CN1265792C - 含有8-22个碳原子的烷基链的烟酸烷基酯在制备提高受试者瘦素水平的药物中的用途 - Google Patents

含有8-22个碳原子的烷基链的烟酸烷基酯在制备提高受试者瘦素水平的药物中的用途 Download PDF

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CN1265792C
CN1265792C CNB028061209A CN02806120A CN1265792C CN 1265792 C CN1265792 C CN 1265792C CN B028061209 A CNB028061209 A CN B028061209A CN 02806120 A CN02806120 A CN 02806120A CN 1265792 C CN1265792 C CN 1265792C
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伊莱恩·雅各布森
迈伦·K·雅各布森
金辉泰
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Abstract

本发明涉及烟酸和烟酸酯(如烟酸烷基酯)增加受试者中瘦素量的用途。结果是,可以通过施用足够量的烟酸或烟酸酯,来提高瘦素的水平至缓解量,从而治疗诸如以受伤为特征的疾病。本发明还公开了所治疗的各种疾病和模式。

Description

含有8-22个碳原子的烷基链的烟酸烷基酯在制备 提高受试者瘦素水平的药物中的用途
相关申请
本申请要求2001年3月8日提交的临时申请60/274,349的优先权,该临时申请在此引入作为参考。
技术领域
本发明涉及烟酸衍生物及烟酸在调控瘦素调控通路中的用途。具体地,下文将阐述烟酸和它的衍生物(如烟酸酯,尤其月桂基烟酸酯)刺激瘦素的产生的作用。
背景技术
瘦素(leptin)是一种167个氨基酸的蛋白,由ob基因编码。它是在鉴定有肥胖倾向的品种,即″ob/ob″小鼠的分子缺陷小鼠的研究过程中被鉴定出的。已经发现大多数瘦素是由黄色脂肪组织(white adipose tissue)产生,极少量由棕色脂肪组织产生。与此分子有关的专利文献例如美国专利6,132,724;6,124,448;6,124,439;6,068,976;6,048,837和5,795,909,它们都引入本文作为参考。
最初的有关瘦素的报道提示它是一种由脂肪细胞衍生的信号传导分子,即“adiposat”,该分子限制食物的摄入及增加能量的消耗。支持这一观点的证据包括,当给由于基因或饮食的原因而导致肥胖的啮齿动物注射瘦素后,可以观察到体重下降并且对代谢的控制得到改善。在ob/ob小鼠中,由于其ob基因中具有突变而导致合成有缺陷的瘦素分子,这些分子在细胞内发生降解,因此在这样的小鼠中瘦素的作用尤其重要。ob/ob小鼠都表现肥胖,有糖尿病,并且不育,它们的活力、代谢和体温水平都下降。此外,瘦素缺陷型ob/ob小鼠的伤口愈合大大延迟。全身或局部给予瘦素已经证实在该模型中增强伤口的再上皮化。见Frank,et al.,J.Clin.Invest.106:501-509(2000)。因此,ob/ob小鼠已用作测试药物使受损的伤口愈合能力逆转的模型系统。
