CN101742916A - 减轻视黄酸治疗副作用和/或改进疗效而不干扰疗效的方法 - Google Patents
减轻视黄酸治疗副作用和/或改进疗效而不干扰疗效的方法 Download PDFInfo
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Abstract
本发明涉及烟酸烷基酯(特别是烟酸肉豆蔻基酯)抑制与视黄酸治疗有关之副作用的用途。本发明还涉及改善皮肤细胞分化的方法,其通过施用一定量的足以增加胱天蛋白酶-14(Caspase-14)和聚丝蛋白表达的烟酸烷基酯来实现。这些分子表达的缺陷也可以用这种方式进行治疗。
Description
相关申请
本申请要求2007年2月28日提交的申请号为60/903,937之申请的优先权,其通过引用以整体并入本文。
技术领域
本发明涉及烟酸衍生物减轻由视黄酸治疗引起之副作用和/或改进疗效而不干扰视黄酸疗效的用途。更具体地,烟酸衍生物例如直链烟酸烷基酯(尤其是烟酸肉豆蔻基酯)减轻视黄酸治疗的副作用(例如但不限于紧绷(tightness)/干燥、刺痛、灼痛和麻刺感),如下文所述。本发明还涉及通过增加胱天蛋白酶-14(Caspase-14)和聚丝蛋白(filaggrin)的表达来改善皮肤细胞的分化。
背景技术
类视黄醇——维生素A(视黄醇)的天然代谢物和合成类似物——是皮肤功能的重要调节剂。Fisher,等,Faseb J 1996;10:1002-13。因可能用于外用治疗皮肤光损伤,全反式视黄酸(维甲酸)(主要的生物活性天然类视黄醇)多年来成为一个研究热点。1986年有报道称,经数月治疗后,视黄酸可使皮肤更光滑、皱纹减少以及色素减少。Kligman等,J Am AcadDermatol 1986;15:836-59。
皮肤长期暴露在日光下会导致一系列进行性的变化,包括皮肤肌理的丧失、表皮和角质层逐渐变薄(Gilchrest,Br J Dermatol 1996;135:867-75)、真皮表皮交界处变平(Benedetto,Clin Dermatol 1998;16:129-39)、产生色素沉着过度的区域(Gilchrest,同上)、皱纹以及非典型形态的角质形成细胞(其可能是角化病和非黑素瘤皮肤癌的前体)的累积(Cho等,J Am Acad Dermatol 2005;53:769-74;Lober等,J Am AcadDermatol 2000;43:881-2)。光损伤在表皮和真皮部分均会发生,在这些部分中类视黄醇已被证明具有显著的药理效应。Gendimenico等,SkinPharmacol 1993;6增刊1:24-34;Varani等,J Invest Dermatol 2000;114:480-6;Cho等,同上。在光损伤皮肤的表皮中,长期外用类视黄醇治疗导致表皮层和颗粒层厚度呈剂量依赖性增加、角质层致密、黑色素含量减少以及表皮异型(epidermal atypia)改善。Fisher等,同上;Cho等,同上;Olsen等,J Am Acad Dermatol 1992;26:215-24;Machtinger等,Br JDermatol 2004;151:1245-52。在角质形成细胞中,类视黄醇诱导增殖,这可能是由表皮生长因子受体活化所导致的表皮增生介导的。Rittie等,JInvest Dermatol 2006;126:732-9。
