CN102361642A - 用升高的剂量的熊去氧胆酸治疗非酒精性脂肪性肝炎的方法 - Google Patents
用升高的剂量的熊去氧胆酸治疗非酒精性脂肪性肝炎的方法 Download PDFInfo
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Abstract
本发明涉及用于治疗非酒精性脂肪性肝炎(NASH)的方法,该方法通过向需要这些治疗的患者施用升高的剂量的熊去氧胆酸(UDCA)或其药学上可接受的盐,其中患者在治疗中显示显著地改进的血糖特征。
Description
本申请要求2009年3月17日提交的美国临时专利申请第61/160,955号的权益,其通过引用据此并入。
发明领域
本发明涉及通过向需要其的患者施用升高剂量的熊去氧胆酸(UDCA)治疗非酒精性脂肪性肝炎(NASH)的方法。
背景技术
肝是人体内最大的器官,位于右上腹部的上部。这一器官是高度复杂的和专门的,并且执行许多重要的生化功能。重要的肝功能包括从身体除去毒素和制造与能量储存和血液凝固相关的蛋白。肝也涉及储存矿物、维生素和糖原形式的葡萄糖,其以大的量被代谢以提供能量,并且也在血流中血红细胞代谢和某些代谢副产物的分解中起作用。
NASH是通常以纤维化为特征的慢性肝疾病的一种形式。NASH有时发展成肝硬化和肝细胞癌,并且在一些患者中可能需要肝移植。患有NASH的患者通常经受脂肪沉着、组织变性、炎症、细胞变性、肝硬化、游离脂肪酸的升高和其它这样的异常情况。NASH涉及肝中组织学变化的发展,其与受过量的酒精摄入但不存在酗酒诱导的那些相当。大泡性脂肪变性和/或小泡性脂肪变性、小叶和肝门炎症和有时具有纤维化和肝硬化的马洛里小体是NASH的特征。NASH也通常与高脂血症、高血糖症、肥胖症和II型糖尿病关联。肥胖症是最常见的生理学病况,其伴随NASH,约70%或更多的NASH患者显示临床诊断的肥胖症。NASH患者中肥胖症的程度一般与脂肪变性的量相关并与非胰岛素依赖性糖尿病无关。然而,非胰岛素依赖性糖尿病增加脂肪性肝炎的患病率,尤其是在需要胰岛素的患者中。死亡之前患者的体重减轻似乎不减轻脂肪变性并且有时反而在死亡之前体重减轻的肥胖患实际上可能具有更高的脂肪性肝炎发病率。疾病在30岁以下的任何患者中很少发生,但是在患者50多岁和60多岁时是特别普遍的。以脂肪性肝炎和炎症为特征的其它临床病况包括过度禁食、空肠改道术、全胃肠外营养、慢性肝炎C、Wilson疾病和不良药物影响如来自皮质激素、钙通道阻断剂、高剂量合成雌激素、甲氨蝶呤和胺碘酮的那些。
NASH的发病机制是未知的,但是脂肪变性程度与纤维化程度之间似乎存在关系。参见,例如,Wanless等人,Hepatology,12,1106(1990)。另外,NASH可能起因于许多不同基因和生活方式因素的相互作用。线粒体损伤、氧化应激和代谢失调都已经牵涉到脂肪性肝炎的致病。当存在时,疑似NASH的患者的最初评价是疲劳和右上腹部不舒服。肝肿大在百分之90的病例中见到。超声检查法目前是用于检测肝的脂肪浸润的最好方法。升高的肝细胞游离脂肪酸可以引起膜损伤与继发炎症,可能的胆汁淤积和亚细胞器功能障碍。细胞死亡和纤维化跟随持续的炎症,并且如果损伤继续,则肝硬化发生。脂肪性肝炎现在被认为是晚期肝疾病的重要原因并且可能是未知数目的隐源性肝硬化病例的原因。参见Powell等人,Hepatology,11,74(1990)。不幸地,在肝硬化确定之后,可获得的治疗性模式仅是原位肝移植。
NASH患者特有地具有正常至高水平的血清转氨酶,如天冬氨酸转氨酶(ASAT或AST)和丙氨酸转氨酶(ALAT或ALT)水平。在NASH患者中ASAT水平可以高于ALAT水平。在NASH患者中γ-谷氨酰转肽酶(γ-GT)水平也通常升高。
