CN1191835C - 嘧啶基核苷的制药用途 - Google Patents
嘧啶基核苷的制药用途 Download PDFInfo
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- CN1191835C CN1191835C CNB008041032A CN00804103A CN1191835C CN 1191835 C CN1191835 C CN 1191835C CN B008041032 A CNB008041032 A CN B008041032A CN 00804103 A CN00804103 A CN 00804103A CN 1191835 C CN1191835 C CN 1191835C
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Abstract
本发明提供了治疗线粒体疾病的方法。本发明方法包括施用嘧啶基核苷如三乙酰基尿嘧啶核苷等。本发明还提供了缓解或根除与线粒体疾病相关的症状的方法。特别适于本发明的治疗方法的线粒体疾病包括由一或多种嘧啶的缺乏所致的线粒体疾病。
Description
发明领域
本发明总的来说涉及线粒体疾病,更具体地说,涉及通过施用嘧啶基核苷如三乙酰基尿嘧啶核苷治疗线粒体疾病的方法。
发明背景
线粒体疾病的发生方式一般为遗传性的、偶发的和后天获得的。遗传性线粒体疾病的发病率和死亡率都很高。最严重的类型,如利氏综合症(亚急性脑脊髓病坏死),每年诊断后死亡率高达50%。多因子型的线粒体疾病包括更常见的疾病如亨廷顿氏病、帕金森氏病,阿尔茨海默氏病,以及更常见的某些类型的糖尿病、心脏病、偏头痛和中风。事实上,老化过程本身也与线粒体机能的发展性退化有关。
线粒体疾病定义如下:由核DNA或线粒体DNA的基因缺陷所导致的线粒体代谢失调。该疾病可以是如常规孟德尔疾病的母系遗传性疾病,或者可以是由体细胞突变而得的继发性疾病。该代谢失调可发生在各种基因水平,从DNA和RNA到蛋白质。它们可影响线粒体DNA的复制,转录,进出线粒体的大分子的转运,或一些作用部位位于线粒体内部的大分子的功能。一直以来,关于线粒体病因学的讨论都集中在线粒体(氧化性)机能的退化。然而,很多线粒体疾病的症状都和经常被忽视的细胞器的基本的生物合成(非退化性)功能有关。线粒体的生物合成功能之一就是尿苷的合成。
患有不同线粒体疾病的患者很有可能会伴有尿苷的功能性缺陷,因为全程嘧啶合成的限速步骤(二氢乳清酸辅酶Q氧化还原酶,EC 1.3,99.11)位于线粒体内膜,并与电子传递链偶联。已知培养基中有线粒体功能障碍的细胞因其在DHO-QO活性中的功能缺陷,依赖于外源性的尿苷生长存活。
遗传型的线粒体疾病的流行病学大部分还是未知的。据估计,美国1/4000到1/1000的活产婴儿在10岁以前会被诊断出线粒体疾病。大体上与儿童期癌的发病率不相上下。当然,更常见地,线粒体起重要作用的老化的退化性疾病影响多达220-85百万的美国人。尽管线粒体疾病的作用范围很广,目前还没有可被接受的治疗方法来解决如此有影响和重大的问题。
因此,仍需要在本领域内提供一种治疗作为一种类型的线粒体疾病的方法。
发明概述
由于本发明者认识到了某些嘧啶基核苷在线粒体疾病中的作用,本发明提供了一种相应的方法来治疗线粒体疾病。因此,根据本发明,提供了治疗线粒体疾病的方法。本发明包括向已患有线粒体疾病或有患有该病风险的对象施用有效量的化合物I:
其中:
R1为OH、NHCOCH3,或NH2,
R2为H、CO2H或
其中:
X是具有选自H、C1-3烷基、OH、NH2和卤素的取代基的C1-C22烷基、C1-C22链烯基或C1-C22链炔基,或者其中X是H。
R3、R4和R5独立地是具有取代基的任意取代的C1-C22烷基羰基,所述取代基选自C1-3烷基、OH、NH2,卤素和H。其中R3,R4,和R5中至少有一个不是H。
