CN111936148A - 用于非酒精性脂肪肝病的乳糖醇及口服药物剂型 - Google Patents
用于非酒精性脂肪肝病的乳糖醇及口服药物剂型 Download PDFInfo
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- CN111936148A CN111936148A CN201980023588.3A CN201980023588A CN111936148A CN 111936148 A CN111936148 A CN 111936148A CN 201980023588 A CN201980023588 A CN 201980023588A CN 111936148 A CN111936148 A CN 111936148A
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Abstract
本发明涉及药物领域,具体地涉及治疗有效量,优选1‑20g/天的剂量的乳糖醇用于在有此需要的哺乳动物中治疗和预防非酒精性脂肪肝病的用途。本发明提供了在涉及非酒精性脂肪肝病的治疗和预防上有效的手段的范围扩展。
Description
本发明涉及药物领域,并且更具体地,涉及用于治疗和预防非酒精性脂肪肝病的药剂。
脂肪肝病或非酒精性脂肪肝病-NAFLD(肝脂肪变性、脂肪浸润、肝的脂肪变性)是一种病症,其中多于5%的肝质量是脂肪,主要是甘油三酯类。如果脂肪含量超过该器官重量的10%,则多于50%的肝细胞包含脂肪,并且脂肪堆积分布遍及整个肝组织。
脂肪肝病的起因是代谢综合征–代谢紊乱和激素改变。在这种情况下,糖尿病和血液中升高水平的脂质伴随形成心血管并发症的威胁发展。
肝细胞的脂肪变性可能由以下引起:
-酒精滥用;
-肥胖症;
-一些病毒感染(乙型和丙型肝炎病毒);
-营养失调;
-糖尿病代谢紊乱;
-肝酶(ALT、AST、GGT)升高;
-尿素循环的遗传性缺陷和脂肪酸的氧化;
-遗传因素;
-某些药物,例如,非甾体抗炎药。
NAFLD基于胰岛素抵抗(胰岛素的细胞免疫)和代谢紊乱,主要是脂质和碳水化合物代谢紊乱。由于在进食或在增加的脂解(脂肪组织中的脂肪分解)的条件下肝中增加的脂肪酸摄入而发生肝脂肪变性。
NAFLD是暴露于以下风险因素组合的多因素疾病:
-腹型肥胖症(男性腰围-大于94cm,以及女性腰围-大于80cm);
-酒精和有害食物滥用;
-作为血液中高水平脂质、血液中甘油三酯类增加至高于1.7mmol/L的水平、胆固醇水平升高以及高密度脂蛋白水平降低的结果的动脉粥样硬化;
-血压升高至高于130/85mm Hg的水平;
-糖耐量减低、延长高血糖症(2型糖尿病);
-胰岛素抵抗;
-从事有毒物质作业;
-服用多种药物;
-胃肠道手术后;
-患有一些遗传性质的慢性病。
NAFLD包括以下发展阶段:
1)肝脂肪变性-脂肪夹杂物堆积在肝实质细胞中;
2)非酒精性脂肪性肝炎-大量脂肪夹杂物变高;
3)纤维化-过多的脂肪夹杂物破坏肝细胞,并且形成了促进用纤维性组织替代肝组织的脂肪囊肿;
4)作为NAFLD结局的肝硬化,具有发展肝细胞癌的增加的风险。
它出现在以下阶段:
-肝实质细胞脂肪变性-肝细胞没有被损坏,器官的功能实际上没有受损;
-肝实质细胞渐进性坏死-由于脂肪堆积、细胞死亡、囊肿形成、间充质细胞反应发生;
-肝硬化前阶段-器官的结缔组织被间充质组织替代;
-肝硬化阶段。
非酒精性脂肪肝病(NAFLD)是全世界最广泛的肝病之一。因此,根据流行病学研究,全世界10-40%的人口患有NAFLD(Buyeverov A.O.:Chronic liver diseases:a briefguide for practitioners.2nd ed.—M.:Medical News Agency,2014,137p.;Fattyliver degeneration and ischemic heart disease.Geriatric aspects:Monograph/ed.Khoroshinina L.P.,M.,Concept Design LLC,2014,346p.;Mehtiyev S.N.et al.:Non-alcoholic fatty liver disease in questions and answers(etiology,modernconcept of pathogenesis,clinical features,principles of diagnosis andtreatment)/Textbook.-SPb.,2011,53p.Trukhan D.I.:Non-alcoholic fatty liverdisease in the practice of a"first contact"physician/Clinical prospects ofgastroenterology,hepatology,2012,N.1,pp.3-9)。