CN1960722B - 烷基呋喃在制备抗糖尿病药物中的用途 - Google Patents
烷基呋喃在制备抗糖尿病药物中的用途 Download PDFInfo
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Abstract
本发明涉及一种或多种合成或天然烷基呋喃化合物在制备用于预防和/或治疗糖尿病和胰岛素抗性的药物中的用途,从而预防了患有心血管、神经、皮肤、肾、眼部和感染疾病的危险。也公开了一种或多种合成或天然烷基呋喃化合物在美容性处理与糖尿病相关的皮肤病症中的用途。
Description
技术领域
本发明涉及一种或多种合成的或天然的烷基呋喃在制备用于预防和/或治疗糖尿病、胰岛素抗性、肥胖、超重、血脂异常症和由此导致的患有心血管、神经、皮肤、肾、眼和感染疾病危险的药物中的用途。本发明还涉及一种或多种天然或合成的烷基呋喃用于局部超重和/或蜂窝组织(cellulite)的美容性处理和用于糖尿病患者皮肤病症的用途。
背景技术
糖尿病为慢性疾病,通常与其它疾病例如超重或血脂异常症有关,或与心血管疾病的危险有关。糖尿病也是25至74岁患者失明的主要原因。患有糖尿病2至4次者更易于患有心脏病,患有5次者更易于患中风。糖尿病定义为慢性高血糖症状态:禁食血糖超过7mmol/l或1.26g/l则确诊为糖尿病。如果血糖保持1.1至1.26g/l之间,必须通过口服获得高血糖。糖尿病分为两种主要类型:胰岛素依赖型和非胰岛素依赖型。在某些孕妇中也存在另一类型的糖尿病。
I型,或胰岛素依赖型糖尿病也称为儿童期糖尿病,因为它通常在较小年龄就发生,发病峰值为12岁。患这种疾病的患者占糖尿病患者的10至15%。这种类型的糖尿病的发生很突然且发展快速。一般认为其是一种自身免疫疾病,即,由改变或破坏人体细胞的免疫***紊乱引起。免疫***逐渐破坏了胰中胰小岛(islets of Langerhans)β细胞,从而导致释放的胰岛素量逐渐减少。当所有β细胞受到破坏后,不再生成胰岛素。这意味着尽管可摄取足量葡萄糖,但其却不能转运到细胞中产生能量。为了抵消这种不足,注射胰岛素来阻止血糖增加是非常重要的。胰岛素不能口服摄取,因为它可被胃灭活。这种类型糖尿病的确切病因未知。
II型或非胰岛素依赖型糖尿病为最常见的形式(几乎占90%病例),这种形式没有前述形式严重,逐渐发病。常发病于40岁后成年人,通常与超重有关。在大多数II型糖尿病人中,胰腺生成足量甚至过量胰岛素。在这种情况下,胰腺确实生成胰岛素,但不能及时或不能充分地满足需要,或者身体产生抗胰岛素应答。尽管身体生成足量的胰岛素,但细胞通常不能正常应答,因为位于细胞表面的识别位点被修改。胰岛素不再被识别,葡萄糖也不能足量进入细胞产生能量。太多的葡萄糖保留在血液中,引起高血糖水平。负责调解葡萄糖代谢的胰腺通过生成更多的胰岛素来应答这种紊乱。这引起恶性循环:胰腺逐渐生成越来越多的胰岛素,以至于不能向提供细胞葡萄糖。这就是为什么II型糖尿病首先表现出高胰岛素水平。必须修改识别位点以便能识别胰岛素。大多数II型糖尿病患者可通过减轻体重和增加体力活动而实现这一点。在更多的晚期病例中,药片形式的治疗是必须的。这些病人有发展成心脏病和高血压病的危险。
另一类存在的糖尿病也称为妊娠期糖尿病(Gestational diabetesMellitus)(GDM),仅发现在怀孕妇女中,她们仅在怀孕初期发生或经诊断患有高血糖或葡萄糖耐量受损,而在产后期结束时血糖下降。患有已知糖尿病并怀孕的妇女不属于这种类型。妊娠期糖尿病发病频繁,有6%的妊娠妇女会患有此病。这给母亲和胎儿带来了很多危险,例如妊娠期高血压、先兆子瘤、剖腹产术增加,并且这种病如果发病越早而且对高血糖症处理不当则后果更加严重。在儿童中,其会增加新生儿死亡、巨大胎儿、助产损伤、呼吸性窘迫、新生儿低血糖、血胆红素过多症和低钙血症的危险。除了短期并发症,患有妊娠期糖尿病的妇女在10至15年后有患II型糖尿病的危险。经过较长时期后,她们的孩子也可能会有患肥胖症和患糖尿病的风险。研究表明,糖尿病母亲中血清和羊膜液体中镁的水平异常低。这一低镁血症影响胎儿,可导致先天性畸形和早期新生儿低钙血症。必须采用饮食处理,如果餐后血糖(glycaemia)不能被调节且超过了7.8mmol/l,则必须给药胰岛素。
而且,糖尿病对皮肤有很多后果,尤其是II型糖尿病。已知糖可以通过米拉德反应(Maillard reaction)与蛋白结合,导致形成晚期糖基化终末产物(AGE),这种产物整体增加了皮肤和组织衰老。最近,经研究证明在这一不可逆反应中,脂质起启动子作用,而且遗传因子增加个体的易感性。最高的AGE水平发现在缓慢更新的组织中,例如腱、骨、皮肤、软骨和淀粉样组织(amyloidal tissues)。这些AGE产物影响基质的机械性质(减少弹性)和限制组织更新。而且,已证实基质金属蛋白酶(MMP-2/3)的增加和严重的微循环疾病是糖尿病足溃烂发病的主要原因,糖尿病足溃烂为由于缺乏抗慢性炎症的愈合(因子)引起的病症。最近,有证据表明糖尿病患者皮肤屏障中水的含量减少、表皮细胞增生减少和受调节的脱皮会导致在皮肤屏障保护中发生重大疾病,类似于衰老、刺激或干燥皮肤。糖尿病也限制了抗细菌和真菌感染作用的能力,细菌和真菌感染可将较小的损伤转化成严重的感染,甚至如果不予治疗则可能导致截肢。
非胰岛素糖尿病(II型糖尿病)的一个主要原因是肥胖,但这一疾病并不是必然导致糖尿病。脂肪细胞增加了胰岛素需要量,肥胖人群形成了对胰岛素作用的抗性。这样,血糖或糖含量持续较高,引起糖尿病。肥胖也可加重胰岛素依赖型(I型)糖尿病。据估计,肥胖人群患有糖尿病的危险是常规体重人群的两倍。目前,由Laval大学小组进行的工作证实,iNOS基因(生成一氧化氮的可诱导酶)经遗传性删除的小鼠不会发展成与肥胖相关的糖尿病(Nat Med 2001,Oct;7(10):1138-43.Targeted disruption of inducible nitric oxide synthase protects againstobesity-linked insulin resistance in muscle.Perrault M,Marette A)。
目前,除了与II型糖尿病和妊娠期糖尿病有关,肥胖还是慢性病理学的病因学中继衰老后的第二因素。在2004年,约64%的成年美国人患有超重。据估计,到2008年,34%的成年美国人将患肥胖症。肥胖症指体脂肪指数过高,由每日卡路里摄取和能量消耗失调引起:身体摄取的多于其使用的,因而“贮存”了部分过量的能量。然而,大量因素可加重这一失调,结果导致肥胖或至少体重增加,这些因素包括:遗传、饮食***达到了40%,而在突尼斯,其中年龄超过30岁的人中40%患有肥胖。值得关注的现象是儿童肥胖,其正在急剧增长。在法国,对10个月大至8岁儿童的研究表明肥胖为10%,而不是预期的3%。在日本,儿童肥胖增加了53%,在英国,某些年龄组增加了65%,在USA为60%。
