CN103608006B - 包含n‑乙酰基‑l‑半胱氨酸的组合及其用途 - Google Patents
包含n‑乙酰基‑l‑半胱氨酸的组合及其用途 Download PDFInfo
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Abstract
本发明涉及N‑乙酰基‑L‑半胱氨酸、硒代甲硫氨酸形式的硒和褪黑激素的组合，以及包含此种组合的医药产品或药物组合物，其用于治疗各种疾病和病症，例如包括各种癌症类型的良性和恶性瘤形成、自身免疫性疾病、神经退行性疾病、内分泌疾病、2型糖尿病、所有类型的纤维化、淀粉样变性、子宫内膜异位、多囊卵巢综合征、痛经、皮肤疾病。N‑乙酰基‑L‑半胱氨酸、硒代甲硫氨酸形式的硒和褪黑激素的组合还用于皮肤美容处理并用作抗菌剂。
Description
发明领域
本发明涉及N-乙酰基-L-半胱氨酸、硒，优选为硒代甲硫氨酸(selenomethionine)和褪黑激素(melatonin)的组合，以及包含此种组合的药物组合物，其用于治疗各种疾病和病症，例如包括各种癌症类型的良性和恶性瘤形成(neoplasia)、自身免疫性疾病、神经退行性疾病、内分泌疾病、2型糖尿病、所有类型的纤维化、淀粉样变性、子宫内膜异位、多囊卵巢综合征、痛经、皮肤疾病包括白癜风、秃头症和银屑病。该组合还用作抗菌剂并用于美容目的。
背景技术
胞内氧化还原(redox)环境的控制和调节是与细胞过程基础相关的。例如，细胞周期氧化还原失去控制可导致更多氧化剂环境，促进从G1期进展至S期并因而导致异常增殖，其为各种瘤形成的标志。并且大多数慢性炎性疾病也伴随氧化还原失去控制。朝向更为氧化胞内环境的调节异常因而与异常增殖和炎症相关并因此最终相关于疾病，所述疾病例如但不限于，癌症、神经退行性疾病、糖尿病、异常伤口愈合、纤维化。此外，在氧化环境中，蛋白质可被氧化修饰，该过程之后通常形成聚集物，也为淀粉体的形式。
外部刺激控制细胞的功能状态，影响关键蛋白质的功能和基因表达。通过信号子将信号传感并转导至由蛋白质翻译后修饰操纵的特定效应物质(effectors)，其中硫醇(-SH)还原/氧化(redox)转化发挥基础作用。蛋白质中的敏感性半胱氨酸残基构建所述氧化还原转化，其中“敏感性”表示源自特定蛋白构象的更低的半胱氨酸/胱氨酸氧化还原对(SH/S-S)的电化学势。在例如酶、受体、转运体、转录因子、结构元件、蛋白质运输合成(protein trafficking synthesis)和降解调节体以及细胞骨架结构中的硫醇氧化还原转化都深深影响整体细胞内稳态(cellular homeostasis)。
哺乳动物细胞中氧化剂的产生来源于以活性氧类产生结束的诸如糖酵解和线粒体呼吸链的基础过程，其间最稳定的代表是氢过氧化物(H2O2)。所 产生的氧化剂必须在严格控制下且需要氧化途径的逆转。该氧化还原控制受到若干低分子量物质以及复杂酶网络的影响，其中包括，谷胱甘肽还原酶(GR)和硒依赖性谷胱甘肽过氧化物酶家族(GPx)。还原型谷胱甘肽(GSH)是在大多数生物体中的一显性小分子量硫醇类，其氧化还原电势被在细胞中负责氧化还原控制的许多酶类使用，包括GR和GPx，以再循环它们自身的氧化还原状态。
还原型谷胱甘肽(GSH)是以相对高浓度，甚至超过10mM存在于所有人体组织中的三肽。其在体内具有许多重要功能。如上所述，其可被视为主要的内源性抗氧化剂，参与：1)控制细胞氧化还原状态；以及2)控制信号相关性蛋白质，包括外部刺激受体(例如激素受体)的氧化状态。其在多种代谢和生化反应中发挥基础作用，例如DNA合成和修复、蛋白质合成、前列腺素合成、氨基酸转运和酶活化。其还参与调节一氧化氮循环，解毒许多致癌物及其它外源性物质并对于许多免疫系统部分中的最佳响应具有重要作用。因此，体内大多数系统可受谷胱甘肽系统状态的影响。例如，谷胱甘肽缺陷状态包括HIV/AIDS、化学和传染性肝炎、前列腺癌及其它癌症、白内障、阿尔茨海默病、帕金森病、慢性阻塞性肺病、哮喘、辐射中毒、营养不良状态、艰苦躯体应激和老化(arduous physical stress and aging)，并已与次优免疫响应相关。低谷胱甘肽还强烈涉及如在癌症、AIDS、败血症、创伤、烧伤以及甚至运动训练过度、以及在躁郁症、重度抑郁症和精神分裂症中所见的消瘦和负氮平衡。
谷胱甘肽合成自氨基酸L-半胱氨酸、L-谷氨酸和甘氨酸。半胱氨酸的巯基(硫醇)基团(SH)用作质子供体并负责谷胱甘肽的生物活性。半胱氨酸的供给是细胞合成谷胱甘肽中的限速因子，因为半胱氨酸是相对稀有的营养素。因而已在各种疾病和病症中建议补充谷胱甘肽。
然而，口服摄取的谷胱甘肽可在胃中已然分解且未通过胃肠道良好吸收。因此通过直接补充谷胱甘肽提升谷胱甘肽水平是困难的。用作谷胱甘肽前体的替代补充剂被用于增加谷胱甘肽的血浆浓度。N-乙酰基-L-半胱氨酸(下文中NAC)是相比谷胱甘肽更为简单的分子，在几乎所有组织和细胞中自由扩散并是谷胱甘肽最为生物可利用的前体。在测试其调控细胞氧化还原状态效力的数个硫醇试剂中，NAC持有最大的人类使用前景。NAC临床使用中相关优势是实质上无副作用。此化合物在临床上已长期可用作溶粘蛋白剂 以及扑热息痛中毒后的解毒剂。
近年来还已认可NAC具有其它有益性质。例如，已报道NAC具有抗炎作用并已将其加至非甾体抗炎药(NSAID)家族。本公开发明人之前已表明在体外哺乳动物细胞中，NAC抑制增殖并促进沉默，进一步在终末分化中进化(WO02/051405A1，T.Parasassi等(CellDeath and Differentiation(2005)，12卷，10期，第1285-1296页)；E.K.Krasnowska等(Free Radicals Biology and Medicine2008，45(11):1566-72)以及A.C.Gustafsson等(BMC Cancer(2005)，5:75)。就此已发现NAC对于癌细胞具有显著的抗增殖效应并还已发现在子宫内膜异位治疗中有效。此外它已被用于治疗多囊卵巢综合征(PCOS)以及用于治疗各种其它疾病和病症，例如作为肾脏保护剂、间质性肺病(interstitial lung disease)、精神分裂症、躁郁症和抑郁症，并已被建议用于各种其它用途。
因此，NAC对于多种用途是有效的。然而，长期NAC治疗导致NAC血药浓度降低，因此必须增加其有效浓度并相应增加不希望的副作用的风险(L Pendyala和P J Creaven，Cancer Epidemiol Biomarkers Prev1995；4:245-251)。为抵消NAC的衰退效应，提出了脉冲治疗以可具有清除期。另一可能的解决方案将是降低NAC有效点的浓度，其对于短期治疗还将是有利的。
近来对于硒(下文中Se)和褪黑激素(下文中Mel)二者的保护和/或治疗作用已有了广泛兴趣。例如已建议补充Se用于预防癌症，作为抗氧化剂或免疫增强剂。同样地褪黑激素已被研究用于治疗癌症、免疫疾病及各种其它障碍。尽管如此，也还报道了这两种物质的争议效果。例如，已承认了Mel的抗氧化剂作用，但其有时还被报道作为助氧化剂(CemeliE，Baumgartner A，Anderson D.Mutat Res.2009；681:51-67；Caluba HC，Abuja PM等FEBS Lett.2001；502(3):127-31；Radogna F等Toxicology and AppliedPharmacology2009；239:37–45)。