有时,NAFLD是代谢综合征中的第一个器官损伤,而且是糖尿病或心血管疾病发展和进展的重要预测因子(Fatty liverdegeneration and ischemic heart disease.Geriatric aspects.Monograph/ed.Khoroshinina L.P.,M.:Concept Design LLC,2014,346p.;Azizov V.A.et al.:Non-alcoholic fatty liver disease and cardiovascular complications:what is therelationship?/Eurasian Journal of Cardiology,2013,N.1,pp.63-69;Schiff,Yu.R.etal.Alcoholic,medicinal,genetic and metabolic diseases/trans.from English;ed.by Mukhin N.A.et al.,M.,GEOTAR-Media,2011,480p.)。一般来说,脂肪病会在40-60岁之间发展,而女性则更经常遭受。该病还影响儿童。在指数(体重(千克)除以身高的平方(平方米))为30的超重的情况下,脂肪肝病的概率为40%。
NAFLD结合了一连串的肝损伤,包括肝脂肪变性、非酒精性脂肪性肝炎(NASH)、脂肪纤维化和脂肪肝硬化(Fatty liver degeneration and ischemic heartdisease.Geriatric aspects.Monograph/ed.Khoroshinina L.P.,M.,Concept DesignLLC,2014,346p.;Trukhan D.I.Non-alcoholic fatty liver disease in the practiceof a"first contact"physician/Clinical prospects of gastroenterology,hepatology,2012,N.1,pp.3-9;Schiff Yu.R.et al.Alcoholic,medicinal,genetic andmetabolic diseases/trans.from English;ed.by Mukhin N.A.et al.,M.,GEOTAR-Media,2011,480p.;Korneeva E.V.et al.Pathophysiology of metabolic syndrome/Monograph,M.,"Higher Education and Science"Publishing House,2012,136p.)。已知NASH是代谢综合征的一种共病状态,事实上,它是这种病理的肝表现(Fatty liverdegeneration and ischemic heart disease.Geriatric aspects.Monograph/ed.Khoroshinina L.P.,M.,Concept Design LLC,2014,346p.;Korneeva E.V.etal.Pathophysiology of metabolic syndrome/Monograph.-M.,"Higher Education andScience"Publishing House,2012,136p.;Stelmakh V.V.et al.Energotropicpathogenetically oriented therapy with succinate-containing drugs in non-alcoholic fatty liver disease:Methodological recommendations,SPb.,TacticStudio,2014,40p.)。具有代谢综合征的NASH的发展涉及37.5%的病例(Arapkina O.M.:Non-alcoholic fatty liver disease–metabolic syndrome/Medical Almanac,2010,N.1,pp.162-163)。具有肥胖症的NASH发生占20-47%的病例,具有2型糖尿病的占15%的病例,具有血脂异常的占20-80%的病例。已知在忽视和不治疗的情况下,在5-25%的病例中,NASH会随着门静脉高压、肝细胞衰竭和肝细胞癌的发展而进展为肝硬化的结局(Fattyliver degeneration and ischemic heart disease.Geriatric aspects.Monograph/ed.Khoroshinina L.P.,M.,Concept Design LLC,2014,346p.;Schiff Yu.R.etal.Alcoholic,medicinal,genetic and metabolic diseases/trans.from English;ed.by Mukhin N.A.et al.,M.,GEOTAR-Media,2011,480p.;Shaposhnikov A.V.Hepatooncoprevention.Concept and principles of implementation/Manual for physicians,M.,Forte print,2013,80p.)。