因为与NASH-关联的疾病(例如,肥胖症和II型糖尿病)的患病率在增长,NASH的患病率也预期增长。因此,这一疾病已经成为美国以及其它国家新出现的公共问题。目前,对于NASH不存在证实的治疗。因为这一疾病通常影响肥胖患者或患有代谢疾病或糖尿病的患者,对体重控制和糖尿病的治疗已经被用于尝试治疗NASH并且已经在改进肝病况中显示一些短期的功效。然而,这些治疗不是没有与它们的使用关联的副作用或困难。因此,对于具有优良的安全特征的药理学治疗仍存在未满足的需求,该治疗提供长期肝保护性治疗。
UDCA(也称为熊去氧胆酸)是天然存在的亲水性胆汁酸。UDCA小量存在于人胆汁中,并且大量存在于某些种类的熊中。其是苦味的白色粉末,包含实际上不溶于水但更溶于肠液的晶体颗粒。UDCA易溶解于乙醇和冰乙酸,微溶于氯仿,略溶于乙醚并特别不溶于水。UDCA在商业上在商标URSO和URSO下销售用于患有原发性胆肝硬化的患者的治疗。UDCA在商业上也在商标下销售用于患有胆囊结石的患者或用于在经历快速体重减轻的肥胖患者中预防胆囊结石形成。
已知UDCA的肝保护特征(抗凋亡、抗氧化、细胞膜的稳定剂)和免疫调节特征。已经证明UDCA在某些慢性肝疾病中是有效的,其中其显示改进肝功能(Festi等人,Curr Clin Pharmacol 2(2):155-77(May 2007)),并且显示产生疏水性的和可能地毒性的胆酸的减少(Angulo,CurGastroenterol Rep 4(l):37-44(2002年2月))。
在接受一年的13-15mg/kg/天的UDCA治疗的NASH患者的小的试点研究中,发现UDCA改进肝酶和脂肪变性水平,但不改变纤维化或炎症(Laurin等人,Hepatology 23(6):1464-67(1996年6月))。在另一研究中,在患有NASH的患者中以随机的安慰剂对照的试验评价13-15mg/kg/天UDCA治疗的两年的功效。Lindor等人,Hepatology 39(3):770-78(2004年3月)。Lindor研究未显示UDCA治疗组与安慰剂组之间的任何差异。最近,Georgescu和Georgescu,J Gastrointestin Liver Dis 16(l):39-46(2007年3月)的开放性研究评估己酮可可碱、氯沙坦、阿托伐他汀和UDCA在NASH患者中的功效并发现15mg/kg/天的UDCA治疗组显示ALAT和γ-GT水平的显著的降低,但是在脂肪变性、炎症坏死或纤维化方面无改进。所有上面提到的研究以13-15mg/kg/天的剂量进行,并且它们中无一确定UDCA为对NASH的适当的有效的治疗。
已经报道:剂量应答与在患有原发性胆肝硬化(van Hoogstraten等人,Aliment Pharmacol Ther12(19):965-71(1998年10月))、原发性硬化性胆管炎(PSC)(Harnois等人,Am J Gastroenterol 96(5):1558-62(2001年5月);Mitchell等人,Gastroenterology 121(4):900-07(2001年10月))和良心肝内妊娠胆汁淤积(Mazzella等人,Hepatology 33(3):504-08(Mar 2001))以及胆囊纤维化(van de Meeberg等人,Scand J Gastroenterol 32(4):369-73(Apr 1997))的患者中的UDCA存在关系。然而,进行评估UDCA对患者结局和存活率的影响的在成人PSC患者中28-30mg/kg/天的UDCA的更新完成的研究断定,UDCA可能与严重的不良事件的更高的发生率和较差的总结局相关,其可能因此优于在PSC中用UDCA获得的生物学改进。
在这一研究中,患有PSC的成人患者登记了在七个不同的美国药物中心的28-30mg/kg/天的UDCA对安慰剂的随机双盲对照试验。更特定地,150位PSC成人患者在2002年和2005年被登记并且用UDCA或安慰剂治疗达6年。在治疗前和在第5年患者进行肝脏活组织检查和胆管造影术。每3个月进行常规肝试验。患者每年被评估,并且在第2年和第5年进行内窥镜检查。主要结局指标是肝功能代偿不全、胆管癌、肝移植或死亡的发展。