视黄酸诱导角蛋白K6、K16和K17(它们通常在过度增殖的表皮细胞中表达)的表达,这表明类视黄醇在基部和/或较下部的表皮棘层中促进细胞增殖。Eichner等,Br J Dermatol 1996;135:687-95。类视黄醇还可使色素沉着过度的皮肤变浅,降低培养黑素细胞中酪氨酸酶的活性(Hoal等,Cancer Res 1982;42:5191-5;Kang等,Am J Clin Dermatol 2005;6:245-53),抑制增殖和脂质合成以及改变培养的人皮脂腺细胞(sebocyte)中角蛋白的表达。Zouboulis等,J Invest Dermatol 1991;96:792-7。在真皮中,其效应包括促进成纤维细胞增殖(Varani等,同上),促进胶原蛋白产生(Griffiths等,N Engl J Med 1993;329:530-5)以及减少细胞外基质的降解(Fisher和Voorhees,同上)。
真皮中胶原蛋白的降解是形成皮肤皱纹的主要因素。长期使用视黄酸使真皮修复区中的胶原蛋白基质沉积显著增加,这种效应似乎导致了对光损伤皮肤进行视黄酸治疗时的皱纹减少。(Cho等,同上;Kang等,同上)。
尽管视黄酸对于光损伤皮肤具有诸多优势(Kang等,同上),但是它常常伴有显著的皮肤刺激性,这限制了使用其进行治疗的依从性。Lowe等,J Cosmet Laser Ther 2004;6:79-85。最常报道的视黄酸治疗相关副作用包括皮肤上的刺激性、干燥、脱皮、红斑以及灼烧感。Lowe等,同上。这些副作用常常导致治疗的中止。
因此,需要一种减少或消除视黄酸治疗相关副作用的方法。
导致类视黄醇副作用的机制尚不完全清楚,但已知视黄酸治疗削弱角质层的屏障功能(其可通过TEWL测量进行评估)。Tagami等,Br JDermatol 1992;127:470-5。屏障削弱已被归因于类视黄醇诱导的表皮增生(Varani等,Arch Dermatol Res 2003;295:255-62)以及终末分化程序的改变(Fisher等,同上)。红斑(其反映表皮细胞因子(如IL-I)的产生)可能是由类视黄醇刺激角质形成细胞的增殖直接导致或者由表皮屏障削弱而导致。Wood等,J Invest Dermatol 1996;106:397-403;Blanton等,ProcNatl Acad Sci USA 1989;86:1273-7。类视黄醇诱导的角质层致密(Olsen等,同上;Machtinger,同上)可能与屏障削弱有关,这是因为角质层厚度是屏障功能的主要决定因素(Ya-Xian等,Arch Dermatol Res 1999;291:555-9;de Jongh等,Br JDermatol 2006;154:651-7)。
烟酸衍生物已被开发用于向皮肤最佳地外用递送烟酸(Jacobson等,Developing Topical Prodrugs for Skin Cancer Prevention.In:Fundamentals of Cancer Prevention(Alberts DS,Hess,Lisa M.编)BerlinHeidelberg:Springer-Verlag,2005:139-60),并已显示在光损伤皮肤中促进表皮分化,从而导致角质层和表皮厚度的增加以及皮肤屏障功能的增强(如通过TEWL速率降低来评估)。Jacobson等,ExperimentalDermatology(待发表)。烟酸衍生物还描述于美国专利No.6,337,065、6,677,361、6,750,234和6,924,299中,其均通过引用以整体并入本文中。
一种这样的烟酸衍生物是烟酸肉豆蔻基酯,其被开发用于向皮肤最佳地外用递送烟酸。已显示,烟酸肉豆蔻基酯在光损伤皮肤中促进表皮分化,从而导致角质层和表皮厚度的增加以及皮肤屏障功能的增强(如通过TEWL比率降低来评估)。Jacobson等,Experimental Dermatology(待发表)。
