且据报道在遗传易感的个体中是在疾病发作之前(Irvine EJ&Marshall JK.Increased intestinal permeabilityprecedes the onset of Crohn’s disease in a subject with familialrisk.Gastroenterology.2000;119(6),1740-1744)。
因此,本发明提供用于预防和/或治疗克罗恩病(特别地,通过降低肠通透性)的瑞巴派特或其药物组合物。所述方法可有利地用于诱导治疗以减少炎症、减轻症状和/或诱导如下所定义的缓解,和/或用于维持治疗以预防达到缓解的人的疾病复发(relapse或recurrence)。
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疾病及其症状的发病,包括在先前治疗之后完全或部分缓解的患者中其复发。其还意味着包括在递减(de-escalation)或中止先前治疗之后维持疾病症状的缓解和/或不恶化。此外,其还包括预防疾病并发症,例如肠梗阻、溃疡和瘘、肛裂、结肠癌、关节炎、葡萄膜炎、结节性红斑、坏疽性脓皮病或口疮性口炎。
“治疗”在本文中应当理解为能够消除、抑制、减缓或逆转疾病进展和/或抑制小肠或胃肠道其它部位慢性炎症的疗法。其还意味着涵盖改善或减轻疾病的临床症状,例如腹痛、腹泻、腹胀、便血、口疮、疲劳、食欲降低和体重减轻、营养不良、皮肤炎症等。
本发明进一步提供一种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/或治疗克罗恩病的方法。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/或治疗克罗恩病的药物中的用途,尤其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,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风险中的人的克罗恩病的方法中,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。
“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克罗恩病,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(LAMA test;e.g.,Sequeira I.R.et al.(2014)PLoS One;9(6):e99256)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克罗恩病的发病。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,瑞巴派特用于与至少一种有效抗克罗恩病的其他药物的组合疗法中,其中所述其他药物可以与瑞巴派特同时、分开或顺序施用。组合疗法优选用于治疗活动性克罗恩病的方法。更优选地,组合疗法用于诱导治疗以减少炎症、减轻症状和/或诱导缓解。
术语药物意味着涵盖小分子,即分子量小于约900g/mol,和大分子,尤其是抗体。至少一种有效抗克罗恩病的其他药物优选选自5-氨基水杨酸盐、皮质类固醇、免疫抑制剂、抗生素和抗体。更优选地,所述其他药物选自皮质类固醇、免疫抑制剂和抗体。最优选地,所述其他药物是皮质类固醇。
5-氨基水杨酸酯是抗炎化疗剂,主要用于治疗轻度至中度克罗恩病。这些化合物包括美沙拉嗪(即,5-氨基水杨酸、5-ASA或美沙拉嗪)及其共轭衍生物,因它们的抗炎性质而已知,例如柳氮磺吡啶、奥沙拉嗪和巴柳氮。优选地,5-氨基水杨酸盐选自美沙拉嗪和柳氮磺吡啶。
皮质类固醇是一类抗炎药物,其用于帮助减少消化道中的炎症和减轻症状。根据本发明,与瑞巴派特组合使用的皮质类固醇优选选自泼尼松、泼尼松龙、甲泼尼龙、氢化可的松或布地奈德。其可以有利地进一步与至少一种硫代嘌呤组合以提供三重组合。皮质类固醇可以口服、直肠或静脉内施用。
在一个实施方案中,皮质类固醇是口服剂型(例如,片剂或胶囊)。这种形式通常施用于患有中度至重度活动性疾病的人。口服布地奈德也有利地用于轻度或中度疾病,其影响小肠末端和结肠始端。.
在另一个实施方案中,皮质类固醇是直肠形式(例如栓剂、灌肠剂或直肠泡沫),并且优选选自氢化可的松、甲泼尼龙和布地奈德。直肠形式尤其适合于患有影响结肠或直肠下部的活动性疾病的人。其特异性地靶向受疾病影响的区域,因此与口服形式相比具有较少的副作用。
在另一个实施方案中,皮质类固醇是静脉内施用的,优选选自氢化可的松和甲泼尼龙。静脉内施用特别适用于患有严重活动性疾病的患者。.