由于无用和对不良影响的考虑在数据安全和监测委员会的推荐之后终止研究。在登记时,UDCA(n=76)和安慰剂(n=74)组在性别、年龄、疾病持续时间、血清ASAT和碱性磷酸酶(AP)水平、肝组织和Mayo风险评分方面是相似的。在治疗期间,ASAT和AP水平下降;对于UDCA组下降的量比安慰剂组更大(p<0.01)。在研究结束时,UDCA中的28位患者(37%)对安慰剂中的仅17位患者(23%)到达预确立的临床终末点之一。当为基线分层特征调整之后(Mayo风险评分,胃食管血管曲张的存在和组织学阶段),主要的终末点的风险(即,死亡、肝移植、用于肝移植的最低列表标准、肝硬化、食管和/或胃静脉曲张或胆管癌)对于UDCA患者比对于安慰剂患者大2.2倍(p=0.011);对于死亡或移植,调节的相关风险是3.3(p=0.029)。到达主要终末点的风险不被年龄差异、性别或大肠炎的存在修改。严重的不良事件在UDCA中比安慰剂处理组中更普遍(61%vs.43%:p=0.03)。基线Mayo风险评分与较差的结局强烈相关,因为起始活组织检查上肝硬化的存在,但是这些影响在治疗组之间无不同。
这一研究的结论是:28-30mg/kg/天的UDCA治疗与PSC中血清肝试验中的改进相关联,但是长期治疗不改进存活率,并且可能相反与更高比率的严重不良事件和较差的结局关联。
本发明为NASH患者提供新的治疗方案。
发明概述
本发明涉及一种用于治疗NASH的方法,其通过向需要其的受治疗者施用每天每kg体重约28-35mg的剂量的熊去氧胆酸(UDCA)或其药学上可接受的盐。在一种实施方式中,与治疗前水平相比,该方法降低患者的纤维化水平和/或肝炎水平。在另一实施方式中,患者的血糖指数在治疗期间基本上是稳定的。适合的治疗期间可以包括3个月、6个月、9个月、12个月、2年、3年、4年、5年等以及更长。在一种实施方式中,患者还患有II型糖尿病。在另一种实施方式中,该方法进一步包括施用抗糖尿病药物如噻唑烷二酮。
附图简述:
图1是显示如实施例2中所描述接受30mg/kg/天的UDCA持续一年的NASH患者中平均ALAT水平(IU/L)对时间的图。
图2是显示如实施例2中所描述接受30mg/kg/天的UDCA持续一年的NASH患者中ALAT水平的平均变化对基线的图。
图3是显示如实施例2中所描述接受30mg/kg/天的UDCA持续一年的NASH患者中平均ASAT水平(IU/L)对时间的图。
图4是显示如实施例2中所描述接受30mg/kg/天的UDCA持续一年的NASH患者中ASAT水平的平均变化对基线的图。
图5是显示如实施例2中所描述接受30mg/kg/天的UDCA持续一年的NASH患者中平均γ-GT水平(IU/L)对时间的图。
图6是显示如实施例2中所描述接受30mg/kg/天的UDCA持续一年的NASH患者中γ-GT水平的平均变化对基线的图。
发明详述
本发明提供通过施用28-35mg/kg/天的UDCA治疗NASH的方法。这一方法对患者提供显著的益处,包括例如,转氨酶水平的降低(例如,ALAT和ASAT),γ-GT水平的降低,减少的纤维化和减少的炎症。另外地,28-35mg/kg/天的UDCA向通过这一方法治疗的NASH患者提供显著地改进的血糖指数。具体地,根据本发明用28-35mg/kg/天的UDCA治疗的NASH患者经历稳定水平的血糖过多、胰岛素血症和HbAlc,而用安慰剂处理的NASH患者随着时间流逝具有升高的水平的血糖过多、胰岛素血症和HbAlc。这是本发明的令人惊奇的和非常有益的效果。
UDCA的化学名称是3α,7β-二羟基-5β-胆甾烷-24-酸)。UDCA具有以下分子结构:
根据本发明,UDCA可以其酸的形式或作为其药学上可接受的盐单独被施用。提供的所有重量基于游离酸的等同重量,除非另外说明。本发明还包括药物制剂,其以单个或多个剂量合并UDCA或其药学上可接受的盐与一种或多种药学上可接受的载体、赋形剂、稀释剂和/或添加剂。这些药学制剂可以根据本领域技术人员已知的常规方法制备。