根据结构式(I)的典型化合物包括三乙酰基尿嘧啶核苷。因此,在本发明的另一个实施方案中,提供了治疗线粒体疾病的方法。本发明的方法包括向已患有或有患该病风险的治疗对象施用有效量的2’,3’,5’-三-O-乙酰基-1-β-D-尿苷(此后称为“三乙酰尿苷”)。
在本发明的另一个实施方案中,提供了缓解或根除与线粒体疾病相关的一种或多种症状的方法。本发明的方法包括向需要治疗的治疗对象施用有效剂量的通式I的化合物,其中R1-R5和X的定义如上。
同样,在本发明的另一个实施方案中,提供了缓解或根除与线粒体疾病相关的一种或多种症状的方法,该方法包括向已患有或有患该病风险的治疗对象施用有效量的三乙酰基尿嘧啶核苷。
发明详述
本发明是基于以下的发现作出的:嘧啶基核苷如三乙酰基尿嘧啶核苷和相关的化合物可有效地治疗线粒体疾病,其中在该疾病中存在嘧啶的生物合成的降低。本发明的方法是对当前最常规的治疗线粒体疾病的方法的一种改进,因为嘧啶基核苷如三乙酰基尿嘧啶核苷不仅补充了患者自身嘧啶的生成,还增加了***的嘧啶浓度。这些增高的嘧啶浓度反过来维持了体内组织的自然代谢过程及生物合成过程,尤其是那些高代谢负荷的组织如神经、肌肉和器官组织。
许多被广义地划分为线粒疾病病的疾病暗示了一种或多种嘧啶基核苷的缺乏。所有的嘧啶基核苷(除了乳清酸)都可以用尿苷为起始化合物来合成。因此,尿苷的缺乏会导致所有其他的嘧啶基核苷的缺乏,并会留下后遗症。所以,仅补充尿苷(例如,施用三乙酰基尿嘧啶核苷等)能改变许多的症状和疾病状况。
本发明提供了通过施用一种或多种嘧啶基的核苷、它们的前体等来治疗线粒体疾病的方法。
根据本发明,适于治疗的生物体包括任何带有嘧啶生物合成途径的生物体,包括但不局限于哺乳动物如人、牛、羊、马、猫、犬等。
本文所用的嘧啶基核苷及其前体包括如下通式I的化合物:
其中:
R1为O、OH、NHCOCH3,或NH2,
R2为H、CO2H或
其中:
X为具有选自H、C1-3烷基、OH、NH2和卤素取代基的C1-C22烷基、C1-C22链烯基或C1-C22链炔基,,或者其中X为H。
R3、R4和R5独立地是具有取代基的任意取代的C1-C22烷基羰基,所述取代基选自C1-3烷基、OH、NH2,卤素和H,其中R3,R4,和R5中至少有一个不是H。优选地,取代的烷基羰基没有支链并具有5至22个碳原子。
本发明实施中计划使用的烷基羰基R基团包括氨基酸的羰基衍生物(例如,当氨基酸取代基位于烷基羰基的α碳上时)、一元羧酸、二元羧酸等等。在本发明的一个方面,计划用于本发明实施中的二羧酸的取代基具有约3到22个碳原子。
本发明的实施中计划用作取代基的氨基酸的羰基衍生物包括甘氨酸、L-型旋丙氨酸、缬氨酸、亮氨酸、异亮氨酸、酪氨酸、脯氨酸、羟脯氨酸、丝氨酸、苏氨酸、胱氨酸、半胱氨酸、天冬氨酸、谷氨酸、精氨酸、赖氨酸、组氨酸、肉毒碱、鸟氨酸等的羰衍生物。
通式I的典型化合物包括三乙酰基尿嘧啶核苷、四乙酰基胞嘧啶核苷、三乙酰基乳清酸酯及其类似物等。在本发明中,优选的嘧啶基核苷为三乙酰基尿嘧啶核苷。
简单地说,通式I表明了自然存在的D构型的活性化合物,但本发明(除非特别说明)也包括了异构体(例如显示酮-烯醇互变异构的化合物)、L构型的化合物、和D构型和L构型化合物的混合物。优选自然存在的D构型的化合物。
本发明的化合物可以以可药用盐的形式存在,例如但不局限于碱金属(如钠、钾)盐、碱土金属(如锰、镁、钙)盐、铵盐或四烷基铵盐如NX’4+(其中X’为Cl-4)。可药用盐保留了母体化合物中所希望的生物学活性,但没有不希望的毒性的盐类。
在本发明的另一个实施方案中,用于治疗线粒体疾病的方法,以及缓解或根除线粒体疾病相关的症状的方法还包括施用一种或多种维生素和辅因子。根据本发明,计划使用的维生素包括硫胺素(B1)、核黄素(B2)、烟酸(B3)、吡哆辛(B6)、叶酸、氰钴铵(B12)、生物素、硫辛酸、泛酸等。根据本发明计划使用的辅因子包括辅酶Q、丙酮酸钙等。