因此,本发明的一个目的是使用烟酸衍生物来治疗由视黄酸治疗所引起的副作用。本发明还涉及通过使用这些烟酸衍生物来改善皮肤细胞分化。
优选实施方案详述
实施例1
为了研究视黄酸疗法与烟酸肉豆蔻基酯(myristyl nicotinate,MN)的联用,在患有轻度至中度面部光损伤的对象中进行临床研究,其中烟酸肉豆蔻基酯是增强皮肤屏障功能的亲脂性烟酸衍生物。
本研究所选的所有对象均为年龄在30岁到60岁之间的女性,其菲茨帕特里克皮肤分类(Fitzpatrick Skin Classification)评分为I到IV,根据改良的格洛高分类(Glogau Classification)I至II级界定为轻度至中度皮肤光损伤,并通过woods光可视化扫描(woods light visual scan)确定脸部存在皮肤变色。
将所述对象随机分配到每组20个对象的三个组中。在开始进行视黄酸治疗前一个月,其中一组(第3组)开始在整个脸部早晚施用含有5%烟酸肉豆蔻基酯的制剂。第1组和第2组则以同样的方式应用安慰剂制剂,其中用肉豆蔻酸肉豆蔻基酯替代了烟酸肉豆蔻基酯。在开始进行视黄酸治疗(基线)后,第1组(安慰剂/安慰剂+RA)继续使用上述安慰剂制剂,第2组(安慰剂/MN+RA)开始使用含有5%烟酸肉豆蔻基酯的制剂,而第3组(MN/MN+RA)则继续使用含有5%烟酸肉豆蔻基酯的制剂。在应用含有安慰剂或烟酸肉豆蔻基酯的制剂后随即在夜间使用药物浓度为0.025%的视黄酸治疗。由于所述对象具有轻度至中度的光损伤,因此在本研究中选择该视黄酸强度。
在整个研究期间,还向所述对象提供了用于面部清洁和防晒的温和型液体清洁剂和防晒霜。清洁后,对象在整个面部应用所分给的测试保湿剂[烟酸肉豆蔻基酯(5%)或者用肉豆蔻酸肉豆蔻基酯替代烟酸肉豆蔻基酯的安慰剂],每天应用两次。在本研究的用药阶段,对象在应用测试保湿剂之后在面部应用视黄酸制剂(0.025%),每天在夜晚应用一次。
评价了5%烟酸肉豆蔻基酯制剂对皮肤屏障功能之替代标志、临床和感官刺激性以及与视黄酸应用有关的临床疗效的影响。利用眶周皮肤活检样品来评估角质层的厚度,测定经表皮水份丢失(transepidermal waterloss,TEWL)的速率作为屏障功能的替代量度,通过临床分级评价耐受性,并通过临床分级、患者自我评估以及分析活检样品的表皮厚度来评估疗效。
角质层致密通常伴随着视黄酸治疗而发生,而对于屏障功能增强与角质层厚度增加相关性的研究(Ya-Xian等,同上;de Jongh等,同上)提出了一种可能性,即角质层致密是参与视黄酸治疗相关之屏障削弱的一个因素。
因此,评估了取自研究对象眶周活检样品的角质层厚度。在基线处和治疗12周后,经认证的皮肤科医生从经随机化设计之每组中随机选择的7个对象的面部左侧或右侧收集了2mm钻孔活检样品。对所述钻孔活检样品进行福尔马林固定,包埋在石蜡中,切成5μm的横切片,在载玻片上封片并进行苏木精-伊红染色(H&E)。
使用10倍物镜(0.45复消色差透镜)的奥林巴斯倒置显微镜和尼康数码CCD照相机拍摄经H&E染色的横切片的组织学图像。使用ImageJ图像分析软件(NIH)来分析图像以及进行测量。测量了乳突上(suprapapillary)表皮厚度(从真皮乳突顶部到颗粒层顶部测量)和角质层的厚度(从颗粒层顶部到角质层顶部测量)。对于每个标本来说,测量了5个不同的位点,并计算了平均值。
在基线处,安慰剂/MN+RA组的角质层厚度的平均值略高于安慰剂/安慰剂+RA组,但该差异并非统计学显著性的。已用5%烟酸肉豆蔻基酯治疗一个月的MN/MN+RA组的角质层厚度平均值高于其它两组,但并未达到统计学显著性(p<0.05)。然而,先前的研究表明,光损伤皮肤经过5%烟酸肉豆蔻基酯治疗3个月会引起角质层厚度增加超过50%。因此,MN/MN+RA组的平均值与其它组的平均值相比约高出11%,这与已知的烟酸肉豆蔻基酯的作用一致。