在本发明中,UDCA的典型剂量在约28-35mg/kg体重每天(mg/kg/天),优选地约28-30mg/kg/天,更优选地约30mg/kg/天的范围内。剂量可以作为单一剂量被施用或可以分成一个或多个剂量,如每天2至6个剂量,和优选地每天2至4个剂量。优选地,UDCA的剂量每天在早晨和在晚上被施用。准确的剂量将取决于施用频率和模式,治疗的受治疗者的性别、年龄、体重和一般状况,治疗的病况的性质和严重性,同时被治疗的任何夹杂症的存在和本领域技术人员了解的其它因素。优选地,UDCA剂量随食物一起施用。
本发明的药物组合物可以被配制以包括其它活性成分,例如,营养补充剂如维生素E,抗糖尿病药物如磺脲类(例如,甲苯磺丁脲、醋酸己脲、妥拉磺脲、氯磺丙脲、格列吡嗪、格列苯脲、格列美脲和格列齐特),氯茴苯酸类(例如,瑞格列奈和那格列奈),双胍(例如,二甲双胍),α-葡糖苷酶抑制剂(例如,米格列醇和阿卡波糖),胰高血糖素类肽(GLP)类似物和激动剂(例如,GLP-1、艾塞那肽、exendin-4和利拉鲁肽),DPP-4抑制剂(例如,维格列汀和西他列汀),糊精类似物,PPARα和/或γ配体(例如,阿格列扎),钠依赖性葡萄糖载体1(SGLT-1)抑制剂,果糖1,6-双磷酸酯(FBP酶)抑制剂,噻唑烷二酮(包括罗格列酮、比格列酮、曲格列酮和其它格列酮类),胰岛素和其它治疗剂。适合的药学上可接受的载体、赋形剂、稀释剂和/或添加剂包括,例如,媒介物、填充剂、溶剂、稀释剂、表面活性剂、着色剂、防腐剂、崩解剂、助流剂、润滑剂、芳香剂、粘合剂和湿润剂。
本发明的药物组合物可以通过任何适合的途径施用,所述途径如口服、直肠、鼻、肺、局部(包括面颊和舌下)、经皮、脑池内、腹膜内、阴道和肠胃外(包括皮下、肌内、膜内、静脉内和皮内)途径,口服途径是优选的。优选的途径将取决于受治疗者的一般状况和年龄,以及治疗的病况的性质。
本发明的药物组合物可以被配制用于以固体剂型如胶囊、片剂、粉末和颗粒和以液体剂型如溶液、乳液、悬浮液、糖浆和酏剂被口服施用。如果合适,根据本领域熟知的方法,固体剂型可以制备有包衣如肠溶包衣,或可以其它方式被配制以提供活性成分的控制释放或持续释放。
实施例
本发明随后通过以下实施例被描述。这些和本说明书任何地方的其它实施例的使用仅是说明性的,并且绝非限制本发明或任何示例的形式的范围和含义。同样,本发明不限于本文描述的任何具体的优选的实施方式。事实上,在阅读本说明书之后,本发明的改进和变型对于本领域的技术人员是明显的,并且可以被作出而不偏离其精神和范围。因此本发明仅受权利要求的范围,以及与权利要求的范围等同的全部范围所限定。
实施例1:UDCA制剂
本发明的药物组合物的实施例包含250mg UDCA(或500mg UDCA)联合以下无活性的成分:微晶纤维素、聚维酮、羟基乙酸淀粉钠、硬脂酸镁、乙基纤维素、癸二酸二丁酯、加拿巴蜡、羟丙基甲基纤维素、PEG 3350、PEG 8000、鲸蜡醇、十二烷基硫酸钠和过氧化氢。这一药物组合物可以被配制为用于口服施用的膜包衣的片剂。
实施例2:28-35mg/kg/天的UDCA用于治疗NASH的临床研究
进行多中心随机双盲安慰剂对照的研究以检测28-35mg/kg/天的UDCA在患有组织学上证实的NASH且ALAT和/或ASAT大于50IU/L的患者中的功效和耐受性。共120位患者计划接受UDCA或安慰剂持续12个月的时间。治疗随膳食一起施用。在研究中,定期监测肝生物化学、耐受性和副作用。在研究中,鼓励过重和肥胖患者通过低热量饮食之后减肥并维持一定水平的体力活性。允许患者采取用于关联的医学病况的药物治疗。在12个月末期,患者经历研究评价的结束并且研究治疗被停止。
研究人群:
入选标准:患者年龄大于18岁;与NASH相容的肝脏活组织检查:在刚过去的18个月中与肝细胞气胀(ballooning)和/或肝小叶坏死关联的脂肪变性>20%的存在;在筛选就诊中ALAT或ASAT水平>50IU/L(在刚过去的12个月中有至少3个升高的转氨酶水平);