本发明方法适用于治疗所有的线粒体疾病,特别是那些与嘧啶缺乏相关的线粒体疾病,尤其是那些与尿嘧啶核苷缺乏相关的线粒体疾病。适于用本发明方法治疗的具体的线粒体疾病包括MELAS(伴有乳酸血症和中风样发作的线粒体脑病)、MERRF(肌阵挛、癫痫和具有红纤维破碎型(ragged red fibers)的肌病)、NARP/MILS(神经源性肌肉无力、运动失调、视网膜色素变性/母系遗传性利氏综合症)、LHON(勒伯尔遗传性视觉神经病)“线粒体性失明”、KSS(克-塞综合症)、PMPS(皮尔逊骨髓胰腺综合症)、CPEO(慢性发展性外源性眼麻疲)、利氏综合症、阿尔伯氏综合症、多种线粒体脱氧核糖核酸缺失综合症、线粒体脱氧核糖核酸衰竭综合症、复合物I缺乏症、复合物II(SDH)缺乏症、复合物III缺乏症、细胞色素C氧化酶(COX,复合物IV)缺乏症、复合物V缺乏症、腺嘌呤核苷酸转位子(ANT)缺乏症、丙酮酸脱氢酶(PDH)缺乏症、乙基丙二酸酸尿伴乳酸血症、3-甲基-戊烯二酸酸尿伴乳酸血症、感染期渐退性(during infection)顽固性癫痫、感染期渐退性阿斯伯格综合症、感染期渐退性孤独症、注意力缺乏多动症(ADHD)、感染期渐退性大脑麻椑、感染期渐退性朗诵困难、母系遗传性血小板减少和白血病、MNGIE(线粒体肌病、周围自主性神经病变、胃肠功能失调和癫痫)、MARIAHS综合症(线粒体性共济失调,复发性感染,失语,低尿酸血症/脊髓发育不全(hypomyelation),癫痫发作和二羧酸酸尿)、ND6肌张力障碍、感染期渐退性周期性呕吐综合症、3-羟基-异丁酸血尿伴乳酸血症、糖尿病伴乳酸血症、家族性单侧性纹状体坏疽(FBSN)、氨基糖甘相关性耳聋、扩张形心肌病、脾淋巴瘤、吴尔弗拉姆综合症、多线粒体DNA缺失综合症及肾小管性酸中毒/糖尿病/共济失调综合症。
本发明的另外一个方面提供了治疗患有线粒体疾病的哺乳动物
(如人等)的方法,该疾病由以下情况(但不局限于)所引起:创伤后脑损伤和大脑皮层昏迷,中风(本发明方法对预防及防止病灶扩散有效)、阿尔采木痴呆、雷维小体性痴呆、亨廷顿氏疾病、肌萎缩性脊髓侧索硬化、帕金森氏病、肝肾综合症、急性肝衰-NASH(非洒精性肝衰)、糖尿病(尤其是II型),抗癌转移/未分化癌治疗、特发性充血衰、房颤(非瓣膜性)、午非-帕金森-怀特综合症、特发性心传导组滞,急性心肌梗塞病灶扩散的预防、家族性偏头痛、肠道激惹综合症、非Q-波心肌梗塞继发性预防、先兆经期综合症、肝肾肾衰竭综合症的预防、抗磷脂抗体综合症、子痫/先兆子痫、卵性不育症、缺血性心脏病/心绞痛、夏德雷格和未分类的自主神经功能障碍综合症。
在另一个实施方案中还提供了治疗与药物有关的副作用相关的线粒体疾病的方法。与线粒体疾病相关的药剂类型包括反转录酶抑制剂、蛋白酶抑制剂、DHOD抑制剂等。具体的反转录酶抑制剂包括叠氮胸苷(AZT)、司他呋啶(Stavudine(D4T))、扎西他滨(Zalcitabine(ddC))、去羟肌苷(Didnosine(DDI))、氟碘阿糖尿嘧啶(Fluorodiodoarauracil(FIAU))等。具体的蛋白酶抑制剂包括利托那韦(RITONAVIRTM),茚地那韦(INDINAVIRTM)、沙喹那韦(SAQUINAVIRTM)、奈非那韦(NELFINAVIRTM)等。具体的二氢乳清酸脱氢酶抑制剂(DHOD)包括来氟米特(LEFLUNOMIDETM),布喹那(BREQUINARTM)等。
由于线粒体疾病的某些症状与一种或多种的嘧啶缺乏有关,故本发明的另一个实施方案提供了用于缓解或根除一种或多种与线粒体疾病有关的症状的方法。与线粒体缺乏相关的症状包括肾小管性酸中毒(RTA)、视力损伤、痴呆、癫痫发作、心肌病、骨骼肌病、外周肌病、自主性肌病等。