对于Se，一组大型试验显示未实现预期的前列腺癌或其它癌症的预防(LippmanSM等，Journal of American Medical Association.2009；301(1):39-51)。EAKlein(JNatl Cancer Inst.2009；101:283-285)采用警示结论：“完成良好的大规模对照试验不总是验证我们相信生物学所指示的且我们的模型系统是现实世界中临床结果的不完美估量。”并且，虽然报道了Se对于 糖尿病风险的预防作用并归因于其"胰岛素样"活性以及含硒酶的抗氧化特性，但一前瞻性研究未报道硒与糖尿病风险之间的任何显著相关性(Akbaraly TN等，NutrMetab(Lond).2010；7:21)。
现有技术
Balansky等，“Interactions between N-acetylcysteine and sodium selenitein modulating the clastogenicity of urethane and2-acetylaminofluorene inmice”，Int.J.Cancer，108卷，2004，第158-161页，公开了组合使用NAC和Se用于在癌症治疗中减弱细胞毒性药物和化学预防剂的副反应。
Safarinejad等，“Efficacy of selenium and/or N-acetyl-cysteine forimproving semen parameters in infertile men:a double-blind,placebocontrolled,randomized study”，J.Urol.，181卷，1期，2009，第741-751页，网络公开于2008年12月，公开了组合或单独使用NAC和Se用于在男性不育症中改善精液质量。组合给药NAC和Se导致附加有益效果。
等，“Synergistic action of sodium selenite and N-acetylcysteinein acetaminophen-induced liver damage”，Hum.Exp.Toxicol.，27卷，5期，2008，第425-429页，公开了组合或单独使用NAC和Se用于治疗对乙酰氨基酚过量。发现NAC和Se组合相比任一单独试剂给予更好的肝毒性对抗保护。
Emonet等，“Thiols and selenium:protective effect on human skinfibroblasts exposed to UVA radiation”，J.Photochem.Photobiol.，40卷，1期，1997，第84-90页，公开了组合使用NAC和Se以保护细胞免受UVA损害的影响。
Look等，“Sodium selenite and N-acetylcysteine in antiretroviral-naiveHIV-1-infected patients:a randomized,controlled pilot study”，J.Clin.Invest.，28卷，5期，1998，第389-397页，公开了组合口服给药NAC和Se以为了在HIV患者中改善血细胞计数并减少病毒载量的目的。
Sener等，“Melatonin and N-acetylcysteine have beneficial effectsduring hepatic ischemia and reperfusion”，Life Sciences，72卷，2003，第2707-2718页，公开了单独或组合使用NAC和Mel以治疗肝缺血。发现Mel相比NAC更有效，并发现这两种的组合相比单独的任一种更有效。
WO03/077900A1和US2005/0164911A1公开了通过给药NAC、褪黑激 素或其组合预防癌症或神经退行性疾病进展的方法，以及包含NAC和Mel的药物。
WO00531376描述了包含半胱氨酸、硒和褪黑激素连同多种其他组分的组合物。US20070231312、US2011027771、WO9833494和US6207190都描述了包含其他物质，以及NAC、Se和Mel的不同制剂。另外US2004045566描述了包含谷胱甘肽、硒和褪黑激素的组合物用于从烟草烟雾吸收有害组分。所述文献无一描述了使用硒代甲硫氨酸。
在现有技术中所有提及的文献中硒以其本身使用(selenium is used as such)。
发明目标
本发明的一般性目标是提供增加NAC效力的问题解决方案。该目标的一方面是提供医药产品或医药组合，其提供增加的N-乙酰基-L-半胱氨酸(NAC)效力。该目标的一方面是提供医药产品或医药组合，其提供增加的NAC用于治疗哺乳动物例如人类中疾病，例如包括各种癌症类型的良性和恶性增生、自身免疫性疾病、神经退行性疾病、内分泌疾病、2型糖尿病、所有类型的纤维化、淀粉样变性、子宫内膜异位、多囊卵巢综合征、痛经、皮肤疾病包括白癜风、秃头症和银屑病以及细菌感染的效力。该目标的另一方面是提供医药产品，其提供增加的NAC用作抗菌剂以及用于美容目的的效力。
发明概述
本发明发明人表明当NAC与硒代甲硫氨酸形式的硒(Se)以及褪黑激素(Mel)一起给药时N-乙酰基-L-半胱氨酸(NAC)的效果被增强。硒代甲硫氨酸和Mel组合强烈增加NAC效力并还可减少NAC浓度，从而在短期和长期治疗中均改善其效力。在体外和体内测试此组合疗法效力后，采用NAC、Se(例如硒代甲硫氨酸的形式，下文中SeMet)和Mel，发明人还表明避免了Se和Mel的不良效应。
因此本发明提供了NAC、SeMet和Mel的组合用于治疗各种疾病和病症，例如包括各种癌症类型的良性和恶性增生、自身免疫性疾病、神经退行性疾病、内分泌疾病、糖尿病、所有类型的纤维化、淀粉样变性、子宫内膜 异位、多囊卵巢综合征、痛经、皮肤疾病和细菌感染。该组合还用作抗菌剂并用于美容目的。此外本发明提供了包含所述组合的医药产品和药物组合物，以及包括同时给药NAC、SeMet和Mel至患者的治疗方法。
在本发明的一方面中提供了包含单独或一起的N-乙酰基-L-半胱氨酸、硒代甲硫氨酸和褪黑激素，和/或其生理学上可接受的盐的医药产品。单独是指该三种物质是医药产品的部分，但可作为单独单元提供在医药产品的单独隔间中。一起是指该三种物质可替代地被提供在医疗装置的相同部分中，例如作为混合物。该医药产品在本发明的一方面中用于同时、顺序或单独组合给药至哺乳动物。
在一个实施方式中医药产品的组分用于口服给药；例如N-乙酰基-L-半胱氨酸组分是以5-45mg/kg/天的剂量给药，硒代甲硫氨酸形式的硒是以0.4-1.2μg/kg/天的剂量给药且褪黑激素是以0.02-0.08mg/kg/天的剂量给药。该医药产品在一个实施方式中是包含N-乙酰基-L-半胱氨酸、硒代甲硫氨酸形式的硒和褪黑激素的药物组合物。