NASH尤其涉及致动脉粥样硬化血脂异常的表现和加重(Fatty liverdegeneration and ischemic heart disease.Geriatric aspects.Monograph/ed.Khoroshinina L.P.,M.,Concept Design LLC,2014,346p.;Schiff Yu.R.etal.Alcoholic,medicinal,genetic and metabolic diseases/trans.from English;ed.by Mukhin N.A.et al.,M.,GEOTAR-Media,2011,480p.;Drapkina O.M.et al.:Atherogenic dyslipidemia and the liver/Medical alphabet,2012,V.4,N.24,pp.30-35),这增加了缺血性心脏病(IHD)以及与这种病理学相关联的并发症-急性心肌梗死(AMI)和急性脑血管意外(中风)(ACVA)发展的可能性(Fatty liver degeneration andischemic heart disease.Geriatric aspects.Monograph/ed.Khoroshinina L.P.,M.,Concept Design LLC,2014,346p.;Azizov V.A.et al.:Non-alcoholic fatty liverdisease and cardiovascular complications:what is the relationship?/EurasianJournal of Cardiology,2013,N.1,pp.63-69)。NASH在碳水化合物代谢紊乱的进展中也非常重要(Fatty liver degeneration andischemic heart disease.Geriatricaspects.Monograph/ed.Khoroshinina L.P.,M.,Concept Design LLC,2014,346p.;Schiff Yu.R.et al.Alcoholic,medicinal,genetic and metabolic diseases/trans.from English;ed.by Mukhin N.A.et al.,M.,GEOTAR-Media,2011,480p.)。慢性高血糖症类似地引起心血管疾病的高风险。
从生物学的观点来看,NASH是由所谓的“多重平行命中(multiple parallelhits)”假说来解释的,根据该假说,NAFLD的发病机制是以下因素相互作用的模型:诸如胰岛素抵抗、脂质过氧化过程的激活、促炎性细胞因子诸如TNF-α、IL-6、IL-8等的持续产生以及通过脂肪组织产生以下所谓的脂肪细胞因子:瘦素、抵抗素、脂联素(Buyeverov A.O.:Chronic liver diseases:a brief guide for practitioners.2nd ed.,M.:MedicalNews Agency,2014,137p.)。
非酒精性脂肪肝病(NAFLD)的关键来源是胰岛素抵抗和氧化应激。由于胰岛素抵抗的情况,以及因此,发生人体无法使用葡萄糖作为能量来源,这通过激活脂解以及通过从周围组织中提取脂肪酸来补偿。大量的游离脂肪酸(FFA)进入肝,这导致肝实质的脂肪负荷以及脂肪变性的形成。
通常,NAFLD逐渐进展并且是危险的,因为其可能发展为硬化。据推测,在接下来的20-30年脂肪肝病将成为肝硬化需要移植的最常见起因("Transplantation of theliver",National Clinical Recommendations,2013,42pp.)。
肝实质细胞是肝的主要功能细胞,并且每个肝细胞的直径为15-30微米。人肝脏中约有2500亿个肝实质细胞。肝实质细胞的关键损伤导致细胞坏死。在坏死的情况下,肝实质细胞能够通过分割完整的肝细胞来再生成。然而,坏死和再生成的交替触发了肝纤维化的进程,肝纤维化导致肝硬化、门静脉高压、肝性脑病、出血以及其他并发症。
这些疾病在肝纤维化阶段之后发展。肝纤维化是由于细胞外基质蛋白(包括胶原)的过度堆积而发生的结缔组织增殖。已知肝细胞(Liver cell)是由肝实质细胞(hepatocyte)、窦内皮细胞、库普弗细胞(Kupffer cells)和星形细胞组成。肝星形细胞在肝纤维化中起着最重要的作用(Francis J.E.et al.Fibrogenesis I.New insights intohepatic stellate cell activation:the simple becomes complex/American Journalof Physiology-Gastrointestinal and Liver Physiology,2000,V.279,N.l,pp.G7-G11)。