根据线粒体疾病对特定的线粒体特异性生物合成途径的可以影响将其分类。这样,在本发明的另一个实施方案中提供了治疗由线粒体生物合成途径中的干扰或缺陷引起的线粒体疾病的方法。线粒体主要的生物合成途径是用于嘧啶生物合成的途径。由于本发明方法包括施用嘧啶、嘧啶类似物及其前体,本发明方法计划使用的生物合成途径包括用于包含尿苷、胸苷、胞苷等的嘧啶的生物合成途径。嘧啶生物合成途径中一些具体的缺陷包括那些与所关注的途径中特定酶有关的缺陷。这些缺陷包括遗漏酶、缺失的酶表达、活性降低或失活的缺陷(如:变异)酶等等。这些具体的酶包括二氢乳清酸脱氢酶(DHOH)、尿苷单磷酸合成酶(UMPS)等。
本发明还提供了药用组合物,该药用组合物包括含有根据通式I的嘧啶基核苷及其类似物等的单位剂量形式。
这里描述使用的活性成分可与药理学适用的赋形剂一起配制,所选的这些赋形剂使得这些组合物适于经口、经直肠、肠道外(如:静脉内、肌内、动脉内、腹膜内等)或吸入、渗透泵、局部给药、眼部等途径给药。
软膏是一种半固体制剂,其由引入脂肪、腊或合成基体的活性成分组成。
适合的膏剂的例子包括但不局限于油包水和水包油乳液。油包水膏剂可利用合适的乳化剂配制,该乳化剂具有,但不限于与那些诸如十六烷基乙醇或十六烷基十八烷醇(cetostearyl)的脂肪醇以及乳化蜡相似的特性。水包油膏剂可利用乳化剂如cetomacrogol乳化蜡配制。,适合的性能包括能够改变乳液的粘度和在较大的PH值范围内的物理的和化学稳定性的能力。而水溶性或可混合的膏剂基体可包含防腐体系,并且还可被缓冲至PH值维持在可接受的生理环境内。
除了以上描述的局部给药方法,还有许多***地施用本发明化合物的方法。其中之一涉及对象吸入一种由活性化合物组成的可吸入的烟雾悬浮体。这种活性化合物将会经肺吸收到血液中并以药物有效量进入***循环。这种可吸入的颗粒可以为液体或固体,其颗粒具有足够小的粒度以在吸入时能通过口和喉。总之,认为约1到10微米,但更优选1到5微米的颗粒为可吸入的颗粒。
另外一种向治疗对象施用活性化合物的方式包括以液体制剂的滴鼻剂形式或以患者可吸入颗粒的喷鼻剂形式施用液体/液体悬浮液。用于制备滴鼻剂或喷鼻剂的活性化合物的液体药物组合物可以如下方式制备:通过本领域技术人员所熟知的技术将活性化合物与无菌如焦精游离水或无菌盐水的适合载体混合来制备。
其它施用活性化合物的方式包括将包含通式I化合物的药物组合物以固体、溶液、乳液、分散体、胶粒、脂质体等形式口服给药。其中所得的制剂包含本发明的活性化合物,该化合物与适于经鼻、肠、肠道外给药的有机或无机载体或赋形剂混合。例如,活性成分可和常用的无毒的、药理和生理可接受的载体混合制成片剂、丸剂、胶囊、锭剂、糖锭、水性或油性悬浮体、可分散的粉剂或粒剂、栓剂、溶液、乳液、悬浮液、硬胶囊或软胶囊、囊片(caplet)或糖浆或酏剂以及其它适于使用的形式。可使用的载体包括***胶、明胶、甘露醇、淀粉糊、三硅酸镁、滑石粉、玉米淀粉、角蛋白、胶体二氧化硅、土豆淀粉、脲、中等链长度的甘油三酯、右旋糖酐和其它适于制备的、以固体、半固体、液体形式的载体。可以使用另外的辅剂,稳定剂、增稠剂和着色剂。药物制剂中包含有效量(如:治疗有效量)的本发明的活性化合物,以在施用中能产生预期的效果。
粉剂、溶液、悬浮液或片剂中含有包含在生理相容载体中的活性化合物,那些口服给药体系领域的技术人员可以选择使用常规的标准。例如这些制剂可包括一种或多种选自矫味剂(如薄荷、冬青油或樱桃)、着色剂、防腐剂等试剂,以提供剂型美观且美味的制剂。包含与无毒性的药物可接受的赋形剂混合的活性成分的片剂可由已知的方法制备。可使用的赋形剂是,例如(1)惰性稀释剂,如碳酸钙、乳糖、磷酸钙、磷酸钠等;(2)制粒剂和崩解剂,如玉米淀粉、土豆淀粉、藻酸等;(3)粘合剂,如西黄蓍胶、玉米淀粉、明胶、***胶等;和(4)润滑剂,如硬脂酸镁、硬脂酸、滑石粉等。片剂可不包衣,或用公知的技术包衣,以延缓在胃肠道的分解和吸收,从而延长其作用时间。例如,可使用延长作用时间的物质如一硬脂酸甘油酯或二硬脂酸甘油酯。片剂也可采用在美国专利第4,256,108、4,160,425和4,265,874号(在此引入作为参考)中所描述的技术包衣,形成渗透性治疗片剂以控制其释放。