包含单独或一起的N-乙酰基-L-半胱氨酸、硒代甲硫氨酸形式的硒和褪黑激素的医药产品在另一实施方式中是用于上皮给药(epicutaneous administration)。在此医药产品中N-乙酰基-L-半胱氨酸在一个实施方式中是以3-10wt-%的浓度给药，硒代甲硫氨酸形式的硒是以0.3-1wt-%的浓度给药且褪黑激素是以0.01-0.2wt-%的浓度给药。在一个实施方式中该医药产品是包含N-乙酰基-L-半胱氨酸、硒代甲硫氨酸形式的硒和褪黑激素的药物组合物。
在一个实施方式中该医药产品是用于治疗良性或恶性瘤形成，包括各种癌症类型。在另一实施方式中其是用于皮肤美容处理并用于治疗皮肤疾病。该医药产品还可被用于治疗自身免疫性疾病、神经退行性疾病、内分泌疾病、2型糖尿病、所有类型的纤维化、淀粉样变性、子宫内膜异位、多囊卵巢综合征、痛经及其它疾病。在一个实施方式中该医药产品是用作抗菌剂。
包含N-乙酰基-L-半胱氨酸、硒代甲硫氨酸形式的硒和褪黑激素的医药产品在本发明另一方面中是用作抗菌剂，用于连同(together with)或在适用于与体液接触的医疗装置的表面。该医药产品例如可用于此种医疗装置的涂层中，或可并入此种医疗装置材料，例如塑料中。在本发明一个实施方式中N-乙酰基-L-半胱氨酸、硒代甲硫氨酸形式的硒和褪黑激素包含于用于医疗 装置的水凝胶涂层中。用作抗菌剂的该医药产品可进一步包含附加活性化合物例如杀菌药物、贵金属溶液和/或地塞米松。
在一方面中本发明提供了包含单独或一起的N-乙酰基-L-半胱氨酸、硒代甲硫氨酸形式的硒和褪黑激素，和/或其生理学上可接受的盐的抗菌剂。该抗菌剂在一个实施方式中是用在用于医疗装置的水凝胶涂层中。在另一实施方式中其用于与医疗装置的塑料整合(integration)。
在另一方面本发明提供了包含医药产品的医疗装置，该医药产品含有N-乙酰基-L-半胱氨酸、硒代甲硫氨酸形式的硒和褪黑激素，和/或其生理学上可接受的盐以及任选的附加活性化合物例如杀菌药物、贵金属溶液和/或地塞米松。
在一方面本发明提供了包含单独或一起的N-乙酰基-L-半胱氨酸、硒代甲硫氨酸形式的硒和褪黑激素，和/或其生理学上可接受的盐的医药产品的用途，用于治疗包括各种癌症类型的良性和恶性瘤形成、自身免疫性疾病、神经退行性疾病、内分泌疾病、2型糖尿病、所有类型的纤维化、淀粉样变性、子宫内膜异位、多囊卵巢综合征、痛经、皮肤疾病包括白癜风、秃头症或银屑病或者细菌感染。本发明还提供了医药产品用于皮肤美容处理以及作为连同适用于与体液接触的医疗装置的抗菌剂的用途。
在一方面本发明提供了疾病治疗方法，或用于美容目的，包括同时、顺序或单独组合给药N-乙酰基-L-半胱氨酸、硒代甲硫氨酸形式的硒和褪黑激素，和/或其生理学上可接受的盐，至人类或哺乳动物患者。该疾病或美容目的是选自包括各种癌症类型的良性和恶性瘤形成、自身免疫性疾病、神经退行性疾病、内分泌疾病、2型糖尿病、所有类型的纤维化、淀粉样变性、子宫内膜异位、多囊卵巢综合征、痛经、皮肤疾病包括白癜风、秃头症或银屑病或者细菌感染，或皮肤美容处理。
附图简述
在以下说明书中，参照附图将更详细地解释本发明，其中：
图1显示了通过硒依赖性谷胱甘肽过氧物酶(cGPx(Se))和谷胱甘肽还原酶(GR)的谷胱甘肽(GSH)代谢循环。GR活性需要NADPH，其由酶葡萄糖-6-磷酸脱氢酶(G6PDH)活动提供。G6P：葡萄糖-6-磷酸盐；6PG：6-磷酸葡萄糖酸；RO·：烷氧自由基；·OH：羟自由基；ROOH：氢过氧化物。
图2显示了如实施例1中描述的采用NAC+SeMet+Mel治疗三个月对于白癜风患者的作用。
图3A显示了如实施例2中描述的采用NAC+SeMet+Mel治疗一个月对于皮肤纹理的作用。硅橡胶皮肤复制品显微镜图像显示表征皮肤表面微貌的细线网络。注意到治疗后更为规则的网络。放大率:5X或10X，如图栏中所报告的。
图3B显示了一些图3A中图像的快速傅立叶变换(FFT)，显示治疗前样本中普遍单一方向的不规则图案(A和B)，而在治疗后观察到规则环形图案(C和D)。
图4显示了来自实施例3中所述试验的结果。如同指示采用0.2mM甲萘醌和/或0.4mM NAC和/或0.2mM SeMet和/或2mM Mel处理K562细胞。在该柱状图中，符号Se始终指代SeMet。
图5显示了来自实施例3中所述试验的结果。如同指示采用0.133mM甲萘醌和/或0.4mM NAC和/或0.2mM SeMet和/或2mM Mel处理HL60细胞。在该柱状图中，符号Se始终指代SeMet。
图6显示了来自实施例3中所述试验的结果。如同指示采用0.5mM甲萘醌和/或1mMNAC和/或0.2mM SeMet和/或1mM Mel处理HL60细胞。在该柱状图中，符号Se始终指代SeMet。
图7显示了来自实施例3中所述试验的结果。如同指示采用0.133mM甲萘醌、0.2mMSeMet、2mM Mel和不同NAC浓度处理HL60细胞。
图8显示了来自实施例4中所述试验的结果，证实NAC与SeMet和Mel组合的抗增殖和分化作用。增殖基因P21抑制剂(平均5个指数)以及分化标记物SI(5个指数)，ALPI(4个指数)，CLDN1(6个指数)和PCDH1(5个指数)的平均倍数变化。显著性，p<0.05，排除标(*)的两个样本，其中NAC+Se以及NAC+Mel的组合与NAC+SeMet+Mel无显著性差异。在该柱状图中，符号Se始终指代SeMet。
图9显示了单独的NAC与三种物质组合的效应对比。在该柱状图中，符号Se始终指代SeMet。
发明详述
NAC
N-乙酰基-L-半胱氨酸(NAC)是公知的低分子量药物，具有化学式
为了本发明的目的，NAC还可以其二聚形式(di-NAC)给药。
已发现NAC通过各种机理发挥分子和生理效应。NAC的特征主要涉及其硫醇基，其使之在谷胱甘肽(GSH)作用的大多数生物化学途径中是有效的。NAC被细胞处理为L-半胱氨酸并被用于GSH的从头合成中，因此被认为是GSH的前体。
虽然NAC作用机理的细节还未被完全理解，但毫无疑问它们必然归因于其硫醇基。其因而涉及细胞中复杂的硫醇基氧化还原循环，并因而影响细胞氧化还原状态的调节以及胞内和胞间信号。在此氧化还原循环中若干酶发挥作用，其氧化还原转变的发生通过谷胱甘肽(GSH)的氧化/还原。具有NAC介入此图中的在先证据，如图1中总结的，NAC相比于GSH具有相似或甚至更高的效力。在这方面，NAC可被认为是有效的抗氧化剂。
生理学上极为重要的是二硫化物形成和裂解的循环，这是一种调节蛋白活性和细胞信号传导的普遍机理。酶，例如蛋白酪氨酸磷酸酶和酪氨酸激酶，例如在控制细胞周期、细胞增殖和分化中起着关键的作用，且许多这些酶通过其半胱氨酸的氧化还原状态而调节。
NAC曾经并且目前仍然广泛地用作溶粘蛋白剂，其作用方式通常归因于粘液蛋中的敏感的半胱氨酸二硫桥键的氧化还原裂解。此外NAC已为扑热息痛中毒的主要疗法。
近年来NAC还已被确认具有其它有益性质。例如已报道NAC具有抗炎作用，这也是将其加入非甾体抗炎药(NSAID)家族的原因之一。进一步发现NAC抑制细胞增殖并促进沉默，进一步在终末分化中进化。就此已发现NAC对于癌细胞具有显著的抗增殖效应并还已发现其在子宫内膜异位治疗中有效。例如，发明人相对最近发现了NAC对于上皮来源癌细胞具有显著的抗增殖效应(Cell Death and Differentiation2005，12(10):1285-1296；BMCCancer2005，5:75)。