在12周的视黄酸治疗过程中,安慰剂/安慰剂+RA组中角质层厚度减少约24%(p=0.006,与基线处相比),而同时使用烟酸肉豆蔻基酯和视黄酸未导致角质层厚度的减少。在治疗12周时,安慰剂/安慰剂+RA和安慰剂/MN+RA组之间角质层厚度平均值的差异具有高度的统计学显著性(p=0.005)。在12周时,MN/MN+RA组和安慰剂/安慰剂+RA组之间角质层厚度平均值的差异也具有高度的统计学显著性(p=0.003)。这些结果表明,同时使用或者先行且同时使用烟酸肉豆蔻基酯减轻了视黄酸治疗相关的角质层致密。
TEWL速率的测定提供了一种对相对皮肤屏障功能的非侵入性评估。因此,对研究对象面部进行TEWL测量,并用作比较安慰剂组和烟酸肉豆蔻基酯治疗组之屏障功能的替代标志。对于TEWL测量来说,其设备需要特定的温度和湿度范围以实现最佳的运行状态,因此对象在测量之前需要与外界环境平衡至少20分钟。温度保持在66~72°F,相对湿度维持在15~55%。使用与计算机连接的Dermalab设备来测量所研究对象右侧脸颊皮肤表面上两点的TEWL,并计算水份丢失的速率。计算每个TEWL测量在1分钟测量期间的平均值。
在12周期间,安慰剂/安慰剂+RA组中的TEWL速率增加了约45%,这一数值具有高度的统计学显著性(p<0.0001)。安慰剂/MN+RA和MN/MN+RA组中的TEWL速率的平均值也有所增加,但是该变化与基线处相比不具有统计学显著性。在12周时,安慰剂/安慰剂+RA组和MN/MN+RA组之间的差异(p=0.056)显示出趋于统计学显著性的强烈趋势。
这些结果表明,同时使用烟酸肉豆蔻基酯减轻了屏障损伤,而先行且同时使用则提供了与仅仅同时使用相比更好的屏障保护。
临床分级
为了评估视黄酸治疗的耐受性和疗效,在基线处、第2周、第4周、第8周和第12周,针对面部的右侧和/或左侧将对象进行临床分级以获得疗效/效果参数和刺激性/安全性参数。
在第2周、第4周、第8周和第12周,将最严重的耐受性参数(如剥落/脱皮和红斑程度)根据3分制临床评分表进行分级,并测定了平均值。还评估了视黄酸治疗典型的严重性较低的耐受性参数(包括紧绷/干燥、刺痛、灼痛和麻刺感)的发生频率。
剥落/脱皮的程度在所有组中均非常低,并且红斑程度也相对较低,这表明对浓度为0.025%的视黄酸和/或在治疗前和治疗期间每天两次定期使用保湿剂具有普遍的高耐受程度。安慰剂组和烟酸肉豆蔻基酯组之间的任一参数均不具有统计学显著性差异,尽管烟酸酯治疗对象中的红斑分级总是略高。
尽管剥落/脱皮或红斑的水平低,但在本研究中观察到视黄酸的严重性较低但常见之副作用的显著发生频率。针对这些耐受性参数观察到了一致的模式,即同时使用烟酸肉豆蔻基酯降低了紧绷/干燥、刺痛和灼痛的发生频率,并且先行且同时使用烟酸肉豆蔻基酯进一步降低了每种所述参数的发生频率。尽管所报道的麻刺感发生频率相当低(2%),但MN/MN+RA组中该副作用的发生率降至0。
除了临床分级以外,研究对象还完成了收集有关治疗耐受性信息的自我评估问卷。这些自我评估在所有病例中均与临床分级平行进行,即对同样的参数进行评估。总体来说,结果显示烟酸肉豆蔻基酯的使用提高了视黄酸治疗的耐受性。
专家临床分级、患者自我评估以及对活检样品之表皮厚度的分析也被用于研究烟酸肉豆蔻基酯对视黄酸治疗疗效的作用。