当口服剂型为硬的明胶胶囊时,活性成分可与惰性固体稀释剂如碳酸钙、磷酸钙、白陶土等混合。它们还可以软的明胶胶囊形式,其中活性成分与水或油介质如花生油、液态石蜡、橄榄油等混合。
另外向治疗对象***施用活性化合物的方式包括活性化合物的栓剂形式,以使治疗有效量的化合物能够进入***循环。
药物组合物中包含的活性化合物(即通式I的嘧啶基核苷)的数量是在治疗对象中缓解患者线粒体疾病的体征和症状的有效量,其为约0.5g/m2/天到约20g/m2/天,更优选约2g/m2/天到10g/m2/天,在一个更优选的实施方案中为约6g/m2/天。这里使用的单位m2表示表面积(SA),其值由以下公式确定:SA(m2)=(高(cm))0.75×(重量(kg))0.425×71.84÷10000。
依据要给药的活性化合物制剂的溶解度,缓解线粒体疾病的体征和症状的日剂量可分为一个或几个单位剂量给药。例如,对于三乙酰基尿嘧啶核苷每天的总剂量可在1到20g范围内,依据治疗对象的年龄和状态,可以高达每天五次的方案给药或者根据急性加重的情况按需给药。
根据本发明,以适当的日剂量任选施药辅因子与维生素。计划用于本发明方法施药的日剂量列于表I中:
表I
辅因子或维生素 | 日剂量范围 | 目前优选的日剂量范围 |
辅酶Q | 约1-10毫克/千克/天 | 约5毫克/千克/天 |
丙酮酸钙 | 约1-6克/平方米/天 | 约3克/m2/天 |
硫胺素(B1) | 约0.5-5毫克/千克/天 | 约50-200毫克/天 |
核黄素(B2) | 约0.5-5毫克/千克/天 | 约50-200毫克/天 |
尼克酸 | 约0.5-20毫克/千克/天 | 约50-200毫克/天 |
吡哆辛(B6) | 约0.5-5毫克/千克/天 | 约50-200毫克/天 |
叶酸 | 约0.005-0.03毫克/千克/天 | 约0.4-2毫克/天 |
氰钴铵(B12) | 约0.001-0.03毫克/千克/天 | 约0.05-0.5毫克/天 |
生物素 | 约0.005-0.2毫克/千克/天 | 约0.05-0.5毫克/天 |
泛酸 | 约0.5-5毫克/千克/天 | 约50-200毫克/天 |
正如本领域的技术人员所理解的,实际上,以上剂量是通用,可由治疗中心的专业人士根据个别患者的情况(需要考虑到患者的年龄、体重、身高、健康状况等)做出改动。
通式I的化合物可按本领域人员所熟知的方法,并根据F.J.M.Rajabalee.Angew.Chem.Int.Ed.,vol.10,p.75(1971)所述的方法制备;有些是可商购的,如从PO Box 1458,St.Louis,MO 63178的Sigma化学公司获得。
通过参照下面非限制性的例子更详细地描述本发明。
实施例
实施例1-用三乙酰基尿嘧啶核苷治疗线粒体疾病
患者:研究了四个患有线粒体性肾小管性酸中毒(RTA)的患者,线粒体性RTA经常违反简单的分类法如近端型(类型II)或远端型(类型I)小管性病变,因为患者总是镶嵌并表达两种导致高氯(非阳离子间隙)代谢型酸中毒的表型特征。
患者#I是2周岁的女孩,患有利氏综合症、乳酸血症和复合I型缺乏症,她需要200mEq/天的NaHCO3以补充肾小管丢失的碱,并维持高于20mEq/l的血清碳酸氢盐浓度,蛋白尿1+,和明显的具有羟基脯氨酸尿的氨基酸尿。
患者#2是3周岁的女孩,患有利氏综合症和复合IV(COX)缺乏症,需要200mEq/天的NaHCO3。
患者#3是2周岁的男孩,患有利氏综合症、乳酸血症、蛋白尿1+和丙酮酸脱氢酶(PDH)缺乏症,需要210mEq/天的NaHCO3。
患者#4是11周岁的男孩,患有3-羟基异丁酸血症、乳酸血症和脑病,需要468mEq/天的NaHCO3。