在癌症研究中，NAC的抗增殖效应与细胞死亡或毒性无关，但却是由于生理学分化途径的激活带来的，其可被视为是细胞功能朝向起源组织的正常化。
NAC使用中的相关优势是实质上无副作用。缺点是其在长期治疗中效力降低，报道血药浓度降低以致于所需剂量增加，因而还增加了一些不良事件的风险。
NAC与Se和Mel组合
在此基础上，本发明人目的在于通过同时使用可与NAC发挥协同的其它药物减少有效NAC剂量。NAC有效剂量的减少同时用于短期和长期治疗中。为了该目的集中注意至控制硫醇氧化还原循环的酶网络，特别是那些反应通过诸如谷胱甘肽过氧物酶(GPx)和谷胱甘肽还原酶(GR)的酶涉及谷胱甘肽再循环的那些。集中在这些氧化还原反应流上被证明是正确的，通过观察到它们占生物学氧化还原反应的将近99.9%(DPJones.Am.J.Physiol.Cell Physiol.2008；295:C849-C868)以及NAC作用应当主要与这些多元酶活性的修饰相关(Parasassi T，Brunelli R，Costa G，等The Scientific WorldJOURNAL2010；10:1192–1202)。
已报道了采用NAC长期治疗后的GR表达减少(L Pendyala和PJ Creaven，CancerEpidemiol Biomarkers Prev1995；4:245-251)。还存在报道显示补充Mel可获得GR以及硫醇氧化还原反应中另一相关酶：谷胱甘肽过氧物酶(GPx)表达和/或活性的增加(HardelandR，Cardinali DP，Srinivasan V等ProgNeurobiol.2011；93(3):350-84，网络公开日：2010年12月28日；García T，Esparza JL，Giralt M等，Biol Trace Elem Res.2010;135:220-32)。
在此图中，Se代表若干谷胱甘肽过氧化物酶(GPx)的辅因子。Se对于GPx活性是必须的(参见例如Bulato等Free RadicBiol Med.2007；42:118-23)，且在不存在GPx酶的情况下不发挥任何特定抗氧化作用。
发明人因此推论为确保平衡作用而没有不良影响，Se必须为SeMet的形式并与Mel一起给药，即在GR和GPx受到刺激且GPx可完全发挥其活性的条件下。由于这个原因，NAC可保证用于整体动力学进行的还原电势，在此，最终相比谷胱甘肽(GSH)更为有效。
基于硫醇氧化还原系统的生化学，发明人旨在降低NAC治疗浓度情况 下增加NAC的效果并在长期治疗中确保NAC效力。该目的的实现是通过刺激存在于硫醇氧化还原系统中的要素。
为了：1)恢复/增强负责硫醇信号传导氧化还原控制的酶的表达/活性；2)恢复适当的NAC作用，即使在长期治疗中；以及3)减少有效NAC浓度，NAC治疗与硒代甲硫氨酸形式的硒和褪黑激素补充相组合。此组合启发自GPx活性需要硒，以及所报道的褪黑激素在增加GR以及可能的GPx的表达/活性中的作用。
因此，本发明是基于通过增强硫醇氧化还原系统增强NAC作用的目的，该增强是通过：
1)通过补充硒代甲硫氨酸(SeMet)形式的Se刺激谷胱甘肽过氧物酶(GPx)的活性，SeMet是Se的生物可利用形式(bioavailable form)。
2)使用硒代甲硫氨酸代替硒对于该效果十分重要。[2)通过Mel增加谷胱甘肽还原酶(GR)和谷胱甘肽过氧物酶(GPx)的表达和/或活性。
通过测试NAC的抗氧化、抗增殖和分化效应证实了与这两种附加物质组合的NAC作用。NAC、Mel和SeMet形式的Se之间的组合效应以及可能的协同的测试是通过在体外使用两种面临氧化刺激的细胞系(实施例3和4)，以及在白癜风患者体内以及皮肤病学研究中(实施例1和2)。
关于NAC在硫醇氧化还原系统中的抗氧化效应，通过氢过氧化物刺激生成的减少来测量，发现：
1)通过此关联明确增强了NAC作用。在若干情况下与SeMet和Mel组合的NAC相比其自身几乎更为有效三倍。
2)NAC浓度可减小，使用小于一半的浓度达到了相似的效果。
3)出人意料地，当仅组合两种物质，即NAC+SeMet或NAC+Mel时，在一些细胞系统中观察到了不利的氧化效应。这是出人意料的，因为在科学文献中报道这些组合是有利的(Safarinejad MR.J Urol.2009；181:741-51. 等Hum ExpToxicol.2008；27:425-9)。相反，观察到三种物质的组合恢复了细胞保护，具有几乎完全无氧化效应的最终效应。
关于NAC有关减少细胞增殖并诱导分化过程的效应，发现：
1)相比于单独使用NAC，通过与SeMet和Mel组合，NAC的抗增殖作用加倍。
2)NAC的分化作用通过以上组合明确增强了，根据特定标记物，相比于 单独使用NAC提高了30-50%。
3)通过分析一些特定分化标记物，观察到NAC+SeMet或NAC+Mel的组合具有堪比三种物质组合的效应。然而当三种物质组合使用时具有NAC作用整体增加的清楚趋势。
给药
本发明所述的NAC、SeMet形式的Se和Mel的新组合可同时、顺序或单独组合给药至哺乳动物例如人类。同时组合给药是指所有三种物质在相同时间点一起给药至哺乳动物。顺序组合给药是指该三种物质在相同疗程给药至哺乳动物，例如在相同治疗日、治疗周或治疗月期间，以使所有物质组合存在于哺乳动物中，该物质被给药，即在设定顺序中不同时间点给至哺乳动物。单独组合给药是指该三种物质同样在相同疗程给药至哺乳动物以使所有物质组合存在于哺乳动物中，但该物质被给药，即在不规则顺序中不同时间点给至哺乳动物。给药可为局部的或系统的(肠的或肠胃外的)。典型给药方式包括口服给药和上皮给药。其它可能的给药方式包括静脉内、皮内、皮下、肌肉内、阴道内、子宫内、腹膜内、直肠、鼻、鞘内、吸入和膀胱内给药。
制剂
根据本发明的NAC、SeMet和Mel的组合可被给药为单独药物制剂/组合物，各自仅包含三种活性成分中的一种，即分别包括NAC或SeMet或Mel。或者该组合可在包含两种或所有三种活性成分的药物组合物中被给药。在任一情况中，包含仅仅一种或NAC和/或SeMet和/或Mel组合的药物组合物可以药物领域技术人员本身已知的方式被制备。
该药物组合物例如可适于口服给药。此类组合物可以不同形式给药，目前优选为片剂。其它形式，例如胶囊、栓剂、溶液、混悬液、糖浆等也是可想到的。在用于口服给药的剂量单位形式的药物制剂中可混合一种或多种活性成分与用作活性成分载体或媒介的固体、粉状载体或赋形剂，例如乳糖、蔗糖、山梨醇、甘露醇、淀粉、支链淀粉、纤维素衍生物、明胶、柠檬酸、柠檬酸钠、碳酸(酸)钠或另外适当载体；稳定物质例如碱性化合物例如碳酸盐、钠、钾、钙、镁等的氢氧化物和氧化物以及润滑剂例如硬脂酸镁、硬脂酸钙、硬脂富马酸钠和聚乙二醇蜡。然后将混合物加工成颗粒或压制成片。可用只要剂型仍在胃中就保护活性化合物免受酸催化降解的肠溶包衣包覆 颗粒和片剂。该肠溶包衣选自药学上可接受的肠溶包衣材料例如蜂蜡、虫胶或阴离子成膜聚合物等(若优选与适当增塑剂组合)。可往包衣中加入各种染料以区分具有不同活性化合物存在量的片剂或颗粒。