肝星形细胞占正常进行储存类视黄醇的功能的全部肝细胞的15%,类视黄醇是维生素A的前体。在肝实质细胞损伤或死亡的情况下,库普弗细胞开始调补(cannibalize)损伤的肝实质细胞,并分泌细胞因子(TGF-β、PDGF、FGF、HGF、PAF和ET-1)用于肝星形细胞的增殖。肝星形细胞分化成肌成纤维细胞。肌成纤维细胞合成堆积在细胞间基质中的胶原,这导致肝纤维化。因此,肝星形细胞的激活在肝纤维化的进展中起主要作用。
肝星形细胞的激活以以下三个阶段进行:炎性前阶段、炎性阶段、炎性后阶段。
在炎性前阶段,肝实质细胞损伤引起刺激肝星形细胞的增殖的激素的合成,或者通过降低精氨酸酶—一种细胞增殖抑制剂—的活性来增强肝星形细胞的增殖。乙醛或脂质过氧化物的形成刺激基质基因的表达。
在炎性阶段,在由活跃的库普弗细胞和血小板分泌的细胞因子(TGF-β、PDGF、FGF、HGF、PAF和ET-1)的影响下,肝星形细胞增殖并且进一步分化为可以变为纤维细胞的肌成纤维细胞(Marie-Reine Losser et al.Mechanisms of Liver Damage/Seminars in LiverDisease,1996,V.16,N.4,pp.357-367;Anke M.B.C.Tiggelman et al.Transforminggrowth factor-β-induced collagen synthesis by human liver myofibroblasts isinhibited byα2-macroglobulin/Journal of Hepatology,1997,V.26,N.6,pp.1220-1228)。
在炎性后阶段,通过已经分化的肌成纤维细胞来分泌细胞因子和生长因子,以激活未分化的肝星形细胞并且分泌细胞外基质。在肝星形细胞的影响下激活且分化的肌成纤维细胞,形成随后堆积在细胞间基质中的胶原。胶原单体非常不稳定,并且在体温下容易分解,而且分解后的单体聚合,引起肝纤维化(Brenner D.A.et al.Type I collagen generegulation and the molecular pathogenesis of cirrhosis/American Journal ofPhysiology-Gastrointestinal and Liver Physiology,1993,V.264,N.4,pp.G589-G595)。
作为肝纤维化的结局的肝硬化由于堆积的胶原的聚合而发展。产生的胶原进入不溶性纤维。在当饮酒、肝炎、在毒性作用下等时,发生肝实质细胞破坏,再生成被结缔组织替代的情况下,肝硬化也通过肝中的永久性炎症引起和/或支持。肝硬化是严重的病理,并且导致致命的并发症,诸如门静脉高压、食道和胃出血、肝癌、肝性脑病、昏迷等。(GinesР.etal.Management of cirrhosis and ascites/The New England Journal of Medicine,2004,V.350,N.16,pp.1646-1654)。
与上述情况联系起来,包括其发展的全部阶段的非酒精性脂肪肝病的预防和治疗都是相关并且是有社会意义的因素。
本发明的目的是寻找一种在涉及预防和治疗非酒精性脂肪肝病上将有效的新型药剂。
本发明提出使用乳糖醇作为这种药剂。
乳糖醇(系统名:4-O-α-D-吡喃半乳糖基-D-葡萄糖醇)是由牛奶糖(乳糖)合成的糖醇,涉及二糖,具有长时间的使用经验并具有独特的特征。
在欧盟、美国、日本,乳糖醇在食品工业中用作甜味剂,其具有2kcal/g的低能量。因此,据认为是用于新一代功能性营养产品的理想甜味剂。与其他益生元相比,乳糖醇的主要优势还在于其对高温和低pH值的抵抗。这些特性使其能够用于暴露于高温加工,尤其是在烘焙工业和糖果工业中的食品中(Artyukhova S.I.et al.:Use of lactitol inbiotechnology of functional food products/Modern high technologies,2013,N.3,pp.87-88)。
根据药理学指标,乳糖醇属于“轻泻药组”;根据ATC,其属于“渗透性轻泻药”组,并且具有的代码为A06AD12。乳糖醇与其他渗透性轻泻药(基于乳果糖的药物除外)的不同之处在于,渗透特性不是由活性物质而是由其在结肠中的代谢展现。在人体肠道中,没有能够分裂乳糖醇的酶系统,因此它不被小肠吸收,并且以几乎不改变的形式进入结肠。在升结肠中,乳糖醇已经被糖分解微生物区系主动同化。在微生物代谢期间所形成的具有低分子量的短链脂肪族羧酸(SCFA)(乳酸、乙酸、丁酸、丙酸)导致:1)肠道pH降低,从而促进了推进性蠕动的激活;2)由于渗透压和液体潴留的增加而增加了肠内含物的体积和稀释,这促进通过肠的运动。