方法:治疗前后观察血和尿电解质、肌酸、pH值、尿分析和静脉血气。还要获得定量的尿氨基酸和有机酸。三乙酰基尿嘧啶核苷治疗的前三天还要继续服用治疗前口服碳酸氢钠的剂量,然后以能接受的量按周减药至血清碳酸氢盐保持在20mEq/l以上。
治疗:患者接受三乙酰基尿嘧啶核苷约2g/m2口服,3次/天(TID)。
结果:患者#1在24小时的治疗中RTA完全纠正,血清碳酸氢盐保持在20mEq/l以上而无需再口服碳酸氢盐,2星期内她已完全消除了她的羟基脯氨酸尿。
患者#2尿中碳酸氢盐的损耗开始为99Eq/l,治疗前碳酸氢盐***分数(FEHCO3)为9.3%。经过36小时的三乙酰基尿嘧啶核苷治疗后,尿碳酸氢盐损耗为不可测(<5Eq/l)。经过3星期的治疗后,患者只需要治疗前碳酸氢盐剂量的25%以保持正常的血清碳酸氢盐。
患者#3的尿碳酸氢盐损耗为59Eq/l,治疗前FEHCO3为10.0%。用36小时的三乙酰基尿嘧啶核苷治疗后,尿碳酸氢盐损耗为不可测(<5Eq/l);经过3周的治疗后,患者只需要其原先所需碳酸氢盐剂量的10.0%。
患者#4经过1周的治疗后,口服的碳酸氢盐需要量减少了35%,目前正继续治疗。
结论:用三乙酰基尿嘧啶核苷治疗患有线粒体疾病的4名患者,结果四名患者线粒体疾病的肾小管性酸中毒全都被纠正,或显著改善。
实施例2 给患有MARIAHS综合症的治疗对象施用三乙酰基尿
嘧啶核苷的治疗
患者CMZ是一个患有线粒体性共济失调、复发性感染、失语症、低尿酸血症/髓鞘发育不全和癫痫发作(MARIAHS综合症)的孩子,一岁后进行治疗。症状表现为一种原发性的二氢乳清酸脱氢酶缺乏,该缺乏为全程嘧啶合成中的限速步骤,会导致功能的性外源性尿苷的依赖。
治疗:患者3岁开始接受尿苷的治疗,在4.5岁时,改用三乙酰基尿嘧啶核苷治疗,因为其是尿苷的更易吸收的形式。
结果:CMZ症状改善了很多。他的发作次数从两月两次减到两月一次。动作和语言进展显著。目前正在学习字母、辨色、并且开始使用两个单词的句子。存在轻微的躯干共济失调。使用20个月尿苷治疗后的脑部MRI显示白质病变没有进展。尽管开始使用三乙酰基尿嘧啶核苷的前十天内发现了另一次发作,但没有任何生化、血液、或临床的毒性出现。三乙酰基尿嘧啶核苷的初始用量为0.1g/kg/天,两个月内,用量增至0.2g/kg/天,患者出现语言表达、认知能力迅速增强并且降低了其以前的共济失调幅度。近来,她的用量增至0.3g/kg/d,并开始服用0.75g的丙酸钙TID。
结论通过施用三乙酰基尿嘧啶核苷治疗MARIAHS综合症,使患者身体状况明显改善,症状显著减轻。
实施例3-通过向患有多种症状和家族性线粒体疾病的治疗对象
施用三乙酰基尿嘧啶核苷进行的治疗
患者KL是位成人,在诊断她的儿子患有线粒体疾病导致的中风样发作、共济失调和脑病后首次引起调查者的注意。在施用三乙酰基尿嘧啶核苷之前,KL患有复发性肾盂肾炎、感染性中性粒细胞减少、半身不遂/失语性偏头痛、癫痫大发作、大肠和膀胱需要每日四次导管***术、胆汁协同失调、吞咽困难及饭后咳嗽、外周性自发性多神经病、痛觉异常、心脏传导紊乱伴室性心动过速(SVT)及快慢综合症、严重的***性低血压、端坐呼吸且不能不停歇地爬楼梯的功能障碍以及阵发性感觉中枢模糊所至认知力低下,从几小时到几天的记忆力障碍。
治疗KL以剂量为0.05/g/kg/d的三乙酰基尿嘧啶核苷开始治疗
结果从开始接受三乙酰基尿嘧啶核苷治疗,KL没有出现过癫痫发作或偏头痛。她的痛觉异常消失了,尽管还存在一些麻木感。她能够在大多数时间自主排空,每星期只需1-2次口服泻药(I & O cath)。胆汁协同失调也消失了。6星期的三乙酰基尿嘧啶核苷治疗后,她能够走足足一英里,这在过去的两年里由于功能障碍她一直没能做到。快慢综合症还存在。她腕部戴了一只锻炼用数字脉博表,脉博表设定在脉博低于50和高于140bpm时表会发出警告。现在仅在她爬山或爬楼梯时快表报警,而以前在她仅仅站起时就会报警。慢表在一周2-3个晚上的睡觉时发生低至40次的警告。KL的感觉中枢不再模糊,据她本人自己说,她的记忆力是五年中最好的。没发现任何生化或血液学的毒性。