可采用包含活性化合物、植物油、脂肪或其它软胶囊适当媒介的混合物制备软胶囊。软胶囊还可如上所述被肠溶包衣。
硬胶囊可包含活性化合物颗粒或肠溶包衣颗粒。硬胶囊还可包含与固体粉末载体例如乳糖、蔗糖、山梨醇、甘露醇、马铃薯淀粉、支链淀粉、纤维素衍生物或明胶组合的活性化合物。该胶囊还可如上所述被肠溶包衣。
一选项是提供NAC和/或SeMet和/或Mel在缓释制剂(还表示为持续释放或控释)中。通过可以减小活性物质进入血流的扩散和吸收速率，此种制剂可以更长间隔给药更大剂量。随后该剂量在长时间内小量地分配在血液中，例如在每天两次的治疗方案情况中经12+12小时。许多不同的缓释工艺和制剂是现有技术中早已知晓的并可应用于本发明。在此类工艺中活性物质例如被封装在给药位置的体液处不溶或较少溶解的包衣或基质中。具有缓释和胃保护组合效应的制剂也是可以的并被用于本发明中。
用于口服给药的液体制剂可制备为糖浆或混悬液形式，例如包含0.2%至20%重量活性成分且剩余部分由糖或糖醇和乙醇、水、甘油、丙二醇和/或聚乙二醇混合物组成的溶液或混悬液。若需要，此类液体制剂可包含着色剂、调味剂、糖精和羧甲基纤维素或其它增稠剂。用于口服给药的液体制剂还可被制备为干粉形式以在使用前采用适当溶剂重建。
对于局部给药，NAC和/或SeMet和/或Mel可以纯净形式被施用，即作为液体。更优选它们可在包含皮肤病学可接受的载体的组合物/制剂中被给药，其可为固体或液体，即为乳膏、软膏、洗剂、擦剂、粉末等。液体载体的实例包括水、醇或二醇或水-醇/二醇混合物，其中存在的化合物可以有效水平被溶解或分散，任选借助于无毒表面活性剂。可加入增稠剂例如合成聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性矿物材料以形成软膏、洗剂、糊剂、凝胶等。固体载体的实例包括细分固体例如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等。还可加入助剂例如芳香剂以及附加抗菌剂。在一优选实施方式中用于局部给药的盖仑(galenic)制剂包含水、鲸蜡硬脂醇聚醚25硬脂酸甘油酯、三乙醇胺硬脂酸盐、鲸蜡硬脂醇、辛酸/癸酸甘油三酯、二甲硅油、甘油氢化聚异丁烯、聚山梨酯60、戊二醇以及任选的 香草。
对于静脉内或腹膜内给药，活性化合物溶液可在水中制备，任选与无毒表面活性剂混合。分散液的制备还可在甘油、液体聚乙二醇、三醋精及其混合物以及油中，任选包封在脂质体中。最终剂型应为无菌的、流体并在制造和贮存条件下稳定。液体载体或媒介可为溶剂或液体分散介质，包括例如、水、醇、多元醇(例如，甘油、丙二醇、液态聚乙二醇等)、植物油、无毒甘油基酯及其适当混合物。适当流动性的维持可例如，通过形成脂质体、通过在分散液情况下维护需要的粒径或通过使用表面活性剂。可通过各种抗菌剂和抗真菌剂，例如，对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等预防微生物作用。在许多情况下将优选包含等渗剂，例如，糖、缓冲剂或氯化钠。可通过在组合物中使用延缓吸收剂，例如单硬脂酸铝和明胶，带来可注射组合物的长期吸收。无菌注射溶液的制备是通过在合适溶剂中连同上面列举的各种其它成分并入需求量的活性化合物，然后按照规定过滤除菌。至于用于制备无菌可注射溶液的无菌粉末，优选的制备方法是真空干燥和冷冻干燥技术，其获得活性成分加上存在于之前无菌滤过溶液中的任意附加所需成分的粉末。
用于直肠给药的剂量单位可制备为含有与中性脂肪基底混合的活性物质的栓剂形式、或者它们可制备为明胶直肠胶囊形式，包含在具有植物油、石蜡油或用于明胶直肠胶囊的适宜媒介的混合物中的活性物质、或者它们可制备为现成微型灌肠剂的形式、或者它们可制备为给药之前在适当溶剂中重建的干微型灌肠剂制剂的形式。
用于肠胃外给药的溶液可制备为本发明活性成分在药学上可接受的溶剂中的溶液，优选浓度为0.1-10%重量。这些溶液还可包含稳定剂和/或缓冲剂并可制造在不同单位剂量安瓶或药水瓶中。用于肠胃外给药的溶液还可制备为随时使用前采用适当溶剂重建的干剂。
对于NAC，本发明需要严格评估NAC制剂的药品质量以获得有效剂量。NAC不是稳定分子，其活性硫醇残基可被氧气、光照或其它辐射轻易氧化，以至于将无法实现有效剂量。因此制剂优选避光保存。对于口服给药，优选将NAC制备在具有碳酸氢钠的可溶片中，其帮助在溶出期间部分除去来自水的氧。
已观测到高剂量的NAC可引起腹痛。为克服此，一选项是将NAC提供 在具有胃保护的制剂中，其适于防止NAC在胃部释放/溶解。此类制剂是现有技术中公知的并可随同本发明使用。例如可使用抵抗胃液并可在其通过胃后仅在肠中释放药物的片剂包衣。通用制剂包括聚合物例如纤维素衍生物、甲基丙烯酸酯氨基酯共聚物。该包衣通过使用pH敏感性聚合物保护片芯避免在胃酸性环境中分解，该pH敏感性聚合物在已通过胃部后响应pH的增加，溶胀或溶解以释放药物。
剂量
对于口服给药至人类以及其它哺乳动物，NAC的适当日剂量是约5～45mg/kg/天，优选20～30mg/kg/天。SeMet的适当日剂量是约0.0004～0.0012mg/kg/天，优选约0.0008mg/kg/天，且Mel的适当日剂量是约0.02～0.08mg/kg/天，优选约0.04mg/kg/天。该剂量的给予可为每日一次或分为两次或更多，优选三或四次，每日给药各自一或两个剂量(例如丸剂)，其中各剂量可包含例如0.15-3.0g NAC，优选0.3-0.6g NAC并优选一日三次；0.028-0.110mg SeMet或优选约0.055mg SeMet；以及1-6mg Mel或优选约3mg Mel。
对于口服给药，NAC与SeMet的日剂量重量比在4000:1-60000:1的范围内，优选在5000:1-40000:1或25000:1-37000:1的范围内，最优选32500:1。NAC与Mel的日剂量重量比在60:1-2000:1的范围内，优选150:1-1000:1或500:1-750:1，最优选600:1。三种物质典型的日给药剂量重量比是NAC:SeMet:Mel为约32500:1:54。所述物质可以以所述比率同时、单独或在包含所有三种物质的组合物中给药。
对于上皮给药(例如通过乳膏、软膏、洗剂、擦剂或类似物)，NAC的适当浓度为约3-10wt-%，优选5wt-%。SeMet的适当浓度为约0.3-1wt-%，优选0.5wt-%，且Mel的适当日剂量为约0.01-0.2wt-%，优选0.1wt-%。该乳膏、软膏或类似物可每日施用一次或可每日施用两次或多次，优选每日给药三或四次。
对于上皮给药，NAC与SeMet的重量-%比在3:1-33:1的范围内，优选约10:1。NAC与Mel的重量-%比在15:1-1000:1的范围内，优选约50:1。三种物质上皮给药的典型重量-%比是NAC:SeMet:Mel为约50:1:5。所述物质可以以所述比率同时、单独或在包含所有三种物质的组合物中给药。
取决于所治疗的疾病或病症，治疗周期可持续一天或数天直至数月。