除了具有它的剂量依赖性的通便效果外,乳糖醇还具有益生元效果(益生元是不被上消化道消化和吸收的食物组分,但是会被人体大肠的微生物区系发酵,并刺激其生长和生命活动)。它的益生元效果是由于以下事实:当它进入结肠而没有改变时,它被益生元肠道微生物区系作为能源使用,不会被大肠杆菌(Escherichia coli)族的细菌分裂,并且通过抑制其粘附于上皮细胞壁而抑制蛋白水解细菌的生长。乳糖醇通过细菌增强蛋白质合成,减慢毒素的形成。按新陈代谢的类型,乳糖醇与膳食纤维类似,其不会在胃和小肠中被水解和吸收,而是在大肠中用糖分解微生物区系发酵,如已知的,被转化为低级脂肪酸、二氧化碳、氢和生物质。乳糖醇代谢的产物为SCFA,主要是比率为2:1的乙酸和丁酸。乳糖醇和其他二糖之间的根本差异在于通过微生物区系合成的SCFA的不同分布。因此,与乳果糖相比,乳糖醇代谢产生10倍多的丁酸。随后,有机酸被人体吸收并提供2kcal/g的能量值。乳糖醇的总能量值为2.4-2.6kcal/g(与碳水化合物-4kcal/g形成对照)。乙酸分子穿过肠壁并且进入肝,从肝处作为能量底物分布到肌肉组织和内脏器官(心脏、肾、大脑等)。SCFA是结肠细胞代谢的主要能量供体和调节物。
由于乳糖醇是用于分解糖类的结肠细菌(乳酸杆菌(Lactobacillus spp.)、双歧乳杆菌(Lactobacillus bifidus)、嗜酸乳杆菌(Lactobacillus acidophilus)、双歧杆菌(Bifidobacteria))的食物来源,因此它的使用可选择地增加糖分解微生物区系的生物质,并抑制肠杆菌(Enterobacteria)和肠球菌(Enterococi)蛋白水解细菌的生长,该蛋白水解细菌的数目通常在便秘时增长。在乳糖醇和乳果糖在益生元以及对条件致病性细菌和致病性细菌方面的效果的比较研究中,发现乳糖醇的作用更具有选择性。尤其,与乳果糖不同,它不是由大肠杆菌(E.coli)发酵,而是被显著较小数目的葡萄球菌菌株(St.aureus)和梭菌(Cl.perfringens)分裂。比较乳糖醇和乳果糖在治疗便秘上的疗效和安全性的随机临床试验(Amit Maydeo.Lactitol or lactulose in the treatment of chronicconstipation:Result of a systematic/Journal of the Indian MedicalAssociation,2010,V.108,N.11,pp.789-792)示出几乎相同的通便效果,患者对乳糖醇更耐受。与乳果糖相比,乳糖醇示出更少的副作用(分别为31.20±0.80%和62.10±1.10%,p=0.0019)。另外,在小儿科,使用的乳糖醇的有效剂量是乳果糖的有效剂量的几乎1/2(分别为250-400mg/kg/天和500-750mg/kg/天)。
现有技术(国际专利申请WO 0239832 A1,于2002年5月23日公布的)提出使用乳糖醇,优选地以5-15g的日剂量,作为食物产品(或食品补充剂)以改善肠道微生物区系,以及用于预防肠道感染、结肠癌、腹泻或用于增强免疫。
乳糖醇也被批准作为有助于减少肠道中氨形成和吸收的剂用于肝性脑病和高氨血症。
因此,文献(专利GB 2113998A,公布号08/17/1983)提出使用乳糖醇,优选以20-200g/天的剂量,用于治疗作为晚期肝硬化并发症发生的中枢神经系统的紊乱的门体分流性脑病(port-systemic encephalopathy)。在患有这种疾病的患者中,肠中产生的含氮有毒物质,优选为氨,不会被肝中和而进入血液循环并且进入大脑进而损害神经细胞。在该文献中,指明的乳糖醇的治疗性效果还与氨的形成和吸收的减少相关联。
然而,在现有技术中乳糖醇用于治疗非酒精性脂肪肝病(NAFLD)的用途是未知的。迄今为止,尚未对乳糖醇在脂肪肝病的情况中的有效性进行直接研究。
本发明的技术效果是扩展用于预防和治疗非酒精性脂肪肝病的手段的范围。
这种技术效果是通过在有此需要的哺乳动物中使用治疗有效量的4-O-α-D-吡喃半乳糖基-D-葡萄糖醇(乳糖醇)来预防和治疗非酒精性脂肪肝病来实现的。
在优选的实施方式中,哺乳动物是人。
治疗有效量(或治疗性剂量)是出于治疗性或预防性目的使用的活性剂的量(或剂量)。例如,乳糖醇的治疗有效量可以是1-20g/天。
可以在非酒精性脂肪肝病发展的全部阶段向哺乳动物,优选为人给药乳糖醇。
此外,在本发明的一个实施方式中,1-20g/天的剂量的乳糖醇也可以旨在用于预防和治疗肝硬化,肝硬化是非酒精性脂肪肝病的结局。
在一种实施方式中,可以以口服剂型进行乳糖醇的使用。
这样的口服剂型可以是不包含额外佐剂和/或额外活性物质(除活性剂乳糖醇之外)的粉末。可以将粉末放在小袋里。替代地,所述口服剂型(除乳糖醇之外)还可以额外包括药学上可接受的佐剂,并且可以选自粉末、片剂(包括改性的释放片剂)、胶囊、颗粒、糖浆、饮剂、凝胶、板剂(plate)、软明胶糖果等。作为药学上可接受的佐剂,可以添加用于制造现成口服剂型且与活性剂和其他佐剂两者兼容,并且不会对正在进行预防或治疗的患者产生不利影响的各种添加剂。
为了确认使用乳糖醇作为治疗和防范非酒精性脂肪肝病(包括预防和治疗作为NAFLD的结局的硬化)的药剂的可能性,进行了以下试验。
实施例1.