除了上述对瘦素缺陷型小鼠的作用外,瘦素还可以显著促进野生小鼠的再上皮化。另外,STAT 3和过氧化物酶体增殖体活化受体(PPAR)作为瘦素通路的下游调节剂,也参与了皮肤自稳。见Komuvres,et al.,J Invest.Dermatol 115:361-267(2000)。已证实STAT 3在皮肤的重建,包括毛囊再生(hair follicle cycling)及伤口愈合中起必不可少的作用。而且目前已知PPARα激活剂可以使细胞增殖(包括上皮分化)正常化,并加速表皮通透屏障的发育。见Hanley,et al.,J.Clin Inv.100:705712(1997)。最近已证实,PPARα激活剂能抑制鼠的皮肤肿瘤进展,这与PPARα在皮肤生理学中具有作用是一致的。见于Thuillier,et al.,Mol.Carcinogenesis 29:134-142(2000)。
其它对瘦素的研究发现,该分子改变与脂肪生成、脂肪分解及能量代谢有关的多种肥胖特异性基因的转录。它还显示可以触发黄脂肪组织的凋亡。该分子的大多数代谢效应是其与中枢神经系统及周围组织中的受体相互作用的结果。这种受体已经被鉴定出来,它是I类细胞因子受体,与IL-2受体、干扰素受体和生长激素受体属于同一家族。简单的讲,瘦素受体将瘦素信号传递给三种STAT分子:STAT 3,5,和6,它们统称为″fat-STATS″。
对瘦素的已被接受的观点是,它的主要作用是通过调节食物的摄入而防止肥胖、通过对低温中枢的作用而产热。但最近的证据提示,瘦素可能还有另一种作用:即,它表现出抗脂肪活性,其中通过对β氧化作用进行瘦素介导的调节,可防止脂肪酸在无脂肪组织中的过度积累。瘦素可以增加与脂肪酸氧化有关的酶,并且刺激此前未观察到的脂肪分解形式,在该分解中,释放甘油的同时并不成比例地释放游离脂肪酸。
瘦素的多种受体同工型在机体全身各处表达,这提示其还具有额外的对外-神经组织的生理功能。已有许多研究通过测定瘦素对糖类代谢和脂肪代谢及酶表达的影响(如果有)而评价组织对瘦素的反应。如果观察到瘦素对给定的组织有直接作用,就提示传自激素/受体结合的信号传导通路被快速诱导。作用机制可以概述如下:瘦素激活脂肪组织中的STAT 3,瘦素与其受体的结合导致受体寡聚化,JAK激活,再引起STAT磷酸化;磷酸化STATS形成二聚体,移位到细胞核内激活靶基因。简言之:
(i)瘦素激活STAT 3,并增强PPARα活性;
(ii)PPARα/PPRE导致apo A-I在肝细胞中的表达;
(iii)STAT3/PPARα对皮肤自稳而言必不可少;
(iv)PPARα激活剂抑制小鼠皮肤肿瘤的进展。
参见,例如,Bendinelli,et al.,Mol.Cell Endocrin 168:11-20(2000);Unger,etal.,Proc.Natl.Acad.Sci USA 96:2327-2332(1992);Peters,et al.,J.Biol.Chem.272:27307-27312(1997);Hanley,et al.,J.Clin.Invest.100:705-712(1997);Sano,et al.,EMBOJ 18:4657-4666(1999);Thuillier,et al.,Mol.Carcin 29:134-142(2000)。
除了在能量调节中发挥作用,瘦素还能调节内分泌及免疫功能。瘦素水平在炎症和感染期间急剧升高,它可能是宿主对炎症反应产生的一种保护性成分。瘦素的缺陷增加对炎症刺激和感染因素刺激的易感性,而且与细胞因子的产生失调有关。见Faggioni,et al.,FASEB J.15:2565-2571(2001)。
另外,我们可设想如上所述的途径也能导致皮肤的自稳和重建,从而引起表皮屏障的发育,伤口愈合,和毛发生长,而且因免疫功能的增强导致对皮肤肿瘤进展的抑制。这些都概述在图1中。