这一令人担忧的趋势是许多并发症的起源,所述并发症会带来内分泌的、心血管的和精神社会后果(歧视、生活质量降低、疼痛),因而,其需要尽可能早的治疗和诊断。例如,超重增加了由心血管疾病导致的死亡的危险(50%至80%)、与高发病率和死亡率相关的疾病(II型糖尿病,其可被降低30%至45%)的危险、动脉高血压、代谢性疾病、关节和囊状疾病(vesicular disorders)、及某些癌症(结肠癌、直肠癌、***癌、子宫癌、乳腺癌和小囊泡癌)的危险。因此,今天迫切需要适于治疗糖尿病和/或肥胖的药物。
在本发明范围内,体重减轻优选指对抗局部超重。这种局部超重是经脂肪形式证实的,其重量和分布根据性别而不同。女性中,脂肪组织占体重的20%至30%,而在男性中占10至15%。女性的皮下脂肪比男性厚两倍。在男性中,脂肪蓄积在腰周围和腰上部(呈机器人样分布,代谢危险的因素),而在女性中,脂肪蓄积在腰部以下臀股区域(女性型分布(gynoid distribution),与血管危险性无关)。在人体下半部的这些蓄积脂肪的一个特征是难于除去。这些脂肪是用于提供保证生殖(怀孕,尤其是母乳喂养)所需要的能量,因而形成了身体能量需要的最大贮存器。
在细胞水平,脂肪细胞为球状细胞,它的细胞内空间被大量填充有甘油三酯的液泡占据。脂肪细胞可快速改变体积。根据所处环境,这些细胞直径可达40μm至120μm,相当于体积增大27倍。在某些极限情况下,这一增大可达40倍。因此,脂肪细胞是人体主要的能量操纵者,因为它能快速贮存(捕获或脂肪生成)或反过来动员(脂解)甘油三酯-人体主要的能量来源。脂肪生成必须通过活化的脂肪酸来酯化甘油-3-磷酸酯,从而合成三乙酰甘油;相反地,脂解相当于将贮存的三乙酰甘油水解成甘油和脂肪酸。已证实了控制脂解和脂肪生成的不同机理,包括受体例如α-2和/或β-1和-2受体,例如A1型腺苷受体、***素E2、YY类型的Y2受体和NPY神经肽,以及性激素。
因此,关于控制脂肪细胞脂解和脂肪生成的机理的知识得到很大进步。然而,仍在研究用于减肥的许多活性成分,因为已知的活性成分不能完全令人满意。因而,当前真正需要制备能有效帮助减肥的局部用组合物。
蜂窝组织,或局部的脂肪代谢障碍,特征在于脂肪组织的水肿浸润,其改变了身体形状的外观和协调性。如果因为多种原因例如食物过于丰富、不活动和/或衰老,在人体的脂肪生成和脂解之间形成大量不平衡,即,更准确地说,如果由脂肪生成形成的脂肪量显著和不断地高于由脂解消除的量,则在脂肪细胞中会存在甘油三酯的蓄积,如果这种蓄积过度,其可转变为局部超重和/或通常不规则的表皮进行性增厚,称为“橙皮效应”,其密度松弛或呈凝胶状,通常导致难看的体形。该蜂窝组织也影响男性,但在女性中更常见,无论是苗条的还是体格匀称的。脂肪优先集中于人体下半部:臀部、大腿、胃部以及膝盖和踝部。特别地,蜂窝组织由脂肪细胞中甘油三酯的贮存、真皮基本物质的粘度增加导致,进而转变为水分滞留和细胞交换减少。两种机理导致血管和***压迫和组织充血。
发明内容
令人惊奇地是,本发明人已发现合成的或天然的烷基呋喃可用于治疗糖尿病和肥胖症。本发明人也已经发现应用包含这些烷基呋喃的局部用组合物有减肥作用,尤其是用于对抗局部超重和/或蜂窝组织。
因此,本发明的一个主题是一种或多种合成的或天然的烷基呋喃在制备用于预防和/或治疗糖尿病,尤其是II型糖尿病的药物中的用途。
在本发明中,术语“药物”指对于人类疾病具有治疗或预防性质的物质或组合物,和用于预防疾病或治疗目的的兽用组合物。
本发明的烷基呋喃可用于降低血糖(glycaemia)和增加葡萄糖耐量。因此,他们可用于制备药物或食品补充剂,或可用在每天的食物中来预防和/或治疗糖尿病,目的在于调节脂血和/或血糖和/或胰岛素敏感性。
本发明的另一个方面是一种或多种合成的或天然的烷基呋喃在制备用于调节脂血和/或血糖和/或胰岛素敏感性的药物中的用途。所述药物也用于减少体脂量。
脂血是指以脂蛋白和游离脂肪酸形式循环的全部脂质的血液水平。血液中存在的这种类型的脂质(也称为甘油三酯)可能是糖尿病的征兆。本发明的烷基呋喃也能降低循环中的甘油三酯水平。
血糖是指血液中测定的葡萄糖浓度。低于某些阈值,就会发生低血糖。高于某些阈值,其成为高血糖症。参照血糖通常为早晨测定的禁食水平。然而,测定其它的餐前血糖水平,即午餐或晚餐前,或餐后血糖水平即餐后(通常为1小时30分钟后)测定的血糖水平也是有益的,其说明了一天中最高的血糖水平。
本发明的烷基呋喃能降低肝和肌肉中的甘油三酯水平,从而能限制脂肪贮存。本发明的烷基呋喃也增加了高密度脂蛋白(HDL)即优良的胆固醇的血液水平。
本发明的烷基呋喃也能增加能量消耗(肌肉中PGC-1的增加-参照实施例9)。
本发明的另一个目的是一种或多种合成的或天然的烷基呋喃在制备用于预防和/或治疗肥胖症的药物中的用途。
根据本发明的一个优选的变型,所述的烷基呋喃符合下面通式:
其中R1、R2、R3和R4相同或不同,分别代表氢原子、C1-C35烷基,优选C10-C22,更优选C12-C20,进一步优选C13-C17;C1-C35链烯基,优选C10-C22,更优选C12-C20,进一步优选C13-C17;或C1-35炔基,优选C10-C22,更优选C12-C20,进一步优选C13-C17,所述的烷基、链烯基和炔基可被一个或多个卤素和/或被一个或多个选自下述的功能基团取代:环氧基、羟基(-OH)、硫醇(-SH)、醚(OR5)、伯胺(-NH2)、仲胺(-NHR5)、叔胺(-NR5R6)、醛(-CHO)、酮(-COR5)、酰基(-O-CO-R5)功能基,其中R5和R6分别代表氢原子,C1-C35烷基,优选C10-C22,更优选C12-C20,进一步优选C13-C17,或C1-C35烯基,优选C10-C22,更优选C12-C20,进一步优选C13-C17。
在本发明中,优选的烷基呋喃为2位经单取代的那些。因此,所述的烷基呋喃优选为符合下面通式(1)的合成的或天然的2-烷基呋喃,其中R1、R2、R3代表氢原子,R4不代表如前述定义的原氢原子之外的基团。
根据本发明一个优选的变型,所述的烷基呋喃为天然2-烷基呋喃,特别是存在于鳄梨的呋喃非皂化物质(furannic unsaponifiable matter ofavocado)中的,其符合下面通式(1),其中R1、R2、R3代表氢原子,R4代表选自下列(*-R4)的基团:
在鳄梨的呋喃非皂化物质中,以总重量计,2-烷基呋喃占这种非皂化物的30%至70重量%。以油的总重量计,鳄梨油可包含2至4重量%的2-烷基呋喃。
根据本发明的一个优选的变型,使用鳄梨非皂化物的经纯化的呋喃组分制备用于预防和/或治疗糖尿病,尤其是II型糖尿病的药物,其中以所述组分的总重量计,经纯化的呋喃组分包含70至100重量%,优选90至100重量%的2-烷基呋喃。