在该研究中,采用在瘦素基因上有缺陷的小鼠,瘦素基因是一种蛋白质,该蛋白质是肥胖症的超噬菌体。在这些小鼠中,可以很快形成肝脂肪变性。
约8周大的具有缺陷基因的肥胖的雄性小鼠被随机分配到各自具有7只动物的组。7只数目的普通白色实验室小鼠充当对照组。所有动物均保持在23±0.5℃的恒定温度、湿度50±5%、对应于日照时数(7:00-19:00)的光照下。这些动物可以自由获取水和食物。关于小鼠的所有程序和实验均按照用于动物治疗的国际规则进行。
将小鼠分成研究组,并且向它们给药日剂量的乳糖醇(7.5、15.0或30.0mg/kg)和类似剂量的L-鸟氨酸-L-天冬氨酸。L-鸟氨酸-L-天门冬氨酸用于治疗脂肪变性和脂肪性肝炎(各种起源)是已知的(Zhuravleva L.V.et al.:L-ornithine-L-aspartate in thetreatment of non-alcoholic fatty liver disease in obese patients with signsof metabolic syndrome/Medical Practicioner,2015,pp.25-31)。
具有缺陷瘦素基因的小鼠发展慢性炎性肝脂肪变性,并且表示非酒精性脂肪性肝炎(NASH)的动物模型。具有NASH,发生脂肪夹杂物的数目增加,并且炎性损伤的可能增加。对于NASH的重要标准是在没有病毒感染或酒精中毒的情况下,从损伤的肝细胞释放的升高水平的以下血清转移酶指示物:丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)和山梨糖醇脱氢酶(SDH)。作为肝脂肪变性和伴随的继发性炎症的结果,具有基因缺陷的小鼠体内的这些酶的含量增加。
表1概括了从给予乳糖醇、L-鸟氨酸-G-天冬氨酸(LoLa)的小鼠获得的血清中的ALT、AST和SDH指示物,以及从低重量正常小鼠(对照组)和从给予生理盐水的糖尿病小鼠(糖尿病组)获得的血清中的这些酶的水平。与正常小鼠相比,具有基因缺陷的肥胖糖尿病小鼠的ALT、AST和SDH水平显著增加。
如表1所概括的所获得的数据,指明以从7.5至30.0mg/kg/天的剂量施用L-鸟氨酸-L-天冬氨酸后,ALT、AST和SDH降低。同时,用7.5-30.0mg/kg/天的剂量的乳糖醇治疗也导致血清中这些肝酶的剂量依赖性降低。
所获得的肝酶分布与肝组织学相关联。因此,在来自给予生理盐水的糖尿病组的具有基因缺陷的肥胖的糖尿病小鼠中注意到以脂肪滴的形式的肝内脂肪的细胞内堆积。与给药L-鸟氨酸-L-天冬氨酸(LoLa)的小鼠组类似,以治疗性剂量和亚治疗性剂量的乳糖醇持续4周每日给药引起肝中的脂肪堆积的显而易见的减少。
实施例2.
而且,在参与实施例1的研究的所有组的小鼠中评估到体重增加。获得的数据示出在表2中。
在整个四周的研究期期间,糖尿病组的小鼠示出体重增加。而且,相对于用研究药物(乳糖醇)或参考药物(LoLa)治疗的小鼠,未经治疗(未给药乳糖醇和LoLa)的糖尿病小鼠的体重增加。获得的数据示出,向糖尿病小鼠给药乳糖醇诱导剂量依赖性的重量减轻。
实施例3.