在开始施用三乙酰基尿嘧啶核苷治疗的前10个星期,KL的***从4星期缩短到2星期,而且它的周期性的***疾病轻微地出现。月经内的***、孕酮、FSH和LH浓度呈现出持续的黄体相。她没有贫血。她的血红蛋白(Hgb)持续稳定在13g/l。十周后,她的***恢复正常,三乙酰基尿嘧啶核苷及其他药物的注射剂量没有任何改变。目前她正在接受每天三次的0.1g/kg/d的三乙酰基尿嘧啶核苷和0.75g/kg/d的丙酮酸钙的治疗。
实施例4-向患有多种线粒体缺失综合症的治疗对象施用三乙酰
基尿嘧啶核苷的治疗
患者SF是位11岁男孩,四岁以后就患有顽固性麻风病。作为五年级的学生,他几乎不能打棒球。由此发现他患有似乎是多线粒体DNA缺失综合症。这种疾病产生出多个缺失的线粒体DNA片段,并能导致一系列的症状。SK开始恶化,后因恶化的癫痫受过两次重症监护,在接下来的4个月里,在使用抗惊厥的药物过程中有过7次变化。每天夜里他都会出现8-10次癫痫大发作,发作大多数在清晨停止。他还会出现不自觉的上唇抽动。
治疗:最初一星期对患者施用0.05g/kg/d剂量的三乙酰基尿嘧啶核苷,接下来的一星期改为0.16g/kg/d,然后改为0.24g/kg/d。
结果:在前三天他的上唇自动性抽动的紧急情况中他的癫痫发作和上唇的不自愿抽动完全停止。因为他的痛痉宁用量为低剂量(开始使用三乙酰基尿嘧啶核苷治疗前后均为4ug/ml),为了达到8-12ug/ml的治疗浓度增加了痛痉宁的用量,并且三乙酰基尿嘧啶核苷的用量增至0.16g/kg/d。三星期后,三乙酰基尿嘧啶核苷的量增至0.24g/kg/d,并添加0.5g的丙酮酸钙每天三次。这些将会导致他的夜间癫痫的发作暂时增加,三天后,发作停止。几星期后,SF可重新回到学校并且又能打棒球。
实施例5 向患利氏综合症的治疗对象施用三乙酰基尿嘧啶核苷
患者CS是一个2岁女孩,患有利氏综合症、乳酸血症和肾小管性酸中毒,并且在一次选择性经皮胃造口术(PEG)麻醉后,患上高血压危象及急性水肿。由于她的碳酸氢盐的日需要量特别大(25Eg/kg/d),不能满足需要,所以需要胃管输入碳酸氢盐。她患上了PEG手术并发症和脊束、中脑、丘脑的利氏损伤。PEG术后,她昏迷了三天。
治疗:CS接受了三乙酰基尿嘧啶核苷的紧急治疗
结果:开始使用三乙酰基尿嘧啶核苷的12小时内患者的肾小管性酸中毒完全消除了。她不需再补充碳酸氢盐,施用三乙酰基尿嘧啶核苷治疗的两个小时内,她的氨基酸尿得到了改善,血浆氨基酸回到了正常范围,同时接受了连续的肠道外营养。尽管有一些良好的生化反应,但她再也没有从昏迷中苏醒过来,四星期后死于晚期疾病。
尽管已参照了某些优选实施方案详细描述本发明,应当理解修改和变化都落入本发明所描述的和权利要求所保护的精神和范围内。
Claims (26)
1.有效量的通式I化合物在制备用于治疗下列与嘧啶缺乏相关疾病的药物中的用途,其中所述疾病选自肾小管性酸中毒(RTA)、利氏综合症、MARIAHS综合症、线粒体疾病导致的中风样发作、乳酸血症、丙酮酸脱氢酶(PDH)缺乏症、脑肌病、细胞色素C氧化酶(COX,复合物IV)缺乏症、复合物I缺乏症、多种线粒体缺失综合症,和它们的任意组合:
其中:
R1为O、OH、NHCOCH3或NH2
其中:X独立地是H,或者取代的
C1-C22烷基、取代的C1-C22链烯基或取代的C1-C22链炔基,取代基选自H、C1-3烷基、OH、NH2和卤素,
R3、R4和R5每一个独立地是取代的C1-C22烷基羰基,所述取代基选自C1-3烷基、OH、NH2和卤素,或H,其中R3,R4,和R5中至少有一个不是H。
2.根据权利要求1所述的用途,其中所述化合物是2’,3’,5’-三-O-乙酰基-1-β-D-尿苷。