根据本发明的另一个优选的变型,使用鳄梨非皂化物的经纯化的呋喃组分制备用于预防和/或治疗肥胖症的药物,其中以所述组分的总重量计,经纯化的呋喃部分包含70至100重量%,优选90至100重量%的2-烷基呋喃。
根据本发明的另一个优选的变型,使用鳄梨非皂化物的经纯化的呋喃组分制备用于调节脂血和/或血糖和/或胰岛素敏感性的药物,其中以所述组分的总重量计,经纯化的呋喃组分包含70至100重量%,优选90至100重量%的2-烷基呋喃。
所述非皂化物为在碱长时间作用后仍不溶在水中的脂肪部分,其可通过有机溶剂提取。在植物油的大多数非皂化物中主要存在五组物质:饱和的或不饱和烃、脂肪醇或萜醇、甾醇、生育酚、类胡萝卜素和叶黄素颜料。鳄梨油的呋喃衍生物为本领域技术人员已知的化合物,描述在例如Farines.M等人,1995,J.of Am.Oil Chem.Soc.74;473中。对鳄梨的非皂化物质(富含呋喃脂质)在制备具有对***有益和治疗作用的,尤其是用于治疗炎症疾病例如关节炎、牙周炎和硬皮症的药物中的用途已经有所描述了。在本发明中,对于鳄梨的呋喃非皂化物质而言,″烷基呋喃(类)″和″烷基脂质(类)″两种表述是相同的。
所述鳄梨通常选自下述种类:哈斯(Hass)、Fuerte、Ettinger、Bacon、Nabal、Anaheim、Lula、Reed、Zutano、Queen、Criola Selva、Mexicana Canta、Region Dschang、Hall、Booth、Peterson、CollinsonRed,更优选地,选自Hass、Fuerte和Reed种类。优选地,选自Hass、Fuerte、Ettinger或Bacon种类。进一步优选为Hass和Fuerte类。
在鳄梨非皂化物的经纯化的呋喃部组分中,例如由LaboratoiresExpanscience(参照国际申请WO01/21605)开发出的那种,2-烷基呋喃占该组分总重量的70至100重量%,每种确定的呋喃相对重量百分比在下表1中列出:
表I
在国际申请WO01/21605中,Laboratoires Expanscience申请了一种特别的制备方法,使有该方法可以获得呋喃脂质含量超过80重量%,甚至接近100重量%的鳄梨呋喃脂质的选择性提取物。该制备方法包括以下步骤:制备非皂化的鳄梨物质,和使这种非皂化物质经过分子蒸馏的步骤,调节使用的温度和压力获得主要包含鳄梨呋喃脂质的馏出物质。
优选地,非皂化鳄梨物质为在用油处理和皂化之前,由前述的经加热处理的果实制备的,特别地如在专利申请FR-9108301中描述的那样。这种加热处理包含在至少80℃的优选温度,优选80至120℃的温度,控制性干燥果实(优选新鲜的果实)至少4小时,优选24小时至48小时;温度和干燥时间互相依赖。在将油皂化前,可以将其预先通过分离非皂化物质的大部分成分(以浓缩物形式收集)的方式用非皂化物强化(riched)。可使用不同的方法:冷冻结晶、液液萃取、分子蒸馏。特别优选分子蒸馏,优选在约180至约230℃进行,保持压力为10-3至10-2rnmHg。然后,将如上得到的非皂化鳄梨物进行分子蒸馏步骤。这种分子蒸馏步骤是通过利用将温度调节至100至160℃的温度方法和将压力调节至10-3至5.10-2mmHg的压力方法进行的。特别地,温度方法为将温度调节到100至140℃,压力方法为将压力调节到10-3至5.10-2mmHg,以得到主要包含鳄梨呋喃脂质的馏出物。
在国际申请WO04/016106中,Laboratoires Expanscience研发了一种以高收率获得富含呋喃脂质的非皂化鳄梨物的方法,即含有50%至80%,并且含有低含量的重产物(heavy products)和过氧化物。该方法包含下述连续步骤:
(1)将新鲜的或预先制备的鳄梨进行控制脱水步骤,在-50℃至75℃的温度进行;
(2)从脱水果实中提取油的提取步骤,
(3)下述可选择的步骤:
-a.在80至150℃的温度内加热处理经提取的油,任选地,在惰性气体中进行,然后将油浓缩成其非皂化组分,或:
-b.将油浓缩成其非皂化组分,然后在80至150℃温度内加热处理,任选地,在惰性气体进行,然后:
(4)非皂化物的皂化和提取步骤。
在该方法步骤(1)中的脱水通常指本领域技术人员已知的所有可从化合物中提取水的技术。在这些技术中,优选在通风的干燥器中在薄层上和通入热气体流的情况下干燥,干燥温度为70至75℃,干燥8至36小时。在步骤(3)a.或(3)b.中应用的加热处理步骤可在含有或不含有酸性催化剂,优选酸性氧化铝的情况下进行。在步骤(3)a.或(3)b.中的浓缩步骤可使用冷冻干燥或分子蒸馏。
或者,包含烷基呋喃的鳄梨非皂化物组分的制备可使用从鳄梨油提取物方法中得到的副产物作为原料。特别是从新鲜果实中提取得到的油类,没有预先将果实干燥。在这些副产物中,非详尽地包括:i)脂肪相,和ii)从所谓的离心法中得到的水相,或从所谓的“酶”的方法中得到的那些,该酶的方法特别地包含果肉植物细胞的酶预消化步骤以便于脂质从果实中释放出来。脱去粗油类后的离心固体残余物(离心沉积物)也可用作某些用途的原料。而且,再次可选择地,可使用以前剥皮的冷冻果肉和结籽果实。类似地,对来自鳄梨油的除臭释放物也可作为鳄梨非皂化物质和烷基呋喃的来源。同样,在果实(新鲜的或干燥的)机械冷压过程中共生产的鳄梨饼或使用溶剂进行的鳄梨油液-液提取过程中形成的鳄梨饼也可作为另外的原料。最后,尽管鳄梨种子具有低油含量,其也可作为鳄梨脂质的原料,尤其是烷基呋喃的原料。
在本发明中,优选地,经纯化的烷基呋喃的使用比例为占药物总重量的0.001至100重量%,优选总重的0.5至60%,进一步优选占2%至25重量%。本发明药物的给药量取决于受治疗疾病的严重度,和其发病的时间。显然,医师也可根据患者调节剂量。根据本发明的一个优选变型,本发明烷基呋喃的每日治疗剂量有利地为10mg至30g/天,优选为60mg/g至10g/天,更特别地为100mg/天至6g/天,或约0.160至500mg/kg/天,优选1mg/kg/天至160mg/kg/天,更优选16mg/kg/天至100mg/kg/天。
可使用能与本发明的药物联合使用,并优选具有协同作用的降血脂治疗剂,例如甾醇螯合剂(考来烯胺)、氯贝特类(非诺贝特:PPAR-α激动剂)、hmg-coA还原酶抑制剂(洛伐他汀、辛伐他汀)、EPA/DHA(包含ω3的鱼油、EPA=二十碳五烯酸、DHA=二十二碳六烯酸),基因治疗,针对多种起源的高胆固醇血症(原发的、单基因的、多基因的、α-脂蛋白血症)的治疗剂,用于混合型高脂血症的治疗剂,用于高三酸甘油脂血症的治疗剂、用于血脂异常症的治疗剂。通常使用的治疗剂可以是营养物(地中海式饮食(Mediterranean diet)和控制摄入)、通过离子交换树脂的药物、氯贝特类、他汀类、鱼油、抗氧化剂、植物固醇或甾烷醇。