临床分级包括评价作为治疗时间(在第2周、第4周、第8周和第12周)之函数的色素沉着异常(dyschromia)、细纹、浅皱纹、触觉麻木(tactile roughness)和太阳穴松弛。尽管各组之间最初的光损伤程度存在一些差异,但是在所有三组中均观察到了针对色素沉着异常、细纹和浅皱纹的相似改善率。对于触觉麻木也观察到这样的情形,但MN/MN+RA组从第4周到第12周的分数持续显示出较大的改善。在第12周时,MN/MN+RA组的太阳穴松弛分级与安慰剂/安慰剂+RA组相比显示出统计学显著性的较大改善(p=0.02),并且观察到安慰剂/MN+RA组与安慰剂/安慰剂+RA组相比的较大改善的趋势(其未达到统计学显著性(p<0.05))。
在本研究完成时,研究对象还完成了一份有关他们对疗效进行评价的自我评估问卷。这份问卷要求研究对象回答五选一的问题(非常同意、同意、既不同意也不反对、反对、非常反对)。在使用烟酸肉豆蔻基酯的各组中,没有一例对象对疗效的评价低于安慰剂/安慰剂+RA组对象的评价,并且与安慰剂组相比,较高比例的使用烟酸肉豆蔻基酯之研究对象对于五个问题中的四个均认为疗效得到改善。这些结果表明,同时使用或者先行且同时使用烟酸肉豆蔻基酯不干扰视黄酸的疗效,并且通过某些参数表明疗效得以改善。
由于长期进行视黄酸治疗与表皮增厚有关,因此还评估了每组在12周的视黄酸治疗过程中表皮厚度的变化。安慰剂/安慰剂+RA组、安慰剂/MN+RA组和MN/MN+RA组的表皮厚度平均值在基线处时分别为37.9、38.8和39.3μm。经过12周的研究,接受视黄酸和安慰剂霜剂组的表皮厚度平均值减少了约5%。同时接受烟酸肉豆蔻基酯组的表皮厚度增加了约3%,而先于视黄酸且与视黄酸同时使用烟酸肉豆蔻基酯组的表皮厚度增加了约10%。在第12周时,安慰剂/安慰剂+RA组和MN/MN+RA组之间的差异具有统计学显著性(p=0.0007),而安慰剂/安慰剂组和安慰剂/MN+RA组之间的差异显示出这种趋势但未达到统计学显著性(p<0.05)。在第12周时,安慰剂/MN+RA组和MN/MN+RA组之间的差异也具有统计学显著性(p=0.05)。
临床分级、自我评估和表皮厚度测定的结果表明,烟酸肉豆蔻基酯并未对视黄酸治疗的疗效产生负面影响。此外,该结果表明烟酸肉豆蔻基酯的使用增强了视黄酸治疗的疗效。
实施例2
已显示,胱天蛋白酶-14是调控表皮成熟的独特的蛋白酶。这种调控由聚丝蛋白(公认的参与皮肤细胞分化晚期的蛋白)的水解加工所致。胱天蛋白酶-14对聚丝蛋白作用的产物阻止了UVB的光损伤以及水份丢失。参见例如Nicotera等,Nature Cell Biology 9:621-622(2007);Denecker等,Nature Cell Biology 9:666-674(2007),二者均通过引用并入本文中。
Rendl等,J.Investigative Dermatol 119:1150-1155(2002)(其通过引用并入本文中)已显示类视黄醇下调胱天蛋白酶-14。
胱天蛋白酶-14、聚丝蛋白和类视黄醇之间的相互关系提示,它们可能受烟酸肉豆蔻基酯的影响。
为了研究上述假设,在上文提及的对象组(即,在治疗期间,单独接受安慰剂一个月继而联用安慰剂和视黄酸的对象,以及仅接受安慰剂一个月继而联用烟酸肉豆蔻基酯和视黄酸的对象)中研究了胱天蛋白酶-14和聚丝蛋白的表达水平。
在接受3个月的安慰剂加视黄酸的对象中,发现胱天蛋白酶-14的表达平均增加5%;而在接受3个月的安慰剂、视黄酸和烟酸肉豆蔻基酯的对象中,显示出胱天蛋白酶-14的表达在同一时期增加24%。
对于聚丝蛋白的表达来说,接受安慰剂、烟酸肉豆蔻基酯和视黄酸的对象显示出平均增加13%,而未接受烟酸肉豆蔻基酯治疗的对象则未显示变化。
如上所述,这些结果明确地建立了烟酸肉豆蔻基酯与胱天蛋白酶-14和聚丝蛋白相互作用对皮肤细胞分化之有益影响之间的联系。