3.根据权利要求1所述的用途,其中所述取代的烷基羰基没有支链并具有5至22个碳原子。
4.根据权利要求1所述的用途,其中所述烷基羰基是选自甘氨酸、左旋丙氨酸、缬氨酸、亮氨酸、异亮氨酸、酪氨酸、脯氨酸、羟脯氨酸、丝氨酸、苏氨酸、胱氨酸、半胱氨酸、天冬氨酸、谷氨酸、精氨酸、赖氨酸、组氨酸、肉毒碱和鸟氨酸的氨基酸的羰基部分。
5.根据权利要求1所述的用途,其中所述烷基羰基是具有3到22个碳原子的二羧酸的羰基部分。
6.根据权利要求1所述的用途,其中所述疾病是包括线粒体或核DNA中的至少一个突变的原发疾病。
7.根据权利要求1所述的用途,其中所述疾病是心磷脂的缺乏。
8.根据权利要求1所述的用途,其中所述疾病包括嘧啶合成途径中的缺陷。
9.根据权利要求8所述的用途,其中所述嘧啶合成途径中的缺陷是尿苷合成途径。
10.根据权利要求8所述的用途,其中所述缺陷包括在嘧啶合成途径中降低的酶表达和/或活性。
11.根据权利要求10所述的用途,其中所述酶选自二氢乳清酸脱氢酶(DHOD)和尿苷单磷酸合成酶(UMPS)。
12.根据权利要求1所述的用途,其中所述疾病导致低于正常值的尿苷水平。
13.根据权利要求1所述的用途,其中所述疾病是施用药剂前或与施用药剂的同时发生的结果。
14.根据权利要求13所述的用途,其中所述药剂为反转录酶抑制剂、蛋白酶抑制剂或二氢乳清酸脱氢酶抑制剂。
15.根据权利要求14所述的用途,其中所述反转录酶抑制剂为叠氮胸苷(AZT)、司他呋啶(D4T)、扎西他滨(ddC)、去羟肌苷(DDI)或氟碘阿糖尿嘧啶(FIAU)。
16.根据权利要求14所述的用途,其中所述蛋白酶抑制剂为利托那韦、茚地那韦、沙奎那韦或奈非那韦。
17.根据权利要求13所述的用途,其中所述二氢乳清酸脱氢酶抑制剂为来氟米特或布喹那。
18.根据权利要求1所述的用途,还包括在所述药物中组合一种或多种辅因子、维生素、或者两种或多种的混合物。
19.根据权利要求18所述的用途,其中所述辅因子为辅酶Q或丙酸钙之一或其两者。
20.根据权利要求18所述的用途,其中所述维生素选自硫胺素(B1)、核黄素(B2)、烟酸(B3)、吡哆辛(B6)、叶酸、氰钴铵(B12)、生物素、硫辛酸和泛酸。
21.根据权利要求1所述的用途,其中所述通式I的化合物以一定量用在所述药物中,以便以日剂量0.5g/m2-20g/m2施用。
22.根据权利要求1所述的用途,其中所述通式I的化合物以一定量用在所述药物中,以便以日剂量2g/m2-10g/m2施用。
23.根据权利要求1所述的用途,其中所述通式I的化合物以一定量用在所述药物中,以便以日剂量6g/m2施用。
24.有效量的通式I化合物在制备用于缓解或根除与下列有关嘧啶缺乏疾病相关的一种或者多种症状的药物中的用途:
其中:
R1为O、OH、NHCOCH3或NH2,
R2为H、CO2H或
其中:
X独立地是H,或者取代的C1-C22烷基、取代的C1-C22链烯基或取代的C1-C22链炔基,取代基选自H、C1-3烷基、OH、NH2和卤素,
R3、R4和R5每个独立地是具有取代基的C1-C22烷基羰基,所述取代基选自C1-3烷基、OH、NH2,卤素和H,其中R3,R4,和R5中至少有一个不是H,
其中,所述疾病选自肾小管性酸中毒(RTA)、利氏综合症、MARIAHS综合症、线粒体疾病导致的中风样发作、乳酸血症、丙酮酸脱氢酶(PDH)缺乏症、脑肌病、细胞色素C氧化酶(COX,复合物IV)缺乏症、复合物I缺乏症、多种线粒体缺失综合症,和它们的任意组合。
25.根据权利要求24所述的用途,其中所述的化合物是2’,3’,5’-三-O-乙酰基-1-β-D-尿苷。
26.根据权利要求24和25中的任一项所述的用途,其中所述症状为与嘧啶缺乏相关的肾小管性酸中毒(RTA)、视力损伤、痴呆、癫痫发作、骨骼肌病、外周肌病或自主性肌病。
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