将大约8周大的肥胖的雄性小鼠随机分配为各自具有5-7只动物的组,使得两组之间的体重(50-55g)和血清葡萄糖水平(进食后>300mg/分升)类似。瘦的雄性小鼠作为对照组。为了在到达后适应,将小鼠单独放置至少7天。所有动物均保持在受控的温度(23±0.5℃)、相对湿度(50±5%)和日照时数(7:00-19:00)下。动物可以自由获取饲料和水。
有肥胖症倾向的小鼠组(肥胖症组)之一未给药任何药物。其余的肥胖小鼠组形成每天接受乳糖醇或LoLa的口服剂量持续2周的治疗组。在治疗期结束时,从全部研究组的小鼠中,从小鼠球后窦采取100μL静脉血放入肝素化毛细管中,用于针对甘油三酯类和游离脂肪酸进行的血清化学分析。
基于如表3所概括的结果,可以示出,向易患肥胖症的小鼠给药乳糖醇导致甘油三酯类和游离脂肪酸含量的剂量依赖性降低。
因此,所进行的测试和研究可靠地指明,乳糖醇对肝的脂肪变性的过程具有效果,并且对非酒精性脂肪肝病具有积极的治疗性效果和预防性效果。
实施例4.
在本发明的范围内也已经进行了测试,以证实给药乳糖醇将具有抑制肝硬化发展的治疗性效果的假设。
实验是在远交系白色实验室大鼠上进行的。通过以下模拟硬化:采用CC14(嗜肝毒物)的50%的橄榄油溶液以2mL/kg的剂量灌胃给药,持续3周,每周2次,总共6次。为了增强对肝的病理学效果,在整个实验期间,动物们都接受了10%的乙醇溶液。
在建模肝病理学之前,每天向动物组口服给药乳糖醇(15mg),持续4周。即使在肝硬化诱导起始之后,仍继续给药乳糖醇。根据相同的方案并以当量体积用蒸馏水替代乳糖醇向动物的对照组给药。
在大鼠死亡之后评估肝病症。在实验的第41天,对血清中的天冬氨酸氨基转移酶(AST)、丙氨酸氨基转移酶(ALT)、碱性磷酸酶(ALP)进行了生化研究。另外,在实验的第41天对肝的形态状态进行了评估。使用用于其的生化分析仪和标准试剂盒,通过常规方法确定血清酶的活性。用于研究的血液通过导管从股动脉获取。在用苏木精和伊红染色的肝组织学制剂上,使用含25个测试点的Avtandilov目镜分划板确定浸润细胞的数目。在20个视场中对到达到分划板测试点的细胞数目进行计数。通过在20个视场中每个渗透细胞的分划板的点与所有分划板的点的比率计算浸润的相对面积。通过用于图形数据的计算机处理手段确定结缔组织面积。为此,在肝切片的标准区域(由具有将图像传输到计算机的程序的微型视频摄像机拍摄的10个视场的连续显微照片)上测量用picrofuxin染色的结构的面积,并且计算相对于选择的标准区域的百分数。通过使用学生T检验(Student's t-test)和非参数威尔科克森-曼-惠特尼U检验(Wilcoxon-Mann-Whitney U-test)的多元统计方法对结果进行处理。
实验示出对照组中大鼠的显著的死亡率-48.9%,而针对建模肝硬化的背景用乳糖醇注射的大鼠组的死亡率很低-4.2%。
血清的生化研究揭示,在将CC14引入到对照组后,在实验的第40天,ALT、AST和ALP的活性增加(表4)。同时,对于给药乳糖醇的组示出血清的酶活性稳定。
未经治疗(未接受乳糖醇)的大鼠组的肝组织学检查具有器官的小叶结构的明显破坏。肝微静脉、微动脉和胆管发生结构改变。肉芽组织替代死亡的肝实质细胞;血管和肝管的赘生物进展强烈;形成了纤维索和微结节,即所谓的拟叶突。后者是被纤维化斑块包围的肝实质细胞群。在其余的肝实质细胞中,记录到大规模的大滴脂肪变性。给药乳糖醇防范硬化的形态学迹象的发作。肝的小叶结构得以保留。应该注意,直到观察期结束之前,都记录到小滴脂肪变性和门静脉浸润的迹象。
在用乳糖醇治疗的大鼠组中,浸润细胞的含量和结缔组织的面积显著减少(表5)。
实施例5.
以包装在小袋内的粉末形式生产乳糖醇的口服剂型
将不含辅助物质的经筛分的乳糖醇一水合物粉末以10g的数量装在小袋中,并放在纸板箱中。
实施例6.
以胶囊形式生产乳糖醇的口服剂型
将粉末状乳糖醇一水合物进行筛分,并与乳糖粉末按2:1的比率充分混合。将所得的以500mg的数量的混合物放入合适大小的硬明胶胶囊中。
实施例7.