烟酸是辅酶烟酰胺二核苷酸(NAD)和NAD磷酸(NADP)的形成所必需的,在所述形成中,烟酰胺组分是多种生物学氧化还原反应的电子受体或氢供体。具体的说,NAD的功能是作为细胞内呼吸作用中的电子载体,和燃料分子氧化中的辅酶。NADP则作为氢供体参与还原型生物合成,包括脂肪酸和类固醇的合成。NAD也是如此,它同样可以作为一种辅酶起作用。
NAD是三类将ADP-核糖单位转移至蛋白质的酶的底物,所述的酶参与DNA修复,细胞分化和细胞的钙代谢。烟酸按照1.5-4克/天给药可改善血中胆固醇的水平,这与烟酰胺相反。
阿西莫司(Acipimox)是一种商品,它是烟酸类似物和降血脂剂。经证实,它能提高转基因小鼠的血浆瘦素水平。参见,例如Worm,et al.,Eur.J.Endocrin 143:389-395(2000)。
有报道烟酸衍生物对于皮肤细胞的保护,DNA的修复等都有作用,参见如Jacobson等人1999年12月1日提交的美国专利6,337,065,其全文引入本文作为参考。该申请描述了各种烟酸衍生物,包括十二烷基或月桂基烟酸酯。现已发现这类烟酸酯(如月桂基烟酸酯)刺激瘦素生产的程度未见于烟酸的情况中。由于烟酸酯可配制成适于局部用药的物质,因此提供了一种刺激和生产瘦素的新途径。
附图说明
图1是据信能在本发明中起作用的一种假定的机制和效应途径。平线意味着目标状况受到抑制。因此,瘦素对皮肤肿瘤进展的效应是抑制该肿瘤。
图2概述了与体外脂肪细胞中瘦素生产有关的数据。
图3是实验结果的比较,所述实验是设计用于确定当以月桂基烟酸酯的形式给予烟酸后,实验动物的血浆瘦素水平。
图4示实施例2所得数据,在该实施例中测定了血清瘦素水平。″NIA114″是肉豆蔻酯,″NIA 112″是月桂酯。
图5概述了给予烟酸酯后伤口大小变化的结果。
图6是四项目平行实验的结果,这些实验测定了鼠血清瘦素的水平。
优选实施方案详述
实施例1
脂肪组织被认为是动物中瘦素生产的主要来源。因此,设计一些实验来确定烟酸对脂肪细胞中瘦素生产的影响。
人类的脂肪细胞用标准的方法获得,简单的说,从皮下脂肪组织中收集前脂肪细胞,然后用胶原酶处理。将前脂肪细胞铺板,使其进行3周的分化,以形成脂肪细胞。
然后将脂肪细置于0.6ml加有2%小牛血清白蛋白的DMEM/F-10培养基保温。另外,培养时分别加或不加0.1mM烟酸。
24小时后用购买的ELISA试剂盒测定培养基中的瘦素浓度。
结果如图2所示,加了烟酸的培养基中瘦素的生产增加62%。
实施例2
将购买的雌性apoB/CETP双转基因小鼠分成3组,按每笼6只圈养。一组作为对照,接受标准饮食,不加烟酸。背部剃毛,加载与应用于下述第3组的洗液一样的洗液,其中不含月桂基烟酸酯。第2组给予钠盐形式的烟酸,将其溶于饮用水中,浓度为0.75%(0.63%游离酸)。动物的烟酸摄取基于水的消耗来评估,约为1400mg/kg体重,这是基于每100g体重估计消耗23ml水,而平均体重为25g。这相当于70kg的人大约每天8.4g的量。参见Freireich,et al.,Cancer Chemother.Rep.50:219-244(1966),引入本文作参考。对于第3组,背部剃毛,并在剃毛区涂上了月桂基烟酸酯,用的是含10%(wt/wt)月桂基烟酸酯的200mg洗液。所用烟酸酯的量大约是80-800mg/kg,仍然假设平均体重为25g。按照Freireich(上文)所述,这相当于约0.48-4.8g/天/70kg的人。该洗液每天应用并持续13周。
血浆中瘦素水平使用鼠瘦素放射免疫分析商品来测定。空腹16小时后取眶后血管束的血液样本进行RIA。这些血液样本收集后,2000xg离心15分钟,获得血浆。结果如图3所示:口服烟酸确实提高了循环中瘦素的水平,而月桂基烟酸酯在这方面更胜于它。