可使用能与本发明的药物联合使用,并有利地具有协同作用的抗糖尿病治疗剂,例如口服糖尿病治疗剂、针对II型糖尿病的胰岛素治疗剂和/或各种治疗剂,例如葡萄糖捕获剂(glucose captors)和人工胰腺。作为口服糖尿病治疗剂的实例,可提及的包括刺激胰岛素分泌剂(降血糖药磺酰胺)或类似药物(甲苯磺丁脲、氨磺丁脲、格列齐特、格列美脲、格列吡嗪、二甲双胍的衍生物、苯氟雷司)、抑制α-糖苷酶的药物(阿卡波糖和米格列醇)、胰岛素抗性的治疗剂(噻唑烷二酮类或噻唑烷二酮类)例如罗格列酮和吡格列酮,或肥胖症的治疗剂,例如5-羟色胺摄取抑制剂(***)、脂质消化抑制剂(奥利司他)、肾上腺素β3受体激动剂(增加脂解和热生成)或者增加葡萄糖的外周应用(减少脂肪酸的氧化),或增加胰岛素分泌剂,包含GPI、普兰林肽、IGFI和钒的衍生物、格列萘类。
可使用能与本发明的药物联合使用的,并优选具有协同作用的可用于治疗心血管疾病(动脉的、冠状的和大脑高血压和继发的动脉病)和/或支气管肺的和风湿病性并发症,癌症、肝损伤的药物。
以下物质可与本发明的药物联合使用,并优选具有协同作用:降血糖植物或食物、微量元素尤其是有机铬(chromium pidolate)、抗氧化剂、PPAR激动剂-无论是否是天然的、甾醇非皂化物或可能包含同样物质的产品(植物油非皂化物,尤其是大豆油非皂化物、植物奶油或奶油非皂化物及其混合物、天然蜡的非皂化物、油提取物的非皂化物、工业油副产物的非皂化物、动物脂肪提取物的非皂化物、海产油的非皂化物、乳化脂肪提取物的非皂化物、从单细胞生物体中提取的脂质的非皂化物、从藻类和海产生物体中提取得到的脂质的非皂化物,等)、甾醇类、甾烷醇(stanols)、植物甾醇类、植物甾烷醇(phytostanols)、维生素E类、向日葵浓缩物、油菜籽和/或棕榈油、ω3、6或9脂肪酸、防胖营养素。“甾醇”非皂化物为其中甾醇、甲基甾醇和三萜醇含量范围为占非皂化物总重量20至95%重量,优选45-65%重量的非皂化物。在本发明中,可与烷基呋喃联合使用的降血糖植物优选选自:葫芦巴(fenugreek)(Trigonella graenum)、科罗索酸(corosolic acid)(大叶紫薇(Lagestroemia speciosa)树叶子的活性化合物)、匙羹藤(Gymnemasylvestra)、苦瓜果实(Momormodica charantia)的汁液、桉树(eucalyptis)(蓝桉(Eucalyptus globulus))、人参(Panax ginseng)、蓝莓叶(blueberryleaves)(越桔(Vaccinium myrtillus))。
可使用与烷基呋喃联合使用的,并优选具有协同作用的高糖食品或修复血糖平衡的治疗剂,例如抗逆转录病毒剂、糖皮质激素、免疫抑制剂、IFN-α、性甾醇、THS、药丸(the pill)、生长激素、逆交感神经剂、心血管药物、利尿剂、β-受体阻断剂、钙抑制剂、精神药物。
可使用与烷基呋喃联合使用的,并优选具有协同作用的能引起体重增加的高脂血症药物或食物,从而降低其整体的危险,和/或与降血脂药物或食物联合使用以降低体重,并对血糖起作用,获得更宽的功效范围。
粘质植物(Mucilage plants)在治疗高血糖症中起重要作用,因为他们对超重和胰腺过量分泌具有良好的功效。粘质纤维的亲水性,(通过形成凝胶)减少了碳水化合物和脂质的摄取。
在本发明中,与烷基呋喃联合使用的微量元素选自:镁、铬、硒或其混合物。在本发明中,与烷基呋喃联合使用的抗氧剂优选选自:锌、硫辛酸(单独使用或与维生素B12联合使用)、维生素C、黄酮类(绿茶...)、β胡萝卜素、番茄红素或叶黄素、抗糖化物质例如肌肽、N-乙酰基-半胱氨酸、大豆异黄酮、大豆蛋白。
已通过多种机制证明糖尿病患者体内由血糖水平增加诱导的氧化应激的增加。此外,一般认为氧化应激的增加促进了糖尿病并发症,例如大血管和小血管的损害(大血管病和微血管病)的发生。
包含磺酰脲和格列萘类的药物有助于胰腺生成更多的胰岛素。磺酰脲增加胰岛素水平达几小时。在进餐同时摄取的格列萘类使胰岛素增加的时间比磺酰脲短。低血糖为这些治疗的一种可能效果。包含α-糖苷酶抑制剂的药物降低了淀粉和糖的消化和吸收,导致餐后血糖降低。
在这些治疗的常见副作用中,可提及气体和肠胃气胀;然而,可逐渐增加剂量以降低这些副作用。包含双胍(甲福明)的药物主要对肝起作用。他们实质上阻止了肝在不必要时生成新糖。双胍药物可引起副作用,最常见的是胃痛和恶心。为了降低这些副作用,可适当地在进餐过程中摄取双胍。
包含胰岛素敏感度激活剂或PPAR激动剂噻唑烷二酮类(TZD、吡格列酮、罗格列酮)的药物是新类型的治疗剂。这种口服治疗的新类型被称为胰岛素敏感度激活剂或TZD。这些药物治疗胰岛素抗性(这是引起糖尿病的一个主要原因)。胰岛素抗性(insulin resistance)为身体不能适当地使用其生成的胰岛素的一种病症。TZD通过降低胰岛素抗性,使胰岛素(无论是生成的还是给药的)更加有效的起作用,从而有助于降低存在危险的血糖增加。在TZDs引起的可能的副作用中,可提及的包括体重增加、生成水肿(水分滞留)和轻微贫血。
在本发明中,可与烷基呋喃联合使用的降血脂药优选选自:他汀类或贝特类(PPARα激动剂)降血脂药。在本发明中,可与烷基呋喃联合使用的减肥药物优选选自奥利司他()和***()或)。不再使用以前的食欲抑制剂药物(苯异丙胺、芬氟拉明),因为他们有太多的副作用。在法国,仅有两种用于治疗肥胖的药物被授权可销售,它们是奥利司他(()和***(或)。奥利司他()具有阻止在消化道中负责脂肪吸收的酶的效果,因此,其阻止了约30%食物脂肪(甘油三酯)的吸收,其相当于每天摄取1800卡路里时减少150至200卡路里/天。未吸收的脂肪由粪便排出。***(或)是对脑神经递质起作用的分子,该脑神经递质在控制食物摄取中起作用。其具有加强饱胀感和减少食物摄取的性质。
在本发明中,可与烷基呋喃联合使用,并优选具有协同作用的防胖营养剂(anti-fat nutrients)优选选自:阻断脂肪吸收的营养剂,例如壳聚糖,其为从介虫的外骨骼提取得到的纤维、能增加热生成的营养素(″脂肪燃烧剂″)例如麻黄碱(中药麻黄)、咖啡因、茶素和柑桔酪氨酸、CLA(共轭的亚油酸,优选衍生自红花油)、富含ω3的鱼油、仙人掌中得到的脂质、能调节食欲的营养素的干燥提取物(“食欲抑制剂”)例如L-苯丙氨酸和L-酪氨酸、能调节血糖的营养剂例如矿物,例如铬、钒、镁或天然草药匙羹藤(Gymnena sylvestra)、脂肪生成抑制剂例如从藤黄果(Garcinia cainbogia)中提取的羟基柠檬酸和能运输脂肪的物质,例如L-肉毒碱。
本发明的另一个主题是包含一种或多种天然的或合成的烷基呋喃的美容组合物和/或营养组合物在美容处理与超重有关的疾病中的用途.