对于采用NAC和SeMet和Mel的更长治疗周期，例如1-2个月或更多，治疗可为间歇性的。间歇性给药或治疗是指治疗在周期上是中断的，即给药该药物组合物一段时间，例如数天，然后中断给药，其中不给药药物组合物一段时间，例如数天，然后再次接着给药。间歇性治疗可为定期的，例如治疗固定的天数或周数，然后中断固定的天数或周数。实例包括采用每周治疗4天后中断3天或治疗2周后中断1周的重复方案。定期间歇性治疗的一种特殊情况是脉冲治疗，持续定期治疗和中断，例如每隔一天给药或给药两天后中断两天等。不定期重复或具有更复杂计划的不定期间歇性治疗方案也是可想到的，例如取决于对治疗的响应。在本发明不同示例性实施方式中，NAC和SeMet和Mel的处方剂量是给药3-5个连续日后中断2-4日，或给药1-3个连续日后中断1-2日。
NAC、SeMet和Mel的优选剂量将取决于所选特定制剂、给药途径、所治疾病或状况性质以及患者的体重、年龄、状况和物种(人类或动物)。
当NAC连同最佳剂量的SeMet和Mel一起给药时，NAC治疗特定疾病或状况的已知优选剂量可典型地大约减半。作为一实例，用于治疗子宫内膜异位的NAC的优选单独给药剂量是20-90mg/kg/天，优选30-60mg/kg/天，口服给药2个月或更久。当NAC与SeMet和Mel组合给药时NAC剂量可减少至15-30mg/kg/天，给药2个月或更久。
本发明的用途/药物适应症
包含NAC、硒代甲硫氨酸形式的Se和Mel的组合的本发明可被用于其中NAC可被使用或已知具有效应的任何目的，例如在其中谷胱甘肽参与和/或其中硫醇(-SH)还原/氧化(redox)转换发挥基础作用，如在信号传导情况下，还通过激素驱使，或其中可利用NAC的抗增殖促分化效应、抗氧化或抗炎效应的疾病中。其例如可被用于治疗包括各种癌症类型的良性和恶性瘤形成、2型糖尿病、各种类型的纤维化、子宫内膜异位、多囊卵巢综合征、痛经和皮肤疾病，包括白癜风和银屑病。因为蛋白聚集中氧化现象与形成淀粉体的相关性，本发明可被用于预防和治疗各种类型的淀粉样变性，例如阿尔茨海默病。此外其可用作抗菌剂并用于美容目的。其它用途还包括治疗HIV/AIDS、化学和传染性肝炎、白内障、帕金森病、慢性阻塞性肺病、哮 喘、辐射中毒、营养不良状态、艰苦躯体应激、老化、败血症、创伤、烧伤、躁郁症、重度抑郁症和精神分裂症，并用于具有次优免疫反应的患者。
作为皮肤疾病治疗的实例，采用该三种物质组合治疗一个白癜风患者并在治疗三个月后观察到脱色的极度减少(extreme reduction)(实施例1，图2)。
作为美容处理的实例，监控采用含有该三种化合物的盖仑制剂治疗脸部皮肤一个月的受试者的皮肤纹理。采用含有NAC、SeMet和Mel的乳膏制剂联合治疗一个月后，脸部面线表现更为规则，皮肤表现更为紧致和光滑且皮肤不规则和丘疹(pimple)减少。
NAC、SeMet和Mel组合用作抗菌剂
本发明人还表明(实施例5)NAC、SeMet和Mel的组合用作抗菌剂是有效的，例如当包含于诸如乳胶或聚氯乙烯导管的医疗器械或设备上的涂层中时。或者NAC、SeMet和Mel的组合可并入用于医疗装置中的塑料材料中。
例如，水凝胶涂层可被用作用于固体基质表面改性的方法。水凝胶涂层的实例包括基于聚氨酯(PUR)或聚乙烯吡咯烷酮(PVP)的水不溶性水凝胶。除了如同改善材料生物相容性、亲水性和润滑的优点之外，水凝胶涂层还带来了将活性剂例如NAC、SeMet和Mel并入表面的附加可能性。组合亲水性基质与NAC、SeMet和Mel的疏水性药物组合物看起来是特别有前景的。
水凝胶改性表面具有在未改性表面之上的附加优点，因为其可用作用于局部药物递送的药物贮库。例如，在特定情况下药物剂量时间应持续至少数小时，但不超过3天。例如在如同气管切开术管的植入设备情况中，当抗炎活性物质应在一开始释放以预防如同气管狭窄的后续副作用，但之后应不干扰后续愈合过程和上皮形成中的正常细胞分裂，其可为满足需要的。通过连同疏水性NAC、SeMet和Mel使用亲水性水凝胶基质可轻易获得此释放性质，这是因为亲水性基质在其溶胀期间作为药物控释系统的特性。
除了NAC、SeMet和Mel，可在连同医疗器械和设备使用的涂层或塑料中加入另外的活性物质，例如杀菌药物、贵金属溶液和/或地塞米松。
活性剂，即NAC、SeMet和Mel，以及可能的一种或多种附加活性物质可以以两种不同方式并入涂层：I.在任意涂层形成步骤中作为溶液成分，例如在水凝胶涂层聚合期间，或者II.通过浸渍浴。后者方式II.优选作为水凝胶涂层形成后的附加步骤，但其完成也可没有此涂层，而直接至医疗装置。 方式II.可改性如同硅胶导管或聚乙醇酸可吸收缝线的设备，没有聚合物涂层步骤或在聚合物涂层步骤之后加入活性物质。
发明人已证实了活性剂并入的效应，通过测试药物溶解至具有20%甲醇或乙醇的磷酸盐缓冲液(PBS)、提取，以及如果是杀菌药物，通过经抑制生长区域法(数据未列出)。研究了药物溶解速率和负载能力，以及涂层稳定性与工艺参数的依赖关系。发明人观察到NAC、SeMet和Mel在水凝胶溶胀期间的扩散效应，因为物质(NAC、SeMet、Mel)的固体微粒沉淀出涂层至周围溶液。
本发明人表明(实施例5)相比于无涂层骨架材料以及不具有NAC、SeMet和Mel的水凝胶涂覆材料二者，在导管材料(聚氯乙烯、乳胶)上使用包含NAC、SeMet和Mel的水凝胶涂层显著减少了此材料上的细菌生长以及细菌生物膜的形成。
实施例
实施例1：白癜风的治疗
白癜风是一种具有皮肤黑色素细胞减损的获得性色素沉着障碍。因此，白色斑块出现在机体不同部位的皮肤上。白癜风在全世界的患病率在0.1-2%的范围内变化。白癜风对于受影响患者可为心理破坏性的并可影响生活质量、自尊、婚姻和就业(Halder RM，Chappell JL.SeminCutan Med Surg.2009；28(2):86-92.)。精确的发病机理仍然难懂，提出的机理落入自身免疫、生化、氧化-抗氧化、神经性和病毒性标题下。几项研究显示针对黑色素细胞的自由基毒性蓄积导致它们的破坏。事实上，相比于对照患者，白癜风患者的红细胞具有更低水平的谷胱甘肽。
在本实施例中，我们报道了在她颈周和两腋下具有弥散性白癜风的45岁妇女的病例。使用下列口服摄入片形式的商购药物治疗她三个月，治疗方案：0.6g NAC，三次/天；SeMet，55微克/每天一次；Mel，3mg/每天一次；所有这三种药物同样是三天/周，然后中断4天(不给药)。
在三个月治疗的初期和末期拍摄她颈部和两腋下的图片。
未报道不良副作用。
从图2中图片显而易见脱色明显减少，两腋下几乎完全复色。
实施例2：皮肤美容处理
皮肤老化可为肉眼识别的，因为在成人中逐渐发生皱纹、弹性丧失、松垂和变薄。因此，测定皮肤表面纹理在皮肤病学领域中是特别重要的，因为此类测定可用于皮肤诊断以及治疗或美容处理评估。
环境污染对于皮肤的影响具有增加的相关性，皮肤经常被污染剂降解，伴随相关老化和机能障碍。皮肤直接暴露至污染，具有评估为约2平方米个体表面，大于任何其它人体组织。归因于污染的损伤机制主要归属于诱导氧化应激和炎性反应。这些机制驱使我们在轻度老化、油性皮肤、具有丘疹的情况下使用与SeMet和Mel组合的NAC。
一43岁妇女因为其油性皮肤、呈现红肿和丘疹而拜访皮肤科医生。采用盖仑制剂治疗她一个月，该制剂包含：水、鲸蜡硬脂醇聚醚25硬脂酸甘油酯、三乙醇胺硬脂酸盐、鲸蜡硬脂醇、NAC5%、SeMet0.5%、Mel0.1%、辛酸/癸酸甘油三酯、二甲硅油、甘油氢化聚异丁烯、聚山梨酯60、戊二醇、香草。