实施例3
本实施例是“实施例2”的延续。具体地,BALB/C小鼠自肩胛骨至尾部剃毛。然后给这些鼠局部应用不同浓度的月桂基烟酸酯洗液,如上文中实施例2所述,或应用不同浓度的肉豆蔻基烟酸酯洗液。对照组仅接受赋形剂。洗液的用量是4ml/kg/只小鼠。
如上所述测定血清瘦素水平。结果显示,在接受10%月桂基烟酸酯洗液的动物中,血清瘦素水平提升了45%,而接受了肉豆蔻基洗液的动物中,提高了57%(用2%配制剂的情况),和77%(用5%配制剂的情况)。图4显示了这些结果。
实施例4
瘦素和伤口愈合的相关性如上文所述。这种相关性在这些实验中予以研究。
在苯巴比妥钠的麻醉下,给小鼠造成直径约6mm的达全层厚度的伤口。然后每天对它们局部应用20%烟酸酯洗液,共14天。剂量是每次100μl,一天两次。对照组使用不含所述酯的洗液。每天测量伤口的直径。
结果见图5,其显示接受了含烟酸酯的配制剂的小鼠与对照组相比,表现出伤口厚度减小。月桂基烟酸酯效果更好,其减小了43%。
接受了烟酸酯的小鼠与对照组相比,血清瘦素水平经测定提高44%。这些结果在图6中描述。
上述实施例显示了本发明4个不同的特征,包括,一种在有相应需要的受试者中刺激瘦素产生的方法,其通过给所述受试者施用瘦素刺激量的烟酸或烟酸衍生物,如烟酸酯。更优选月桂基烟酸酯,如前文引用的专利文献中所用的那些。尤其优选烟酸本身,或烟酸烷基酯,其中的烷基部分包含1-30个碳原子,任选为取代的碳原子。更优选,所述烷基部分包含1-22个碳原子,最优选1-18个碳原子。受试者优选患有能通过提高瘦素水平而缓解的疾病,包括图1所示的那些,增强免疫功能,皮肤上皮化,毛囊再生,抑制肿瘤形成,如皮肤肿瘤形成,等等。
将烟酸或酯给药受试者的模式有多种。除局部给药以外,还可以考虑口服,缓释(time release),静脉内,皮内或其他给药形式。所述局部给药可以经由膏剂、洗剂、液体、气雾剂、沐浴液、含嗽液、牙膏、管饲剂,或其他局部给药形式。例如,在缓释给药的情况下,“敷剂”,如尼古丁缓释给药所用的类型,绷带、包裹等等都可应用。
烟酸酯的给药量足以刺激瘦素的产生。其剂量可以而且将有变化;但配制剂应保证,例如,约0.1-约10g/天/70kg体重的剂量,更优选约0.1-约7g/天/70kg体重的剂量,最优选约0.4-约5g/天/70kg体重的剂量。
如上所述,对瘦素生产的刺激,除了能导致先前所述的与瘦素有关的效应外,还可以导致抑制皮肤肿瘤,皮肤自稳和重建、表皮屏障的发育、伤口愈合,和毛发生长。
其它应用对于本领域技术人员而言显而易见,无需在此赘述。

Claims (6)

1.含有8-22个碳原子的烷基链的烟酸烷基酯在制备提高受试者瘦素水平的药物中的用途,所述受试者患有可通过提高瘦素水平而治疗的伤口。
2.权利要求1的用途,其中所述烷基链包含12或14个碳原子。
3.权利要求1的用途,其中所述药物是用所述烟酸烷基酯制备的口服给药的药物。
4.权利要求1的用途,其中所述药物是用所述烟酸烷基酯制备的局部给药的药物。
5.权利要求1的用途,其中所述药物包含不止一种烟酸烷基酯。
6.权利要求1的用途,其中所述受试者有皮肤伤口。
CNB028061209A 2001-03-08 2002-03-08 含有8-22个碳原子的烷基链的烟酸烷基酯在制备提高受试者瘦素水平的药物中的用途 Expired - Fee Related CN1265792C (zh)

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