淘汰标准:在刚过去的18个月之前进行过肝脏活组织检查;在刚过去的12个月中转氨酶不多于一个正常值;在刚过去的12个月中患者受UDCA治疗;在肝脏活组织检查和筛选的时间之间多于15%的体重减轻;酒精消耗对于女性高于20g/天或对于男性高于30g/天;存在其它肝炎原因如慢性乙肝或慢性丙肝,与C282Y突变的纯合性关联的增加的血清铁蛋白,原发性胆肝硬化,原发性硬化性胆管炎,明确证明的自身免疫性肝炎(特异性自身抗体、高γ球蛋白血、组织学相容的),α-1抗胰蛋白酶不足,Wilson疾病,HIV感染;NASH的继发性原因:长期的胺碘酮-诱导的NASH,皮质素治疗(corticotherapy),过去2年内肥胖症手术;治疗;儿童B或儿童C级肝硬化;肝癌的存在;用罗格列酮或比格列酮目前治疗的或在过去三年中治疗的肝脏活组织检查;在筛选之前的六个月内用维生素E的治疗;妊娠或哺乳期女性;中心实验室无法读取组织切片。
中止标准:受治疗者在任何时间因为任何原因或无原因自由中止研究,并且对进一步的治疗不存偏见。在预研究评价之后但在接受任何研究药物治疗之前退出的患者不被认为中途推出,并且不被包括在数据库中。被包括在研究中并接受至少一个剂量的研究药物治疗的患者被包括在数据库中并被认为是安全人群的一部分。被包括在研究中并接受一个剂量的研究药物治疗并且对于其至少一种基线后评价是可获得的患者,作为意图治疗(ITT)人群的一部分分析。来自ITT人群的完成研究而无任何大的方案违规的患者作为按实验设计(PP)人群的一部分分析。
中途退出可能因为以下原因发生,尤其是:患者被包括在选择/淘汰标准的违规中;患者因为个人原因(离开、没时间等)选择中止参与;发起人在不良事件之后中止患者;因为严重的方案违规,研究者或发起者中止患者;在研究中患者使用禁用的药物治疗;患者发展即时医学病况或需要手术过程,该过程可能危及患者的继续参与,并中断研究。
在以下事例中研究治疗将被中止:肝转氨酶高于研究前水平5倍的增加(除了在很少的代偿失调的肝硬化病例中,未报道与UDCA关联的肝毒性。NASH中肝转氨酶通常存在起伏,并且相对于研究前水平仅5倍增加而非3倍增加将要求停止研究药物治疗);表皮过敏反应的发生。
主要终末点:主要终末点是12个月时ALAT对基线的百分比变化。次要终末点包括:在12个月时ASAT对基线的百分比变化;在12个月时γ-GT对基线的百分比变化;在12个月时标准化的ALAT的百分比pts;在12个月时标准化的ASAT的百分比pts;纤维化指数的变化(FibroTest);炎症指数的变化(Actitest);代谢综合征标志物的变化;和安全性。
FibroTest是非侵入性血液试验,其提供肝纤维化的定量评估并可以被用于预测晚期的纤维化。ActiTest是非侵入性血液试验,其通过测定坏死和炎症的程度被用于评估肝病的活动。
患者人口统计学概括在表1中。
表1
UDCA | 安慰剂 | ||
N | 62 | 64 | |
平均年龄(SD) | 岁 | 49.8(10.2) | 49.6(12.6) |
性别 | 男 | 75.8% | 75.0% |
平均身高(SD) | cm | 170.5(9.5) | 172.3(9.1) |
平均体重(SD) | kg | 89.5(14.8) | 91.8(17.1) |
吸烟 | 是 | 21.0% | 10.9% |
代谢综合征标志物概括在表2中。
表2
UDCA | 安慰剂 | ||
N | 62 | 64 | |
非胰岛素依赖性糖尿病 | 是 | 24(39%) | 16(25%) |
高动脉压 | 是 | 30(48%) | 20(31%) |
血脂障碍 | 是 | 36(58%) | 32(52%) |
血胆固醇过多 | 是 | 26(42%) | 28(44%) |
高甘油三酯症 | 是 | 24(39%) | 19(30%) |