本发明的另一个目的是包含一种或多种天然的或合成的烷基呋喃的美容组合物和/或营养组合物在美容处理蜂窝组织中的用途。
在本发明中,超重的特征在于相对于非病理学“理想体重”而言的体重超过。本发明的美容性处理可减少或消耗局部过量脂肪,但不能认为这是治疗处理。
已证实局部应用包含一种或多种天然的或合成的烷基呋喃的美容组合物对孕妇或分娩小于6个月的妇女特别有效。本发明还有一个方面是促进减肥的美容性处理方法,尤其是对抗孕妇或分娩小于6个月的妇女的局部超重。本发明范围内所用组合物的一个优点是不需要用醇来制剂,因为其具有的毒性对孕妇或授乳妇女是禁忌的。咖啡因,当前经常使用的减肥制剂,需要醇来增溶,因此本发明避免使用。
在本发明中,″减肥″或″对抗局部超重″指可预防或至少减少皮下脂肪形成的作用,如上所述。特别地,这一作用可理解为减少难看的过量或贮备的脂肪、理解为使体型苗条、理解为加速消除过量脂肪、理解为较好地限制身体外形或重塑体型。在本发明中,″美容处理以对抗局部超重″意思是指明显可用其目测上述作用的美容处理的应用。例如,将根据本发明使用的包含一种或多种合成的或天然的烷基呋喃的局部美容组合物应用在有可能形成这些脂肪局部蓄积的皮肤区域,即这些蓄积已经形成或正在形成的区域。
在本发明中,在美容和/或营养组合物中作为活性成分使用的所述烷基呋喃为例如前述定义的那些。
在本发明中,烷基呋喃的使用比例优选占美容组合物总重的0.001至25重量%,进一步优选占1至10重量%。
食品补充剂可包含0.001至100重量%的本发明烷基呋喃。在食品中,可使用的纯烷基呋喃的含量为占食品总重的0.001至10重量%。
本发明的美容和/或营养组合物也可与下列物质联合使用并且优选具有协同作用:降血糖植物、微量元素、抗氧化剂、防胖营养素、甾醇非皂化物或包含相同物质的产品、甾醇、甾烷醇、植物甾醇、植物甾烷醇、维生素E类、向日葵浓缩物、油菜籽和/或棕榈油、ω3、6或9脂肪酸,例如如上描述的那些。
本发明的药物和美容组合物也可配制成适于口服或局部给药的多种制剂形式。本发明的营养组合物可配制成适于口服给药的多种制剂形式,或食品形式。
当药物、美容组合物或营养组合物经口给药时,他们可以以与本领域技术人员公知的适用于药用、美容用或食品用赋形剂混合的单元剂量或多剂量形式给药。合适的剂型特别地包含片剂、任选经刻痕的片剂、胶囊、粉末、颗粒和口服溶液或悬浮液。合适的多剂量形式特别地包含可饮用滴状物、乳剂和糖浆剂。当制备片剂时,将本发明的烷基呋喃与可接受的赋形剂例如明胶、滑石、淀粉、乳糖、硬脂酸镁、***胶或它们的类似物混合。片剂可任选地经包衣,即,用多层各种物质例如蔗糖包衣,以使它们更容易被摄取或更便于贮存。片剂也可以是具有较大或较小复杂性(complexity)的制剂,目的在于调节活性物质的释放速率。根据想要得到的吸收,可加速、减慢或延迟所述片剂活性物质的释放。通过混合本发明的烷基呋喃与稀释剂可得到胶囊制剂。将得到的混合物灌注于软和硬胶囊中。糖浆形式的制剂可包含本发明的烷基呋喃和甜味剂(优选不含卡路里的)、调味剂和合适的着色剂。水分散粉末或颗粒可包含本发明的烷基呋喃与分散剂或润湿剂、悬浮剂例如聚乙烯吡咯烷酮或甜味剂或味道矫正剂的混合物。
根据本发明的一个变型,所述药物和美容组合物可用于外部局部应用。他们也可包含药学或美容可接受的赋形剂。本发明的药物或美容组合物可以采用任意一种通常用于外部局部应用的盖仑形式(galenic forms)。有利地,根据本发明,药物或美容组合物可以采用以下形式:水、含水酒精或油溶液、水包油乳剂或油包水乳剂或多重乳剂、水或油凝胶、液体、糊剂或固体无水产品、或油利用球状物在水相中的分散液,所述球状物可以是聚合物纳米颗粒,例如纳米球,和纳米胶囊或甚至较好地为离子或非离子类型的脂质颗粒。药物和美容组合物可以包含大量或少量液体,形式为白色或彩色乳膏、软膏、乳状物、洗剂、油膏剂、浆剂、糊剂、泡沫剂、气雾剂或棒状物(stick)。
本发明的药物和美容组合物也可包含通常用于药物和/或美容领域的添加剂,例如亲水或亲脂的胶凝剂、亲水或亲脂的活性成分、防腐剂、抗氧化剂、溶剂、香料、填充剂、化学或矿物过滤剂(filters)、颜料、螯合剂、气味吸附剂、矿泉水和着色剂。这些不同添加剂的量为常规用于药物和/或美容品的量,例如占药物和美容组合物总重的0.01至20重量%。根据他们的类型,这些添加剂可被加入到脂肪相、脂质载体和/或纳米颗粒中。
当本发明的药物和美容组合物为乳剂时,脂肪相的比例可以为占组合物总重的5至80重量%,优选5%至50重量%。以乳剂形式用在组合物中的油、乳化剂、辅助乳化剂可选自在本领域考虑范围内那些常规使用的物质;组合物中乳化剂和辅助乳化剂的含量为占组合物总重的0.3%至30重量%,优选0.5%至20重量%。在本发明可使用的油中,特别提及的包括矿物油、其它植物油(杏油、向日葵油、李子油)、动物源的油、合成油、硅氧烷化油和氟化油(全氟聚醚)。脂肪醇例如十六烷醇(ketyl alcohol),脂肪酸或蜡类例如蜂蜡也可用作本发明的脂肪。在本发明可使用的乳化剂和辅助乳化剂中,特别提及的是脂肪酸酯和聚乙二醇酯,例如PEG-40硬脂酸酯或PEG-100硬脂酸酯,脂肪酸和多元醇酯例如硬脂酸甘油酯和三硬脂酸山梨醇酯。在本发明可使用的亲水胶凝剂中,特别提及的包括羧基乙烯基共聚物(卡泊姆),丙烯酸共聚物例如丙烯酸酯/烷基丙烯酸酯共聚物、聚丙烯酰胺、多糖、天然树胶和粘土。在亲脂性凝胶剂中,特别提及的是改性粘土,例如膨润土、脂肪酸金属盐、疏水性二氧化硅和聚乙烯。
本发明化合物和组合物的给药方法、剂量和最佳的盖仑形式可以通过适用于病人或动物的用于确定药用、兽医、美容用或营养治疗时的常用标准进行确定,例如患者或动物的年龄或体重、他们一般状况、治疗的耐受性、遇到的副作用、皮肤类型。
根据本发明组合物的一个变型,本发明的烷基呋喃可不受任何限制地加入到食品、饮料和营养制品中,包括乳制品(乳酪、奶油、牛奶和牛奶饮料、包含牛奶产品的果酱(spreads)、冰淇淋和酸乳酪)、脂肪基产品(人造奶油、果酱、蛋黄酱、烹调油、油炸油(frying oils)和油醋汁(vinaigrettes))、包含谷物的谷类基产品例如面包、面团(无论这些食品是否经制备的、烘箱烘焙的或加工的)、糕饼(巧克力、糖、口香糖、点心、糖浆、冰糕、上光剂和其它糖浆)、醇类或非醇类饮料(苏打和其它非醇类饮料、果汁、食品补充剂、饮料形式的膳食取代物例如以商品名BOOStTM和EnsureTM出售的那些)和多种产品(鸡蛋、经加工的食物例如汤、用于面团的即用调味料、即用菜品和其它相同类型的产品)。本发明的组合物可采用如下技术直接且不需要任何其它改变地加入到食品、营养品或饮料中,所述技术为:例如共混、输注、注射、混合、吸收、捏合和喷雾。对消耗者而言,也可在食品或饮料消耗前,直接将组合物应用至其中。这些给药方式容易且经济。
给出下述实施例意在阐述本发明,但其并不限制本发明的范围。
实施例
实施例1:
糖尿病患者去斑面部用美容品(总量:100g)
%
水 64.83
羽扇豆肽 7
鳄梨的呋喃非皂化物 2
丁二醇 3
十六烷醇 6
烷基乳酸酯C12-13 2
矿物油 7
鲸蜡硬酯醇醚-20(Ceteareth 20) 2
硬脂酸 1
白桑椹的提取物 1
维生素E 0.50
丙二醇 0.56
EDTA二钠 0.52
三乙醇胺 0.80
防腐剂 0.30
柠檬酸 0.25
尼泊金甲酯 0.11
硬脂醇醚-2 1
焦亚硫酸钠 0.05
亚硫酸钠 0.05
尼泊金丙酯 0.03
实施例2:
用于糖尿病患者皮肤护理的乳膏(总量:100g)
%
医用凡士林 6.00
氢化棕榈油 4.00
辛基癸酸甘油酯 2.00
(glycerol caprylo caprate)
蔗糖酯7(Sucro ester7) 6.00
(二硬脂酸蔗糖酯)
角鲨烷 1.00
小烛树蜡 2.00
蔗糖酯11(硬脂酸蔗糖酯) 0.50
2-烷基呋喃 2.00
向日葵浓缩物 2.00
甘油 5.00
葡萄糖糊精(Glucodextrin) 1.00
氨基丁三醇(Tromethamine) 0.01
黄原胶 0.20
羟甲基甘氨酸酯A 0.60
柠檬酸 0.32
环状聚二甲基硅氧烷(Cyclomethiconol) 5.00
神经酰胺/胆固醇 0.60
纯净水 5.00
实施例3:
用于糖尿病患者皮肤的保护性乳膏(总量:100g)
%
角鲨烷 1.00
硝酸戊四醇酯 4.00
癸基戊酸酯 4.00
十六烷基糖苷 2.00
月桂基醚23OE 1.00
Cutina CBSV 1.00
蜂蜡 0.50
肉豆蔻基肉豆蔻酸酯 1.00