以片剂形式生产乳糖醇的口服剂型
将1,600mg的淀粉、1,600mg的粉碎的乳糖、400mg的滑石粉和1,000mg的乳糖醇混合并压成条。将所得的条粉碎成颗粒,并且通过筛子进行筛分,收集14-16目的颗粒。将获得的颗粒片压成适合的片剂形式,每个片剂重560mg。
因此,在本申请的范围内可靠地证实,给药乳糖醇特别有助于预防由NAFLD引起的硬化改变。
表1.
乳糖醇和L-鸟氨酸-L-天冬氨酸对肝损伤的血清指示物的效果
表2.
测试化合物(乳糖醇)和参考药物(L-鸟氨酸-L-天冬氨酸)对糖尿病小鼠体重的效果
组 | 体重增加平均值(以克为单位) |
低重量小鼠(对照组) | +6.9 |
糖尿病组 | +12.1 |
乳糖醇(7.5mg) | +6.7 |
乳糖醇(15mg) | +5.9 |
乳糖醇(30mg) | +4.8 |
LoLa(7.5mg) | +6.5 |
LoLa(15mg) | +6.1 |
LoLa(30mg) | +6.0 |
表3.
给药乳糖醇和L-鸟氨酸-L-天冬氨酸对血清的甘油三酯类和游离脂肪酸含量的效果
表4.
实验第41天乳糖醇对具有肝硬化的雄性大鼠的肝形态学参数的效果
*指示物与其背景值之间的差异的显著性以p<0.05指明。
**指示物与其对照值的差异的显著性以p<0.05指明。
表5.
实验第41天乳糖醇对具有肝硬化的雄性大鼠的肝形态学参数的效果
*指示物与其背景值之间的差异的显著性以p<0.05指明。
**指示物与其对照值的差异的显著性以p<0.05指明。
Claims (13)
1.治疗有效量的4-O-α-D-吡喃半乳糖基-D-葡萄糖醇(乳糖醇)用于在有此需要的哺乳动物中预防和治疗非酒精性脂肪肝病的用途。
2.根据权利要求1所述的用途,其特征在于,所述哺乳动物是人。
3.根据权利要求1或权利要求2所述的用途,其特征在于,乳糖醇的所述治疗有效量是1-20g/天。
4.根据权利要求1或权利要求2所述的用途,其特征在于,旨在在非酒精性脂肪肝病的全部发展阶段将乳糖醇以1-20g/天的剂量向有此需要的哺乳动物给药。
5.根据权利要求1或权利要求2所述的用途,其特征在于,1-20g/天的剂量的乳糖醇旨在用于防范和治疗由于非酒精性脂肪肝病的肝硬化。
6.根据权利要求1或权利要求2所述的用途,其特征在于,乳糖醇以1-20g/天的剂量以口服剂型使用。
7.根据权利要求6所述的用途,其特征在于,所述口服剂型不包含额外的活性物质。
8.根据权利要求6所述的用途,其特征在于,所述口服剂型是不包含额外的佐剂的粉末。
9.根据权利要求6所述的用途,其特征在于,所述口服剂型可以选自粉末、片剂、胶囊、颗粒、糖浆、饮剂、凝胶、板剂、软明胶糖果,以及进一步包括药学上可接受的佐剂。
10.一种用于在有此需要的哺乳动物中防范和治疗非酒精性脂肪肝病的口服剂型,其包含治疗有效量的4-O-α-D-吡喃半乳糖基-D-葡萄糖醇(乳糖醇)以及,任选地,药学上可接受的佐剂。
11.根据权利要求10所述的口服剂型,其特征在于,其不包含额外的佐剂。
12.根据权利要求10所述的口服剂型,其特征在于,其不包含额外的活性物质。
13.根据权利要求10所述的口服剂型,其特征在于,所述口服剂型可以选自粉末、片剂、胶囊、颗粒、糖浆、饮剂、凝胶、板剂、软明胶糖果,以及进一步包括药学上可接受的佐剂。
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GB2113998A (en) * | 1982-02-05 | 1983-08-17 | Cv Chemie Combinatie Amsterdam | Lactitol for the treatment of liver disease |
WO2002039832A1 (en) * | 2000-11-17 | 2002-05-23 | Purac Biochem B.V. | Use of lactitol for improving intestinal microflora |
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Title |
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KAISA OLLI等: "Independent and Combined Effects of Lactitol, Polydextrose, and Bacteroides thetaiotaomicron on Postprandial Metabolism and Body Weight in Rats Fed a High-Fat Diet" * |
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