免疫抑制剂是抑制免疫系统活性从而减轻炎症的药物。它们优选选自硫代嘌呤、甲氨蝶呤、环孢菌素和他克莫司。特别优选硫代嘌呤和氨甲蝶呤。硫代嘌呤是嘌呤抗代谢物,优选选自硫唑嘌呤和6-巯基嘌呤。它们可以有利地与瑞巴派特和至少一种皮质类固醇或至少一种抗体组合以提供三重组合。
抗生素主要用于轻度至中度疾病,因为它们有助于降低肠内细菌的数量并改变肠内细菌的组成,导致症状的缓解。它们还用于控制感染和克罗恩病并发症,例如脓肿、瘘和隐窝炎。优选地,抗生素选自甲硝唑、环丙沙星、利福昔明和氨苄西林。甲硝唑和环丙沙星是特别优选的,特别是以静脉内剂型。
抗体(生物制剂)是靶向疾病的特定介质(例如,细胞因子或整联蛋白)的蛋白质分子。它们可以是任何来源的,例如来自人或小鼠,包括人源化和嵌合抗体。如本文使用的术语“抗体”意味着包括抗体的抗原结合片段,即包含抗体可变区的片段,例如F(ab')2、Fab'、Fv和scFv片段,以及衍生物,例如已经化学改变(例如聚乙二醇化)的那些。
在一个实施方案中,抗体选自针对TNFα的抗体,优选选自英夫利昔单抗(infliximab)、阿达木单抗(adalimumab)、戈利木单抗(golimumab)、赛妥珠单抗(certolizumab pegol)及其生物类似物。更优选地,所述抗体选自英夫利昔单抗、阿达木单抗及其生物类似物。
在另一个实施方案中,抗体选自抗白细胞介素,例如IL-12和/或IL-23的抗体。优选地,抗体为优特克单抗或其生物类似物。
在仍然另一个实施方案中,抗体选自抗整联蛋白,尤其是抗整联蛋白α4β7的抗体。优选地,抗体选自那他珠单抗(natalizumab)、维多珠单抗(vedolizumab)及其生物类似物。更优选地,抗体是维多珠单抗或其生物类似物。
更特别地,与至少一种其它有效抗如上定义的克罗恩病的其他药物的组合疗法包括以下步骤:向正在用一个剂量的至少一种有效对抗克罗恩病的其他药物治疗的人施用瑞巴派特;以及减少所述其他药物的剂量。
有利地,组合疗法包括步骤:施用瑞巴派特作为对至少一种有效抗克罗恩病的其他药物,尤其是20-60mg泼尼松或等效剂量的其它皮质类固醇的治疗的补充(add-on);以及减少所述其他药物的剂量。
在一个实施方案中,在开始瑞巴派特施用时,即在人开始被给予瑞巴派特的同时,减少所述其他药物的剂量。
在另一个实施方案中,在症状改善(如定义为CDAI减少超过100分或粪便钙卫蛋白减少超过150μg/g)之后减少所述其他药物的剂量。
在患者达到缓解之后,至少一种其它药物可以完全停止,如定义为内窥镜检查(粘膜愈合)和/或CDAI低于150分(临床缓解)和/或粪便钙卫蛋白低于200μg/g粪便(炎症抑制)。
组合疗法也可以有利地用于其它药物的剂量节约,尤其是用于皮质类固醇的剂量节约以预防其副作用。因此,本发明进一步提供用于至少一种有效对抗克罗恩病的其他药物的剂量节约方法中的瑞巴派特。所述方法有利地包括步骤:向正在用一个剂量的至少一种有效抗克罗恩病的其他药物,尤其是20-60mg泼尼松或等效剂量的其它皮质类固醇治疗的人施用瑞巴派特;并且减少所述其他药物的剂量。在一个方面,瑞巴派特用于单一疗法中,即待治疗的受试者仅施用瑞巴派特,并且不接受任何其它有效抗克罗恩病的药物。瑞巴派特单一疗法优选用于预防克罗恩病的方法中,包括预防例如由于具有增加的肠通透性或处于增加的肠通透性风险中而易感该疾病的人的第一次疾病爆发,和/或预防对诱导治疗有响应且达到如上定义的缓解的人的疾病复发。更优选地,瑞巴派特单一疗法用于克罗恩病的维持疗法以预防炎症和/或维持缓解。
本发明进一步提供一种治疗组合,其包含瑞巴派特和至少一种有效抗克罗恩病的其他药物。术语药物意味着涵盖小分子,即分子量小于约900g/mol,和大分子,例如抗体,优选选自针对TNFα、白细胞介素或整联蛋白(例如整联蛋白α4β7)的抗体。至少一种其他药物选自5-氨基水杨酸盐,优选选自柳氮磺吡啶或美沙拉秦;皮质类固醇,优选选自泼尼松、泼尼松龙、甲泼尼龙、氢化可的松或布地奈德;免疫抑制剂,优选硫唑嘌呤、6-巯基嘌呤、甲氨蝶呤、环孢菌素或他克莫司;抗生素,优选甲硝唑或环丙沙星;以及抗体(生物学),优选英夫利昔单抗、阿达木单抗、维多珠单抗及其生物类似物。