防腐剂 0.30
稠凡士林 5.00
胶化的角鲨烷 3.00
鳄梨的呋喃油 10.00
纯净水 56.51
苯氧乙醇 0.80
EDTA钠 0.10
柠檬酸 0.14
山梨酸钾 0.45
甘油 5.00
增稠剂 0.50
氢氧化钠 0.30
聚丙烯酰胺凝胶60° 1.00
维生素E醋酸酯35° 0.50
香料 0.50
羽扇豆肽 1.00
环状聚二甲基硅氧烷 7.00
二氧化硅T102 1.00
染料木黄酮85% 0.10
PEG 300 0.90
实施例4:足部乳膏(总量:100g)
%
Montanov 68.3
氨苯唑K 0.50
Miglyol 812 6
防腐剂 0.30
乳木果油(Shea butter) 1
鳄梨的呋喃油 1
2-烷基呋喃 5
Na2EDTA 0.10
柠檬酸 0.01
防腐剂 0.40
丁二醇 1
胶凝剂 0.25
氢氧化钠 0.4
葡糖酸锰 0.05
锌盐 0.10
纯净水 至终体积
实施例5:
调节血糖和高胆固醇血症的制剂
高胆固醇血症和高甘油三酯血症
非诺贝特 200mg
鳄梨的呋喃非皂化物 100mg
用于带状(banded)胶囊的赋形剂 至终体积
多不饱和鱼脂肪酸 1000mg
鳄梨的呋喃油 500
铬 1
菠萝 50
苹果胶质 50
赋形剂 至终体积
阿伐他汀 10至40mg
2-烷基呋喃 33至100mg
赋形剂 至终体积
粘质(海藻酸钠) 500mg
鱼油 500mg
鳄梨的呋喃非皂化物 100mg
锌盐 1mg
鸡脚参 325mg
岩藻 50mg
用于软胶囊的赋形剂 至终体积
实施例6:营养粉末(总量:100g)
吸附于环糊精上的鳄梨的呋喃非皂化物 50.00
淀粉1500 49.40
硬脂酸镁 0.60
实施例7:减肥乳膏(总量:100mg)
%
丙稀酸脂交聚物(Carbopol Etd 2020) 0.6
黄原胶 0.15
染料木黄酮85% 0.1
醇+咖啡因 3.6
NaOH 0.001
防腐剂 0.9
鳄梨的非皂化物 2
Glucodextrin 2
香料 0.7
二氧化硅 0.3
纯净水 至终体积
实施例8:用于糖尿病患者足部的擦剂(总量:100g)
%
泊洛沙姆184 1.0000
香料 0.2000
纯净水 91.1550
PEG-32 4.0000
防腐剂 1.0000
氯己定 0.1500
苯氧乙醇 0.1000
尿囊素 0.2000
2-烷基呋喃 1.0000
增溶剂 1.0000
氨基丁三醇 0.1950
实施例9:
2-烷基呋喃对代谢的影响研究
1)测试产品
测试用非皂化鳄梨的纯呋哺成份购自Laboratoires Expanscience,商品名为(AV102),包含98重量%的8-11-顺式-顺式-十七烷二烯基-2-呋喃。
2)试验设计
我们使用了用高脂肪/高糖饮食(HF/HS)养肥的雄性成年小鼠(6周龄)。小鼠6周龄后开始喂养HF/HS饮食,并在研究期间继续按这种食物喂养。研究进行两轮:
-预防:一开始喂养HF/HS饮食就给药产品:
-处理(治愈):在HF/HS饮食开始12周后给药产品。
总处理时间(预防和治疗):23周。
每个试验组包含10只小鼠。对该试验而言,设定8个试验组:
-2个对照组:
·阴性对照:给予小鼠正常饮食
·阳性对照:给予小鼠HF/HS饮食
-2个标准组
·HF/HS+TZD饮食(噻唑烷二酮类(罗格列酮-PPARα激动剂):10mg/kg/天
·HF/HS饮食,然后在12周后以10mg/kg/天给药TZD
-2个处理组:
·HF/HS饮食+占饮食总量0.1wt.%的AV102
·HF/HS饮食+重量含量为0.25%的AV102
各个研究在D-7(即,在开始HF/HS饮食前7天)开始,通过对某些动物(n=5)使用腹膜内葡萄糖耐量试验,或对其它动物(n=5)进行静脉注射胰岛素敏感度试验进行葡萄糖耐量分析。在D=0,采集血样,得到所有脂质和脂蛋白参数的基础状况值,然后不考虑体重,随机分配小鼠。每周两次测定每只小鼠的体重和吸收的食物量。在第3、8、15和23周,禁食过夜后采集血样。在第12和18周,某些动物(n=5)接受腹膜内葡萄糖耐量试验,其它的(n=5)接受静脉注射胰岛素敏感性试验。在第19周,采集粪便物,分析脂质组成(甘油三酯测定法)。在第14周(预防)和第20周(预防和治疗),对麻醉的动物进行Dexascan分析来测定骨盐密度、骨骼重量和脂肪含量。在第21和22周,通过间接测热法来测定能量消耗。研究结束时(第23周),处死动物,回收它们的肝、肠、脂肪组织和肌肉,称重,冷冻,贮存在-80℃,用于另外的分析。准备肝和脂肪组织也用于组织学分析。
在第3、8、15和23周,进行下述血液测试:血脂(总胆固醇、甘油三酯、高密度脂蛋白(HDL)″优良″胆固醇、低密度脂蛋白(LDL)″不良″胆固醇、游离脂肪酸);葡萄糖和胰岛素;瘦蛋白(leptin)、TNF-α;转氨酶和碱性磷酸酶(肝毒性)。随后,进行下述分析:脂蛋白特征(通过分子筛色谱);载脂蛋白A1;肝的脂质组成(肝脏甘油三酯、胆固醇和游离脂肪酸);肝和脂肪组织的组织学分析;肝中蓄积的脂质的染色。
3)结果
理论上被小鼠吸收的AV102剂量为0.1%AV102的160mg/kg/天(25g小鼠,进食4g食物/天)和400mg/kg/天(25g小鼠,进食4g食物/天)。在治疗期和预防期可有效地被小鼠吸收的剂量在下表2中列出:
治疗期 | 预防期 | |
AV102(0.1%) | 94±10mg/kg/天 | 136±24mg/kg/天 |
AV102(0.25%) | 183±42mg/kg/天 | 314±72mg/kg/天 |
表2
小鼠摄入的AV102剂量(治疗和预防)
1.食物摄取和体重增加
据证实,对正常喂养的小鼠而言,不同的治疗剂没有影响。也发现,用含有AV102(0.1%或0.25%)的HF/HS饮食喂养的小鼠体重减轻。结果在下表3中列出:
表3:进行HF/HS饮食的小鼠的食物摄取-体重
在下表4中,给出了进行不同HF/HS饮食(正常饮食/仅HF/HS饮食/含有TZD的HF/HS饮食和含有0.1%或0.25%AV102的HF/HS饮食)的小鼠在处理20周后的体重与这些小鼠在处理前的体重的比例(预防0周,治疗12周)。
表4:进行HF/HS饮食的小鼠体重
食物摄取
预防组:观察到进行含0.1%AV102(±3.7克)HF/HS饮食的小鼠的消耗接近正常。在进行含0.25%AV102的HF/HS饮食的小鼠中,观察到正常消耗一直至D56,然后缓慢降低,在处理结束发现恢复到正常值,对结果没有影响(平均消耗3G:同上TZD)。
治疗组:发现活性成分特别是0.25%AV102(4g对照组,3gTZD0.1%AV102,2.5g0.25%AV102)的影响,
体重增加
预防组:在进行含0.1%AV 102的HF/HS饮食的小鼠中,发现所述小鼠体重降低11%;即,恢复到正常体重。在进行含0.25%AV102的HF/HS饮食的小鼠中,发现所述小鼠体重降低32%;在治疗结束时,这些小鼠的体重低于正常饮食小鼠的体重。
→浓度为0.25%的AV102对抗体重增加,可引起进行HF/HS饮食小鼠体重的实质性降低,早在治疗第一天就开始起效。
治疗组:仅HF/HS饮食,小鼠体重增加12%。给食物中加入TZD不能引起超重小鼠体重减少。给食物中加入0.1%AV102引起体重降低11%,恢复至正常值。加入0.25%AV102使小鼠体重的降低提高至33%,即与正常相比,体重实质上减轻了。
→在一定的剂量/时间(几乎立即)作用下,AV102使最初超重小鼠体重减轻,其可引起小鼠体重实质上减轻。
2.血液参数
·脂质
使用HPLC法分析各种胆固醇血液浓度和各种成分。
W=周TG=甘油三酯FFA=游离脂肪酸
表5:
预防组:在用TZD处理3、8、15和23周后观察到总胆固醇、HDL胆固醇水平的显著降低。在该组中,LDL胆固醇水平也显示出下降趋势。在血浆脂蛋白特征中也发现了这种降低,其显示在第8和15周时,HDL、LDL和VLDL(极低浓度脂蛋白)胆固醇成分减少。
用0.1%AV102处理小鼠3和15周后,和用0.25%AV120处理小鼠3、15和23周后,小鼠总胆固醇增加。在第8和15周,用两种剂量的AV102处理的小鼠中,脂蛋白的特征显示出HDL胆固醇成分增加,LDL和VLDL胆固醇成分减少。
用TZD和0.1%AV102处理8周后,发现血浆甘油三酯水平显著降低,而在用这些产品处理15和23周后,没有观察到另外的降低。用0.25%AV102处理3、8、15和23周后,观察到胆固醇水平的显著降低。
游离脂肪酸水平没有显示出显著的改变。