治疗:UDCA以30mg/kg/天的剂量被提供,以两个分剂量随膳食服用——一次在早晨和一次在晚上。安慰剂片(赋形剂,不含活性化合物)被制备以具有与UDCA片剂相似的外观以保证双盲。安慰剂片也像UDCA片剂以相同的分剂量服用。
方法——分配患者至治疗组,选择剂量,并选择用于每位患者的剂量的时间:患者以1∶1(活性∶安慰剂)的比例被随机分配。安慰剂的使用是为了保证试验的双盲性。不存在推测的计划的分层。随机分成四组(两组用于UDCA和两组用于安慰剂)。如按其标签,药物必需以2-4个分剂量同食物一起施用。在本研究中,使用的剂量是30mg/kg/天,并且对于每个患者剂量取决于患者体重。
功效和安全性:功效评价包括血清转氨酶水平以及血清纤维化标志物的测定。具有升高的水平的血清转氨酶和具有指示NASH的肝脏活组织检查的患者(与肝气胀和/或小叶坏死关联的>20%的脂肪变性(Brunt等人,Am J Gastroenterol 94(9):2467-74(Sep 1999))对于研究是适宜的。肝脏活组织检查应当在具有稳定的代谢状况(无最近的体重减轻,无用二甲双胍、磺胺类或胰岛素的最近的(在过去的6个月内)抗糖尿病治疗)的患者中定于小于18个月。肝脏活组织检查的四个原始切片和/或六个空白切片(即,无色的)由病理学家观察。为了切片的均匀集中读取,后者通过苏木精-曙红染色、Hemahin Sirius Red染色和Perls染色着色用于确定组织学入围标准。仅在征得同意签字和确定的组织学之后进行血液试验。
通过测定载脂蛋白Al、总胆红素、γ-GT、α-2微球蛋白、结合球蛋白和ALAT的血清水平以及计算FibroTest和ActiTest评分,进行肝纤维化的非侵入性测定。还根据Laine等人,Hepatology 39(6):1639-46(2004年6月)进行透明质酸、糖缺失性运铁蛋白(CDT)和运铁蛋白的测定。使用简化的稳态模式评估法(HOMA-IR)在生物学方面测定胰岛素耐性,其考虑葡萄糖水平和空腹血糖。胰岛素耐性的临床评价基于腰围测定(原因在于其与内脏肥胖关联)并基于体重指数的计算:(BMI)=体重(kg)/身高(m2)。
结果:参见表3-7。
表3:12个月的平均变化对基线(所有受治疗者)
UDCA | 安慰剂 | p | |
ITT | n=62 | n=64 | |
Δ%血糖过多(SD) | -1%(21) | +11%(24) | p=0.023 |
Δ%胰岛素血症(SD) | -5%(59) | +204%(1357) | p=0.038 |
Δ%HbAlc(SD) | -1%(10) | +8%(15) | p<0.05 |
Δ%HDL(SD) | -1.4%(20) | -1.4%(16) | p=0.944 |
Δ%LDL(SD) | -6.2%(26) | -1%(18) | p=0.285 |
Δ%总胆固醇(SD) | -4.1%(19) | -0.6%(11) | p<0.336 |
Δ%甘油三酯(SD) | +5.6%(37) | +13.3%(41) | p<0.294 |
对血糖(代谢综合征)的影响:安慰剂组中血糖过多增加,而UDCA治疗组中保持稳定。这是统计学显著的差异(p=0.023)。在12个月UDCA治疗组中胰岛素血症降低(p=0.038)。在6和12个月UDCA治疗组中HbAlc降低(p=0.05)。
表4:在12个月时平均变化对基线
ITT | UDCA | 安慰剂 | |
n=62 | n=64 | ||
Δ%ALAT(SD) | -28%(55) | -2%(35) | p<0.001 |
Δ%ASAT(SD) | -8%(59) | +9%(37) | p<0.001 |
Δ%γ-GT(SD) | -51%(28) | +19%(48) | p<0.001 |
标准化ALAT | 25% | 5% | p=0.003 |
标准化ASAT | 32% | 23% | p=0.253 |