以上描述陈述了本发明的各特征,包括用于在接受所述治疗之患者中减轻视黄酸治疗的副作用和/或改善疗效和/或不干扰疗效的方法等,其通过施用一定量的烟酸衍生物(如烟酸酯)来实现。优选地,所述烟酸酯是烟酸烷基酯。尤其优选的是酯部分包含10~18个碳原子的烟酸烷基酯。
向对象施用烟酸酯的方式可有不同,包括经口、时控释放(timerelease)、静脉内、真皮内及其它施用形式,以及外用施用。
外用施用是指将烟酸酯应用于皮肤或粘膜(包括鼻、肺和口的表面膜)的外表面,从而使烟酸酯穿过皮肤或粘膜的外表面并进入深部组织。在优选的形式中,通过皮肤或透皮递送烟酸来外用烟酸酯。“透皮递送”是指烟酸酯扩散穿过皮肤屏障,之后在皮肤酯酶的作用下生物转化成烟酸。可通过在应用至皮肤(该过程称为“涂擦”)之前将烟酸酯置于油性载体中来提高完整皮肤的吸收。被动的外用施用可包括与润肤剂或渗透增强剂联合将烟酸酯直接应用到治疗部位。
所述外用施用是特别优选的,并且可以通过霜剂、乳液、液体、气雾剂、沐浴液、漱口水、牙膏、灌食剂(gavage)或其它外用形式来实现。例如,在时控释放应用的情形中,可采用“贴剂”(例如在缓释尼古丁、绷带、包裹材料等中所使用的类型)。
所述烟酸酯以足以减轻视黄酸治疗之副作用的量来施用。所使用的剂量可以并且将会不同。
本发明还涉及用于改善成熟皮肤细胞分化的方法,其通过施用一定量的足以增加胱天蛋白酶-14和聚丝蛋白表达的烟酸烷基酯来实现(如上所述)。增加这两种分子的表达导致相互作用增加,继而导致皮肤细胞分化的改善。烟酸肉豆蔻基酯是尤其优选的。
本发明的其它方面对于本领域技术人员来说是清楚的,因而无须在此赘述。本文使用的术语和表述用作描述性的、非限制性的术语,并且在使用这些术语和表述时不旨在排除与所显示及描述之特征等同的任何特征或其部分,各种修改均被认为可能在本发明的范围内。
Claims (16)
1.用于减轻视黄酸治疗副作用和/或改进疗效而不干扰视黄酸治疗疗效的方法,其包括向接受所述视黄酸治疗的对象施用一定量的足以减轻所述副作用的烟酸烷基酯。
2.权利要求1所述的方法,其中所述烟酸烷基酯通过外用来施用。
3.权利要求1所述的方法,其中所述烟酸烷基酯通过皮肤或透皮递送来施用。
4.权利要求1所述的方法,其中所述烟酸烷基酯包含8~18个碳原子的直链烷基链。
5.权利要求1所述的方法,其中所述烟酸烷基酯是烟酸肉豆蔻基酯或烟酸棕榈基酯。
6.权利要求1所述的方法,其包括在所述视黄酸治疗的同时施用所述烟酸烷基酯。
7.权利要求1所述的方法,其包括在所述视黄酸治疗之后施用所述烟酸烷基酯。
8.权利要求1所述的方法,其包括向所述对象施用所述烟酸烷基酯一段足以增加角质层厚度或皮肤屏障功能的时间,所述烟酸烷基酯的施用先于视黄酸治疗的施用。
9.权利要求1所述的方法,其包括向所述对象施用所述烟酸烷基酯一段足以增加所述对象耐受视黄酸治疗之能力的时间,所述烟酸烷基酯的施用先于视黄酸治疗的施用。
10.权利要求8所述的方法,其还包括在施用所述视黄酸治疗之前向所述对象施用所述烟酸烷基酯至少一个月。
11.权利要求9所述的方法,其还包括在施用所述视黄酸治疗之前向所述对象施用所述烟酸烷基酯至少一个月。
12.权利要求1所述的方法,其中所述对象是哺乳动物。
13.权利要求12所述的方法,其中所述哺乳动物是人。
14.用于改善皮肤细胞分化的方法,其包括向有此治疗需要的对象施用一定量的足以增加胱天蛋白酶-14和聚丝蛋白之表达并增加它们之间相互作用从而改善皮肤细胞分化的烟酸烷基酯。
15.权利要求14所述的方法,其中所述烟酸烷基酯是烟酸肉豆蔻基酯。
16.权利要求14所述的方法,其包括外用施用所述烟酸烷基酯。
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