治疗组:用TZD处理3周和11周后,观察到总胆固醇、HDL和LDL胆固醇水平的降低。处理3周后,这些小鼠的脂蛋白特征也显示出HDL和VLDL胆固醇成分的减少。
用两种剂量的AV102处理的小鼠3周和11周后,总胆固醇趋向于增加。用0.25%AV102处理小鼠11周,其脂蛋白特征显示出LDL胆固醇成分增加,HDL和VLDL胆固醇成分减少。
用0.25%AV102处理小鼠3周和11周,甘油三酯水平显著降低。而用TZD和0.1%AV102处理,没有观察到甘油三酯水平的改变。
用两种剂量的AV102处理10周后,游离脂肪酸的水平降低。
因此,鳄梨呋喃,特别地,0.25%的鳄梨呋喃:
·能预防性地或治疗性地阻止甘油三酯的升高,引起其非常显著的降低,
·增加了总胆固醇、HDL,减少了LDL、VLDLTZD对TGs几乎没有或没有作用,但其减少了总胆固醇。
·葡萄糖
A-血糖分析
预防组:3周后,每组的葡萄糖水平都降低了。在第8、15和23周,用两种剂量的AV102处理的小鼠中都能观察到这种减少;另一方面,用TZD处理的小鼠中不再观察到这种减少。
TZD减少“结构型(constitutive)”高血糖症,使其恢复到正常值。剂量为0.25%的AV102作用非常显著,比TZD更有效。
与正常饮食组血糖相比,就各组中血糖在第3周和第23周的百分比变化而言,则所有的活性成分对油脂性饮食引起的高血糖症都有作用。AV102为其剂量-效应活性可以以非常明显的方式保持整个研究期间都是如此的化合物。
治疗组:用TZD和0.25%AV102处理3周和11周后,葡萄糖水平明显降低。
B-葡萄糖抗性(IPGTT)
IPGTT=腹膜内葡萄糖抗性试验(禁食)
在肥胖儿童中可发现非常高的葡萄糖失调耐量(disturbed tolerance)占优势。而且,这种占优势的耐受性通常伴有胰岛素抗性。
实验设计:-禁食小鼠,
-测定T0时的血糖
-腹膜内注射葡萄糖
-测定注射后15、30、45、60、90、120和180分钟时的血糖
-对预防组在1、12和18周和对治疗组在第18周进行动力学研究
预防组:IPGTT试验结果显示在第12和18周HF/HS饮食+0.25%AV102的小鼠的曲线下面积(AUC)减少。进行含TZD的HF/HS饮食的小鼠的AUC没有显著性减少。
HF/HS饮食增加了葡萄糖耐量。TZD降低了葡萄糖耐量:在第12周,AUC值介于HF/HS和正常饮食的中间值。在第18周,TZD完全抵偿了HF/HS饮食的影响,恢复到正常动力学。在第12周和18周,与HF/HS相比,0.1%和0.25%AV102显著降低了葡萄糖耐量,作用强于TZD。在这一天,曲线位于正常动力学下。
治疗组:IPGTT试验的结果具有与在预防组观察到的结果相同的特征:观察到用0.25%AV102处理6周的小鼠的AUC减少。
HF/HS饮食诱导较强的葡萄糖耐量。TZD对已经建立的、饮食诱导的葡萄糖耐量没有作用。0.1%和0.25%AV102对这种耐量最有效,具有剂量效应。
C-胰岛素敏感度(预防组)
糖尿病患者患有会导致高血糖症的胰岛素抗性增加。使用的试验为腹膜内胰岛素敏感性试验-IPIST。
实验设计:-禁食小鼠,
-测定T0时的血糖
-腹膜内注射葡萄糖
-测定注射后0、15、30、45、60和90分钟时的血糖
-对预防组在1和12周进行动力学研究
HF/HS饮食减少了对胰岛素的敏感度。TZD恢复对胰岛素的敏感度(15分钟)。在用0.1%和0.25%AV102处理的小鼠中观察到敏感度显著增加。
在下表6中概述了各种结果:
W=周
表6:葡萄糖对代谢的影响
最后,(葡萄糖对代谢的影响),可使用鳄梨二呋喃:
-降低预糖尿病小鼠的血糖,
-治疗由HF/HS饮食诱导的受损的葡萄糖耐量,和
-恢复胰岛素敏感度。
在预糖尿病和肥胖小鼠中,鳄梨呋喃对葡萄糖代谢的调节比TZD更好。
·肝代谢
转氨酶(ALAT和ASAT)不能通过各种处理来改变。所有组中都可观察到碱性磷酸酶(ALP)的增加。在0.25%AV102组中特别高。还注意的是,在对照组中,在整个研究过程中,ALP显示出非常显著地减少,毫无疑问,这反映出与动物衰老有关的骨转化减少。
在TZD和AV102组中,可认为血浆ALP的增加非常适度,没有表现出肝毒性,因为其它的肝酶(ALAT和ASAT)没有被各种处理改变。这种结果可能更多地与如Dexascan证实的骨密度减少相关。
3.脂肪
预防组:用AV102以314±72mg/kg/天(14和20周)和以136±24mg/kg/天(20周)处理后,动物体的脂肪指数显著降低。TZD对这一参数没有影响。用这两种剂量的AV102也观察到瘦蛋白减少。
治疗组:用AV102以183±42mg/kg/天处理8周后,体脂肪指数降低,但是以94±10mg/kg/天处理,不会降低。没有观察到对瘦蛋白有影响。
4.其它参数
·骨密度:在第14周和第20周,在预防组(两种剂量)和治疗组中(0.25%AV102)减少;
·体温:预防组中没有改变。用TZD和AV102的治疗组中有少量升高。
·能量消耗(量热法):没有改变。
·甘油三酯:用AV102,肝和肌肉中的甘油三酯显著减少(预防组:0.25%AV102,和治疗组:0.25%AV102)。在预防组中,粪便中含有的0.1%AV102增加。
5.组织重量
预防组:用AV102,观察到棕色脂肪组织重量的显著减少(>TZD)(剂量依赖效果),在绝对条件(absolute terms)下,观察到肝重量没有改变。同样在绝对条件下,用TZD和AV102(AV102>TZD),观察到肌肉重量减少。
治疗组:用0.25%AV102处理的小鼠中,观察到棕色脂肪组织的重量显著减少。在绝对条件下,观察到肝重量没有改变。如果比较肌肉质量的绝对值,各组没有显著性不同。
6.组织学
在预防组和治疗组中,用0.25%AV102处理的小鼠的肝脏中观察到脂质蓄积的减少。
线粒体的标记:与HF/HS组比较,在所有处理组中观察到显示增加的标记。在用0.25%AV102的治疗组中,观察到最强的效应。
7.mRNAs的分析
在肝中,使用实时Q-RT-PCR分析确定每组5只小鼠中8种基因的mRNA表达。结果在表7中给出。
ACO=乙酰辅酶A氧化酶
PEPCK=磷酸烯醇丙酮酸羧基激酶
GSH-S-转移酶=谷胱甘肽-S-转移酶
CYP7A1=细胞色素P4507A1
ME=苹果酸酶,FAS=脂肪酸合成ACC=乙酰辅酶A羧化酶
肝 | TZD | AV102(0.25%) |
ACO(靶向PPARα) | ↑ | ↑↑↑ |
PEPCK(靶向PPARγ) | ↑ | ↑↑↑ |
GSH-S-转移酶(靶向PXR) | ↑ | ↑ |
CYP7A1(将氧化型胆固醇转化成胆汁酸) | ↑↑ | ↑↑ |
ME、FAS、ACC(脂肪酸合成) | ↑↑ | ↑↑ |
表7:肝中mRNAs的分析
0.25%AV102活化了体内的PPARα和PPARγ激动剂。同TZD一样,0.25%AV102也活化了PXR。最后,0.25%AV102增加了参与脂质和葡萄糖代谢的酶的表达,使由HF/HS饮食诱导的病理学效应正常化。
在棕色脂肪组织(BAT)和在肌肉中,使用实时Q-RTR-PCR分析确定每组5只小鼠中3种基因的mRNA表达。结果在表8中给出。
UCP-1-PGC-1=解偶联蛋白-1
PGC-1=辅助激活因子-1PPARy
MCPT-1=肌肉型肉碱棕榈酰转移酶-1
肌肉/BAT | TZD | AV102(0.25%) |
UCP-1(热生成) | - | - |
PGC-1(线粒体生物合成) | ↑(肌肉) | ↑(肌肉) |
GSH-S-转移酶(靶向PXR) | ↑ | ↑ |
MCPT-1(靶向PPARα)进入线粒体的脂肪酸 | - | ↑↑(脂肪组织) |
表8:肌肉和BAT中mRNAs的分析
0.25%AV102促进了BAT中的β氧化。而且,肌肉中PGC-1的表达的增加可有助于肌肉中线粒体的增加。
4)结论
AV102:阻止了HF/HS饮食导致的体重增加,减少了进行HF/HS饮食的肥胖小鼠的体重,减少了肝和肌肉中的TGs,减少了血糖,增加了葡萄糖耐量,对胆固醇有相反的作用,但增加了优良胆固醇而减少了不良胆固醇,诱导肝和褐脂肪组织中靶向PPARα和γ基因的表达。在肌肉中,倾向于增加PGC-1,其解释了肌肉中线粒体标记的增加。而且,AV102具有良好耐受性。
结论为,高呋喃饮食可限制II型糖尿病和血脂异常症中的超重和肥胖的危险;这将转化为并发的心血管危险的降低。
在男性中,认为可以使用的剂量为AV102约60mg/天,即约0.86mg/kg/天的AV102或约2.8.10-6摩尔/kg/天的AV102。