PPP | UDCA | 安慰剂 | |
n=62 | n=64 | ||
Δ%ALAT(SD) | -23%(59) | +0.8%(37) | P<0.001 |
Δ%ASAT(SD) | -3%(63) | +11%(39) | P=0.007 |
Δ%γ-GT(SD) | -49%(29) | +19%(48) | P<0.001 |
标准化ALAT | 29% | 6% | P=0.004 |
标准化ASAT | 36% | 18% | P=0.048 |
对肝酶的影响:距基线ALAT的百分比变化在3、6和9个月是显著的,最大影响在3个月时被观察到。距基线ASAT的百分比变化在3、6、9和12个月是显著的,最大影响在3个月时被观察到。距γ-GT基线的百分比变化在6和9个月是显著的,最大影响在6个月时被观察到。
表5:对纤维化的个体影响
表6:FibroTest(对纤维化的影响)变化对基线
如表6中所示,与安慰剂组中患者相比,UDCA治疗组中的患者(ITT和PP人群)显示纤维化水平的显著的改进。
表7:ActiTest(对肝炎症的影响)变化对基线
如表7中所示,与安慰剂组中患者相比,UDCA治疗组中的患者(ITT和PP人群)显示肝炎症水平的显著的改进。
安全性结果:UDCA治疗组中GI症状(腹泻、腹痛、蠕动问题)比安慰剂组中更频繁(~3x)。在进入UDCA治疗组时RUQ疼痛和无力比安慰剂组更普遍(~2x),但是该差异在第3个月消失。
总结:在研究中共126位患者(64位安慰剂和62位UDCA)被登记(ITT人群)。有75%男性,平均年龄(±SD)是49.7+11.5岁且BMI(±SD)是30.9±5.1kg/m2。代谢综合征、高血压和II型糖尿病分别在40%、32%和35%的患者中存在。12个月之后,UDCA治疗组中ALAT下降(平均±SD)-28±55%,分别相比于安慰剂组中下降-2±35%(p=0.003)。UDCA治疗组中血清ASAT和γ-GT水平的平均(±SD)下降分别是-8±59%和-51±28%;相比于安慰剂组这些因子分别增加+9±37%(p<0.001)和+19±48%(p<0.001)。所有结果在PP人群中被确认。报道在基线处无力和右上象限疼痛(RUQP)在UDCA治疗组中比在安慰剂组中更频繁。这一差异在治疗过程中很早地消失(3个月)。报道了胰岛素耐性、纤维化、炎症和细胞凋亡的血清标志物的变化。UDCA治疗组经历比安慰剂组更温和的腹泻、腹痛和胃肠道蠕动障碍。
结论:这一随机的、对照试验显示在NASH患者中对28-35mg/kg/天的UDCA治疗的显著的和明显的生化应答,并表明无力和RUQP的症状的改善,而无任何显著的安全性忧虑。
本说明书中引用和/或讨论的所有文献通过引用以其全部并入本文并且其程度如同每份文献被个体地通过引用并入。
Claims (12)
1.一种治疗非酒精性脂肪性肝炎(NASH)的方法,包括向需要其的受治疗者施用每天每kg体重约28-35mg的剂量的熊去氧胆酸(UDCA)或其药学上可接受的盐,
其中与治疗前水平相比所述方法降低患者的纤维化水平和/或肝炎水平。
2.根据权利要求1所述的方法,其中所述剂量是约28-30mg/kg/天。
3.根据权利要求1所述的方法,其中所述剂量以单次日剂量被施用。
4.根据权利要求1所述的方法,其中所述剂量以每天2-4个分剂量被施用。
5.根据权利要求1所述的方法,其中所述患者的血糖指数在治疗期间基本上保持稳定。
6.根据权利要求1所述的方法,其中所述治疗被提供持续至少6个月的时间。
7.根据权利要求6所述的方法,其中所述治疗被提供持续至少12个月的时间。
8.根据权利要求1-7中任一项所述的方法,其中所述UDCA与食物一起施用。
9.根据权利要求1-8中任一项所述的方法,其中所述UDCA每日在早晨和晚上被施用。
10.根据权利要求1-9中任一项所述的方法,其中所述患者患有II型糖尿病。