在一个优选的实施方案中,组合包含瑞巴派特和至少一种选自皮质类固醇、硫代嘌呤和抗体的其他药物。在一个更优选的实施方案中,本发明提供了一种治疗组合,其包含瑞巴派特和至少一种皮质类固醇,尤其是20-60mg的泼尼松或等效剂量的另一种皮质类固醇。
在本发明所述的治疗适应症中,瑞巴派特可以优选以用于口服给药的药物形式使用,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(crushed tablets)、口服溶液、口服混悬液、糖浆、漱口水或漱口液。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300-600mg或300-900mg。
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。
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
每天三次给予几名患有克罗恩病至少5年而对标准治疗没有足够反应的患者瑞巴派特片剂。这些患者具有用各种药物治疗的长期历史,但使用标准选择不能在疾病复发后达到缓解。疾病的严重程度由CDAI来定量,炎症的水平由粪便钙卫蛋白来定量。
克罗恩病活性指数(CDAI)是用于定量克罗恩病患者症状的研究工具。其由八个因子组成,每个因子在用加权因子调整之后相加。克罗恩病缓解定义为CDAI低于150,而严重疾病定义为值大于450。
钙卫蛋白(FC)是一种用作炎性肠病的生物标记的小钙结合蛋白,因为其粪便浓度与疾病严重性良好相关。低于200μg/g粪便的钙卫蛋白值被认为是正常水平。使用市售的酶联免疫吸附测定(ELISA)试剂盒(EK-CAL,Buhlmann)测定粪便样品中的钙卫蛋白值。
实施例1
女性患者,39岁,16年前诊断患有克罗恩回肠结肠炎。在疾病过程中,给予她各种药物,包括口服、肠胃外和局部皮质类固醇、硫唑嘌呤和TNFα抑制剂英夫利昔单抗和阿达木单抗。在针对这些抗体产生影响皮肤和关节的免疫应答之后,患者换成维多珠单(Entyvio),其能够在接下来的22个月稳定她。在疾病复发期间,患者患有腹痛、大便次数增多、关节和肌肉疼痛、微热、疲劳和干性皮炎,粪便钙卫蛋白水平高达1939μg/g,CDAI为358分。她继续用甲泼尼龙24mg/天治疗,但没有成功。与皮质类固醇治疗同时,她开始每天三次给予瑞巴派特100mg,引起疾病快速缓解,如通过治疗6周后疾病症状减轻(CDAI为181点)和钙卫蛋白水平降低至228μg/g证实的。然后,将皮质类固醇剂量减半,没有任何副作用。在另外6周之后,当钙卫蛋白水平降低到63μg/g并且CDAI降低到73分时,完全停止皮质类固醇,患者仅继续用瑞巴派特。迄今为止,没有观察到疾病活动性恶化。
实施例2
男性患者,27岁,5年前诊断患有克罗恩氏回肠结肠炎,并用美沙拉秦(Pentasia)、布地奈德和甲硝唑治疗。在美沙拉秦三个月之后,他发生胰腺炎。随后,将药物换成与泼尼松组合的硫唑嘌呤,随后换成甲氨蝶呤。然而,药物不是良好耐受的,指定患者用生物疗法。他用英夫利昔单抗(Remicade)治疗,随后用阿达木单抗(Humira)治疗。在最后一次复发(钙卫蛋白为2215μg/g;CDAI为479分)之后,给予他40mg/天的泼尼松,但不能达到缓解。他开始采服用瑞巴派特200mg,一天三次,作为泼尼松的补充。在6周之后(钙卫蛋白为356μg/g;CDAI为225分),瑞巴派特剂量调节至100mg,一天三次,泼尼松剂量调节至30mg/天。然后,泼尼松剂量每2周降低10mg,并在另外6周之后完全停止(钙卫蛋白为110μg/g;CDAI为84分)。患者仅继续用100mg瑞巴派特,一天三次。迄今为止没有观察到疾病活动性的恶化。
实施例3
女性患者,32岁,12年前诊断患有克罗恩氏回肠炎。使用布地奈德和美沙拉秦治疗能够维持缓解约10年。随后,她因腹痛和便溏每天3-4次住院治疗,钙卫蛋白水平高达1051μg/g,CDAI为377分。给她开处方硫唑嘌呤,但在两周后由于急性胰腺炎不得不停药。她用50mg/天的泼尼松和同时用100mg瑞巴派特(每天三次)继续治疗。在14天之后,由于临床症状的减轻,泼尼松的剂量调节到25mg,在另外6周之后,钙卫蛋白水平降到122μg/g,CDAI为98分,她仅继续用瑞巴派特。迄今为止,没有观察到疾病活动性的恶化。