皮肤纹理的评估是在皮肤科医生制备的硅橡胶皮肤复制品上，然后通过显微镜观察(图3A)，遵循已报道程序(Setaro M，Sparavigna A.Irregularity skin index(ISI):atool to evaluate skin surface texture.Skin Res Technol.2001;7(3):159-63.)。如同由这些作者阐明的，通过面线分析，皮肤复制品的显微镜检查显示皮肤表面纹理规则性的改变。采用包含NAC、SeMet和Mel的乳膏制剂联合治疗一个月后，脸部面线(face surfaceline)表现更规则，其网络次序具有令人难忘的增加，特别是当对比于治疗前所观察的随机盘绕外观时。遵循Setaro和Sparavigna的方法进行的图像快速傅立叶变换(FFT)分析真实显示(图3B)治疗前具有选定方向的图案-如通过左栏A和B中箭头所示的，指示不规则的纹理。治疗后，FFT分析显示取而代之的是几乎完全规则的环形图案，指示规则的皮肤纹理。
治疗月后，皮肤科医生和病人都报告了可视的皮肤不规则减少连同更紧致和更光滑的外观，皮脂腺分泌正常化且红肿和丘疹消失。
实施例3：对于体外培养母细胞样细胞系(blastoid cell line)的抗氧化效应
方法
使用人类淋巴母细胞(lymphoblastoid)HL60和原红细胞 (proerythoblastoid)K562细胞系，生长在37℃下RPMI1640培养基(Invitrogen，Gibco，Milano，Italy)中，补充10%胎牛血清、5μg/ml青霉素、5μg/ml链霉素、2mM谷氨酰胺，并一周常规传代培养三次。用单独的甲萘醌(对照)，唯一的NAC、NAC+Se-甲硫氨酸(SeMet)、NAC+Mel或NAC+SeMet+Mel处理细胞。在补充SeMet的情况下此补充在试验前两天进行，通过使用缓冲液中的SeMet溶液(浓度如图4-7描述中所示)。在补充Mel的情况下此补充在试验前20小时进行，通过使用乙醇溶液(浓度如图4-7描述中所示)。生长培养基中的乙醇浓度≤1.3%且对照仅具有此溶剂并也平行生长。
通过使用荧光探针5-(和-6)-氯甲基-2',7'-二氯二氢荧光素双醋酸酯，乙酰酯(CM-H2DCFDA)(Invitrogen，Molecular Probes)检测NAC、Mel、SeMet和这些物质组合保护细胞免受氧化刺激的效应。CM-H2DCFDA是细胞渗透性活性氧类指示剂，直至通过胞内酯酶除去其醋酸酯基，并在细胞内氧化才发荧光。因而通过荧光增加监控细胞内氢过氧化物(主要是H2O2)的增加。通过使用甲萘醌进行用于增加H2O2的氧化刺激。
对细胞计数，并注意保持细胞和荧光探针之间比率恒定。细胞洗涤后再悬于浓度为106/ml的2ml HBSS中，然后转移至吸收池并在荧光计比色皿座中37±0.1℃下温和搅拌下平衡15分钟。加入2μl CM-H2DCFDA的DMSO溶液并经时读数荧光强度。在首先读数200秒后，加入适当整份的NAC磷酸盐缓冲液(浓度如图4-7描述中所示)，以及10μl0.1M的甲萘醌乙醇溶液，并继续读数荧光强度。在强度读数期间，样品置于持续温和搅拌下。
在配有氙弧灯的K2荧光计(ISS Inc.Champaign，IL)中持续检测荧光强度20分钟，通过使用495nm处激发以及530nm处发射，带通为8nm。
结果
各自处理后的细胞内氧化响应的代表性结果示于图4、5和6中。不同浓度的甲萘醌、NAC、SeMet和Mel被测试并给出了不同响应，(响应)还取决于细胞系。然而，这三种物质的组合总是导致最为有效地防止氧化驱使的荧光增加。在用甲萘醌氧化挑战(oxidativechallenge)后，DCFDA荧光强度增加。NAC加入导致如通过其斜率评估的此强度增加动力学的相关减少。连同NAC存在的SeMet或Mel具有不同效应，取决于细胞类型以及浓度。
显而易见地，在一些情况下观察到NAC+SeMet或NAC+Mel对不是减少响应而是促进荧光增加，暗示促氧化效应。一代表性实例报道在图6中。然而，即便在这些情况中三种成分NAC+SeMet+Mel的组合也导致了相对于对照的斜率以及因而氧化响应的最大降低。
由NAC+SeMet+Mel组合起作用的强大抗氧化保护可减少60%NAC浓度。此示于图7中，其中通过使用与SeMet和Mel组合的仅0.4mM NAC获得堪比由1mM NAC所发挥的保护。
结论
NAC与SeMet和Mel的组合明确增加了NAC的抗氧化保护。该组合发挥了协同效应，不只是对于NAC作用还对于单独各自三种组分的作用。在若干情况下当NAC与SeMet和Mel组合使用时抗氧化效应是相对于单独的NAC的三倍有效。
可减少NAC浓度，使用小于一半的浓度达到了相似的效果。
出人意料地，在一些情况下观察到了SeMet或Mel，还有与NAC组合的不利的促氧化效应。虽然机理仍在争论，但在文献中报道了Se和Mel二者的反促氧化效应(adverse pro-oxidant effect)。然而，在我们的试验中三种物质的组合(其中Se是SeMet的形式)恢复了抗氧化细胞保护，即便在氧化剂挑战下也具有可忽略的氧化的最终效应。
实施例4：结肠癌细胞中的分化效应。
此前报道了NAC调节细胞增殖和分化，特别是通过转化细胞朝向正常分化途径减少增殖。据报道，此作用发生在正常细胞以及癌细胞中。
如下分析了采用与SeMet或Mel或二者组合的NAC处理的结肠癌细胞系(Caco-2)中增殖和分化相关基因的表达。结果示于图8和9中。
方法
将结肠癌细胞Caco-2(亚克隆TC7，Chantret等，J.Cell Sci.107:213–225；1994)常规维持在包含10%热灭活胎牛血清、FBS(Gibco，Invitrogen)的高葡萄糖DMEM(Gibco，Invitrogen，Milan，Italy)中。在六孔板上以3x103/cm2的密度接种细胞。接种24小时后采用NAC(2mM)和/或SeMet(25nM)和/ 或Mel(25μM)处理细胞。处理72小时后，分析细胞的基因表达。
评估肠上皮细胞分化特有基因表达；两种编码刷状缘水解酶(brush borderhydrolase)，肠碱性磷酸酶(ALPI)和蔗糖酶-异麦芽糖酶α-葡糖苷酶(SI)的基因；两种编码细胞-细胞粘附复合体蛋白，紧密连接蛋白1(tight junction claudin1)(CLDN1)和粘结原钙粘蛋白1(adherent junction protocadherin1)(PCDH1)的基因。还分析了细胞周期的重要抑制剂，作为通常伴随Caco-2细胞分化的细胞周期停滞标记物的细胞周期素依赖性激酶抑制剂1A(CDKN1A/P21waf1/cip1)的表达。使用甘油醛-3-磷酸脱氢酶(GAPDH)作为看家基因。
使用可在：http://www.ncbi.nlm.nih.gov获得的软件Primer-BLAST设计特定引物序列并将其总结在表1中。