Claims (5)
3.根据权利要求2所述的用途,其特征在于所述的烷基呋喃为在鳄梨呋喃非皂化物中存在的天然2-烷基呋喃。
4.根据权利要求2所述的用途,其特征在于所述的天然2-烷基呋喃来自鳄梨非皂化物的经纯化的呋喃组分。
5.一种或多种合成的或天然的根据权利要求1至4中任一项中定义的通式(I)所描述的烷基呋喃在制备用于控制血糖和/或胰岛素敏感度的药物或兽药组合物中的用途。
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2004
- 2004-05-28 FR FR0405782A patent/FR2870742B1/fr not_active Expired - Lifetime
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2005
- 2005-05-27 CN CN200580017371XA patent/CN1960722B/zh not_active Expired - Fee Related
- 2005-05-27 EP EP05773032A patent/EP1765323B1/fr active Active
- 2005-05-27 WO PCT/FR2005/001310 patent/WO2005117856A1/fr active Application Filing
- 2005-05-27 US US11/597,635 patent/US8859617B2/en active Active
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- 2005-05-27 CA CA2566970A patent/CA2566970C/fr not_active Expired - Fee Related
- 2005-05-27 ES ES05773032T patent/ES2331847T3/es active Active
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EP0046595A1 (en) * | 1980-08-27 | 1982-03-03 | Merrell Dow Pharmaceuticals Inc. | Acylated furanyl and thienyl acrylic acids, process for their production, and pharmaceutical compositions |
FR2678614A1 (fr) * | 1991-07-03 | 1993-01-08 | Pharmascience Lab | Compose presentant une activite en tant qu'inhibiteur de la collagenase et medicament le contenant. |
WO1993011101A1 (en) * | 1991-11-27 | 1993-06-10 | Pleshakov, Mikhail Georgievich | Derivatives of arylsulphoacids having hypoglycemic activity |
EP0775480A1 (en) * | 1993-10-25 | 1997-05-28 | S. Richard Huber | Novel lipidic furans useful for skin therapeutics |
US6030993A (en) * | 1996-07-02 | 2000-02-29 | Sang Sup Jew | 2-hydroxypropionic acid derivative and its manufacturing method |
CN1307474A (zh) * | 1998-06-26 | 2001-08-08 | 宝酒造株式会社 | 一种治疗剂 |
WO2001021605A2 (fr) * | 1999-09-22 | 2001-03-29 | Laboratoires Pharmascience | Procede d'extraction des composes lipides furaniques et alcools gras polyhydroxyles de l'avocat, composition a base de ces composes et leur utilisation en therapeutique, cosmetique et alimentaire |
JP2002212177A (ja) * | 2000-11-14 | 2002-07-31 | Takeda Chem Ind Ltd | 脂質代謝改善剤 |
US20030120073A1 (en) * | 2001-04-25 | 2003-06-26 | Seto Christopher T. | Alpha-ketocarboxylic acid based inhibitors of phosphoryl tyrosine phosphatases |
WO2003004484A1 (fr) * | 2001-07-02 | 2003-01-16 | Maruha Corporation | Nouveaux composes aliphatiques, procede de synthese et leur procede d'utilisation |
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KIM,JIN IL ET AL.New antihypercholesterolemic agents 2. Synthesis andbiological activity of ethyl7-(2-furyl)-3,5-dihydroxy-1-heptenoate.KOREAN JOURNAL OF MEDICINAL CHEMISTRY4 1.1994,4(1),第10-15页. * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110604760A (zh) * | 2012-01-13 | 2019-12-24 | 扩展科学实验室 | 鳄梨果皮用于获得富含饱和脂肪族烃和甾醇的鳄梨非皂化物中的用途 |
Also Published As
Publication number | Publication date |
---|---|
JP4795337B2 (ja) | 2011-10-19 |
MXPA06013883A (es) | 2007-01-26 |
ES2364153T3 (es) | 2011-08-25 |
CN1960723A (zh) | 2007-05-09 |
HK1100167A1 (en) | 2007-09-07 |
JP2008501003A (ja) | 2008-01-17 |
CN1960723B (zh) | 2010-09-08 |
US20080081837A1 (en) | 2008-04-03 |
WO2005117856A1 (fr) | 2005-12-15 |
DE602005016680D1 (de) | 2009-10-29 |
ES2331847T3 (es) | 2010-01-18 |
CN1972661B (zh) | 2011-03-16 |
EP1765323A1 (fr) | 2007-03-28 |
FR2870742A1 (fr) | 2005-12-02 |
CN1972661A (zh) | 2007-05-30 |
EP1765323B1 (fr) | 2009-09-16 |
CA2566970C (fr) | 2012-08-28 |
CN1960722A (zh) | 2007-05-09 |
CA2566970A1 (fr) | 2005-12-15 |
FR2870742B1 (fr) | 2008-03-14 |
ATE442845T1 (de) | 2009-10-15 |
US8859617B2 (en) | 2014-10-14 |
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