用患者样品获得的结果显示瑞巴派特能够控制疾病症状、使钙卫蛋白水平正常化和诱导缓解,甚至在那些耗尽标准治疗选择的患者中。由于伦理原因,治疗开始作为皮质类固醇治疗的补充,但是据信即使开处方作为唯一治疗,它也是有效的。重要的是,注意到单独使用皮质类固醇不能完全抑制疾病症状,而且仅使用皮质类固醇,两名患者的钙卫蛋白均没有低于200μg/g的粪便和CDAI低于150分。而且,单独使用瑞巴派特的长期疗法似乎是良好耐受的,并且能够维持缓解。
Claims (25)
1.在预防和/或治疗克罗恩病的方法中使用的瑞巴派特。
2.根据权利要求1使用的瑞巴派特,其中所述方法包括组合瑞巴派特至少一种有效抗克罗恩病的其他药物。
3.根据权利要求2使用的瑞巴派特,其中所述方法包括步骤:向正在用一个剂量的至少一种有效抗克罗恩病的其他药物治疗的人施用瑞巴派特;并且减少所述其他药物的剂量。
4.根据权利要求3使用的瑞巴派特,其中在瑞巴派特施用开始时减少所述其他药物的剂量。
5.根据权利要求3使用的瑞巴派特,其中在症状改善之后减少所述其他药物的剂量。
6.根据权利要求2至5中任一项使用的瑞巴派特,其中在所述人达到症状缓解之后中止所述其他药物。
7.根据权利要求1至6中任一项使用的瑞巴派特,其中在治疗克罗恩病的方法中使用瑞巴派特。
8.根据权利要求7使用的瑞巴派特,其中所述方法包括向患有活动性克罗恩病的人施用瑞巴派特以诱导症状缓解。
9.根据权利要求1使用的瑞巴派特,其中所述方法是单一疗法。
10.根据权利要求9使用的瑞巴派特,其中在预防克罗恩病的方法中使用瑞巴派特。
11.根据权利要求9或10使用的瑞巴派特,其中所述方法包括向疾病症状缓解的人施用瑞巴派特以预防疾病复发。
12.一种治疗组合,其包含瑞巴派特和至少一种有效对抗克罗恩病的其他药物。
13.根据权利要求2至8中任一项使用的瑞巴派特或根据权利要求12的治疗组合,其中所述其他药物选自5-氨基水杨酸盐,优选选自柳氮磺吡啶和美沙拉秦;皮质类固醇,优选选自泼尼松、泼尼松龙、甲泼尼龙、氢化可的松和布地奈德;免疫抑制剂,优选选自硫代嘌呤、甲氨蝶呤、环孢菌素和他克莫司;抗生素,优选选自甲硝唑和环丙沙星;以及抗体,优选选自英夫利昔单抗、阿达木单抗、维多珠单抗及其生物类似物。
14.根据权利要求13使用的瑞巴派特或治疗组合,其中所述其他药物选自皮质类固醇、免疫抑制剂和抗体。
15.根据权利要求13或14使用的瑞巴派特或治疗组合,其中所述其他药物为皮质类固醇,优选20至60mg的泼尼松或等同剂量的另一种皮质类固醇。
16.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克罗恩病。
17.根据权利要求16使用的瑞巴派特,其中所述患有增加的肠通透性的人是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。
18.根据权利要求16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。
19.根据权利要求16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。
20.根据权利要求16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。
21.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、漱口水或漱口液。
22.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片剂。
23.根据权利要求21或22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,优选肠缓释释放或肠控制释放形式。
24.根据权利要求21或22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。
25.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600mg的日剂量施用。。
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