在TRIzol试剂(Invitrogen)中提取总RNA。采用1U DNAse I(Invitrogen)处理来自各样本的一微克总RNA并采用200U SuperScript III逆转录酶(Invitrogen)逆转录，在20μl(终体积)中使用250ng随机引物。在ABI Prism7000(Applied Biosystems，Monza，Italy)上进行实时定量，在包含10ng cDNA和0.6μl各引物(10μM)的25μl反应体积中使用5Prime RealMasterMix SYBR ROX2.5X(Eppendorf，Milan，Italy)，根据下列方案：95℃下10分钟1循环，三步骤40循环，包括95℃下20秒，60℃下40秒，以及68℃下45秒。所有试验重复进行三次或更多次单独分析。各反应运行阴性对照(无模板)以证实无污染，并通过熔融曲线分析确认放大特异性。所有数据分析为具有标准偏差的平均值并使用ANOVA通过p参数评估显著性。为测定相对转录物丰度，使用2-ΔΔCT法(Livak KJ，SchmittgenTD.Methods2001；25:402-408.)。
表1
结果
结果示于图8和9中，显示了当细胞置于各自处理时五种基因的基因表达增加(倍数变化)。实时定量RT-PCR数据毫无疑问地显示：
1)相比于单独的NAC，通过与SeMet和Mel组合，NAC的抗增殖作用(如通过P21基因增加表达所示)加倍。
2)NAC的分化作用(如通过标记基因SI、ALPI、CLDN1、PCDH1增加表达所指示的)通过以上组合明确增强了，标记基因的表达相比于单独的NAC增加了40-80%。
3)虽然当分析一些特定分化标记物，例如ALPI、CLDN1和PCDH1时观察到NAC+SeMet或NAC+Mel的配对组合具有堪比三种物质组合的效应。然而当三种物质组合使用时具有整体增加分化诱导的清楚趋势。
实施例5:医疗装置水凝胶涂层中NAC、SeMet和Mel的抗菌效应
方法
水凝胶涂层：
使用如现有技术中已知的基于聚氨酯(PUR)和聚乙烯吡咯烷酮(PVP)，设计用于医疗聚合物设备的水不溶性水凝胶聚合物涂层，来涂覆聚氯乙烯导尿管以及乳胶导尿管。此水凝胶涂层的表征之前已通过傅里叶变换红外衰减全反射(FTIR-ATR)光谱、相对于未涂覆骨架材料和对猪组织配合端面(porcine tissue counter-face)的静态和动态摩擦因子、水润湿角和显微观察进行。发明人进行的测试(数据未示出)证实水化状态下表面成分、超亲水性和润滑性的改变，包括摩擦因子降低。在具有水凝胶涂覆内表面的聚氯乙烯导尿管情况 中观察到毛细管作用现象，证明了涂层和水分子之间的高亲和力。
细菌生长和生物膜形成：
为测量对于附着固着细菌(adherent sessile bacteria)形成的影响，根据Nickel和同伴所述的工艺(Antimicrob Agents Chemother.1985；27(4):619-24)构建人工导管。所使用导管材料是乳胶、采用含贵金属水凝胶涂覆的乳胶、采用NAC、SeMet和Mel(NAC+SeMet+Mel)涂覆的乳胶以及采用贵金属和(NAC+SeMet+Mel)二者涂覆的乳胶。将人工导管装置连接至两升容器，其用作保持在37℃水浴中的体外膀胱。通过设为递送50ml/h的泵将含大肠杆菌(E.coli)的培养基从容器泵送通过该人工导管。在暴露至大肠杆菌之前和之后测试该导管10cm2的中段部位。在这些试验中使用的大肠杆菌菌株分离自具有导管相关性尿路感染的患者。所用培养基是补充0.4%营养肉汤的人工尿液。该细菌存储在-70℃下试管(倾斜)中的倾斜琼脂上并以10小时间隔连续培养。通过采用分光光度计(600nm)使用作为生长参数的标准化浊度监控该体外膀胱内的细菌生长。
使含大肠杆菌的人工尿液通过人工导管10小时并通过取样导管材料表面监控细菌生物膜的发展。无菌移除承载固着菌的样本盘用于扫描电子显微术。另外，通过在无菌磷酸盐缓冲盐溶液中低输出声波刮导管盘的表面获得有活力附着细菌的定量计数。安排稀释级数至10-4并涂抹在营养琼脂上，从中获得定量板计数。从人工导管移除指定用于SEM的导管标本并将其置于由5%戊二醛的二甲胂酸盐缓冲液(0.1M，pH7.2)构成的固定液中在22℃，1小时，然后在一系列含水醇溶液(20-100%和Freon113-乙醇溶液(30-100%)中脱水并接着晾干。在镀金机中用金涂覆样本并通过使用扫描电子显微镜检查。
结果
导管盘表面刮擦物在营养琼脂上的生长显示：相比于未涂覆骨架材料，水凝胶涂覆材料上的有活力大肠杆菌数目显著降低。当将NAC、SeMet和Mel加至水凝胶时关注到附着细菌菌落数目的进一步急遽降低。
骨架材料上的菌落数目：100
水凝胶涂覆材料上的菌落数目：73
具有NAC、SeMet和Mel的水凝胶涂覆材料上的菌落数目：58
SEM检查显示导管乳胶、贵金属涂覆乳胶、(NAC+SeMet+Mel)涂覆乳胶、和贵金属+(NAC+SeMet+Mel)涂覆乳胶盘在暴露至大肠杆菌前不具有显著量的乙醇杀死细菌细胞。暴露至人工尿液中大肠杆菌细胞10分钟后，在乳胶盘上看到显著量的粘附细菌细胞而在贵金属涂覆乳胶或(NAC+SeMet+Mel)涂覆盘上具有最小菌落，且在贵金属+(NAC+SeMet+Mel)涂覆盘上无菌落。定植10小时后，未涂覆乳胶盘的特征性片状表面被大量粘附细菌完全闭塞，其被嵌入大量细菌自身的无定形胞外多糖以形成厚附着生物膜。在贵金属涂覆导管盘和(NAC+SeMet+Mel)涂覆导管盘上具有稀少生物膜形成现象而在采用贵金属和(NAC+SeMet+Mel)的组合的涂覆盘上无生物膜。
Claims (9)
1.药物组合在制备用于治疗皮肤疾病的医药产品中的用途，所述药物组合由(i)N-乙酰基-L-半胱氨酸；(ii)硒代甲硫氨酸形式的硒；和(iii)褪黑激素，和/或它们生理学上可接受的盐组成。
2.根据权利要求1的用途，其中所述医药产品用于给药至哺乳动物。
3.根据权利要求2的用途，其中所述医药产品用于口服给药。
4.根据权利要求3的用途，其中N-乙酰基-L-半胱氨酸与硒代甲硫氨酸的日剂量重量比在4000:1-60000:1的范围内，且N-乙酰基-L-半胱氨酸与褪黑激素的日剂量重量比在60:1-2000:1的范围内。
5.根据权利要求1的用途，其中组分(i)N-乙酰基-半胱氨酸，(ii)硒代甲硫氨酸和(iii)褪黑激素是用于上皮给药。
6.根据权利要求5的用途，其中N-乙酰基-L-半胱氨酸与硒代甲硫氨酸的日剂量重量比在3:1-33:1的范围内，且N-乙酰基-L-半胱氨酸与褪黑激素的日剂量重量比在15:1-1000:1的范围内。
7.根据权利要求5或6的用途，其中组分(i)是以3～10wt-％的浓度给药，组分(ii)是以0.3～1wt-％的浓度给药且组分(iii)是以0.01～0.2wt-％的浓度给药。
8.根据权利要求5-7中任一项的用途，其中所述医药产品用于皮肤处理。
9.药物组合在制备用于治疗白癜风的医药产品中的用途，所述药物组合由(i)N-乙酰基-L-半胱氨酸；(ii)硒代甲硫氨酸形式的硒；和(iii)褪黑激素，和/或它们生理学上可接受的盐组成，其中组分(i)以5～45mg/kg/天的剂量给药，组分(ii)以0.4～1.2μg/kg/天的剂量给药，以及组分(iii)以0.02～0.08mg/kg/天的剂量给药。
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