11.根据权利要求1-10中任一项所述的方法,还包括施用抗糖尿病药物。
12.根据权利要求11所述的方法,其中所述抗糖尿病药物是噻唑烷二酮。
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CN116782898A (zh) * | 2020-10-23 | 2023-09-19 | 深圳君圣泰生物技术有限公司 | 小檗碱熊去氧胆酸盐的组合物及其用于治疗脂肪性肝病、糖尿病和高脂血症的方法 |
US12274718B2 (en) | 2019-07-30 | 2025-04-15 | Kobiolabs, Inc. | Composition and method for preventing, alleviating, or treating liver injury |
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- 2010-03-16 MX MX2011009757A patent/MX2011009757A/es not_active Application Discontinuation
- 2010-03-16 CN CN2010800119928A patent/CN102361642A/zh active Pending
- 2010-03-16 KR KR1020117024296A patent/KR20120008034A/ko not_active Withdrawn
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CN114245743A (zh) * | 2019-07-30 | 2022-03-25 | Ko生物技术有限公司 | 预防、缓解或治疗肝损伤的组合物和方法 |
CN114245743B (zh) * | 2019-07-30 | 2023-12-08 | Ko生物技术有限公司 | 预防、缓解或治疗肝损伤的组合物和方法 |
US12274718B2 (en) | 2019-07-30 | 2025-04-15 | Kobiolabs, Inc. | Composition and method for preventing, alleviating, or treating liver injury |
CN115038459A (zh) * | 2020-01-28 | 2022-09-09 | 希尔帕医疗保健有限公司 | 熊去氧胆酸的给药方法 |
CN116782898A (zh) * | 2020-10-23 | 2023-09-19 | 深圳君圣泰生物技术有限公司 | 小檗碱熊去氧胆酸盐的组合物及其用于治疗脂肪性肝病、糖尿病和高脂血症的方法 |
Also Published As
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US20120071451A1 (en) | 2012-03-22 |
ZA201107578B (en) | 2013-06-26 |
WO2010106420A1 (en) | 2010-09-23 |
KR20120008034A (ko) | 2012-01-25 |
EP2408457A1 (en) | 2012-01-25 |
RU2011139643A (ru) | 2013-04-27 |
MX2011009757A (es) | 2012-02-28 |
IL215195A0 (en) | 2011-12-29 |
AU2010224587A1 (en) | 2011-09-22 |
CA2755708A1 (en) | 2010-09-23 |
JP2012520866A (ja) | 2012-09-10 |
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