CN102256488A - 伴随代谢失衡慢性肾病的治疗组合物和治疗方法 - Google Patents
伴随代谢失衡慢性肾病的治疗组合物和治疗方法 Download PDFInfo
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Abstract
这里所公开的是治疗慢性肾病和/或代谢失衡的组合物和方法。特别是，这里举例说明的是涉及同时给药RAS抑制剂和合用药物的方法，此方法可改善内皮紊乱和内皮NO。也公开了治疗出现慢性肾病症状以及至少一种代谢失衡症状的患者的方法，例如代谢症状的一种或一种以上诊断标准。
Description
相关申请
本申请要求美国申请号61/106,602(申请日：2008年10月19日)为优先权，该美国申请在此被全文引用。
背景技术
糖尿病目前影响8％的美国人口，发病率正在上升。糖尿病的一个最显著并发症是产生肾病，后者可发展为末期肾病，需要透析或移植。目前血管紧缩素转移酶抑制剂(ACEI)和血管紧缩素受体阻滞剂(ARBs)用于治疗糖尿病肾病，好处被认为是在某种程度上单独降低血压的作用1-4。然而，最近的研究表明，ACE抑制剂和ARBs在延缓1型糖尿病肾病方面没有效果，尽管可以有效地阻碍视网膜病变5。其他团体也报道了ACE抑制剂在伴随肾病的假原发性2型糖尿病中不起作用6-8。这些观察与ACE抑制剂和ARBs在阻碍糖尿病大鼠肾病中所知的保护作用相反9，10。
糖尿病肾病中ACE抑制剂不起作用的机制还不清楚。然而，一些接受ACE抑制剂或ARBs的糖尿病肾病患者体内的醛固酮水平反而升高(称之为“胆固醇骤增”)11，12，13。建议在使用ACE抑制剂的过程中，加入醛固酮抑制剂14，但是这些治疗通常被高血钾所限制，两种治疗合并使用时高血钾较为普遍。
本发明是基于发明人的发现，即，内皮一氧化氮的缺失是造成ACE抑制剂和/或ARBs在糖尿病肾病中不起作用的潜在因素。本发明为提高ACE抑制剂和ARBs在预防和治疗糖尿病肾病中的疗效提供了一种新方法。特别是，基于一系列的发现，揭示在糖尿病状态下ACE抑制剂和ARBs没有响应的机制。
新治疗药物的研发通常是基于这些药物在目标疾病动物模型中的疗效。在这方面，已经报道了大量的大鼠和小鼠糖尿病肾病模型。然而，直到最近，没有任何模型与人类糖尿病肾病相像。虽然已经知道1型糖尿病(如链脲霉素感应的糖尿病大鼠)和2型糖尿病模型(如db db小鼠)，但是这些模型仅出现轻度蛋白尿和糖尿病肾病的早期改变，例如：肾小球膜和基底膜增厚。重要的是，这些模型没有出现人类糖尿病肾病观测到的临床表现(肾病蛋白尿、肾小球滤过率(GFR)的逐步降低)，和组织损伤(肾小球膜溶解、肾小球膜结节、血管病变和肾小管间质疾病)。人类糖尿病肾病好模型的缺乏阻碍了我们对疾病发病机制的理解，并且也使得新治疗的检测变得困难。的确，对糖尿病肾病好模型缺乏的担忧促使NIH组建团队开发这样一个动物模型15。
发明者16-19(也见20)最近采用内皮型一氧化氮合酶缺失的小鼠建立一个动物模型，非常接近人类糖尿病肾病，因此，不能产生内皮一氧化氮。已经显示，当用链脲霉素在这些小鼠体内诱导糖尿病时，它们出现了人类糖尿病肾病的各个方面，包括临床表现(肾病蛋白尿、渐进型肾功能衰竭和早期死亡)，组织表现(包括肾小球膜膨胀、结节和肾小球膜溶解、足状突细胞异常、血管损伤、肾小管间质疾病)，以及分子变化(转化生长因子β(TGF-β)和血管内皮生长因子(VEGF))表达增加)。据研究者所知，这也是第一个可同时出现视网膜病变和肾病的糖尿病模型。重要的是，这些小鼠的肾病可用胰岛素预防21，有效地降低血压18，与人类内报道的相似。
最初期望ACE抑制剂和ARBs在糖尿病肾病模型中起作用，正如在其它模型中显示的9。的确，再次验证了ACE抑制剂和ARBs可以阻碍注射给药链脲霉素的野生型小鼠出现糖尿病肾病。然而，令研究者惊奇的是，相同的治疗在糖尿病eNOSKO小鼠体内无效。
附图说明
图1显示ACE抑制剂可有效降低野生型糖尿病(DM)小鼠的血压。图1所显示的是不给予治疗(无TX)、ACE抑制剂依那普利(DM依那普利)，和ARB替米沙坦(DM替米沙坦)的效果。ACE抑制剂和ARB都可以显著降低野生型糖尿病小鼠的血压(BP)。
图2显示ACE抑制剂(依那普利)和ARBs(替米沙坦)也可改善野生型糖尿病(DM)小鼠的肾小球膜肿大(A)和肾小球Ⅳ型胶原沉积(B)。这些被认为是糖尿病肾病的早期变化。
图3显示ACE抑制剂和ARBs在降低内皮NO缺乏的糖尿病小鼠血压中疗效较差。3(A)显示ACE抑制剂和ARBs对非糖尿病eNOSKO小鼠血压的影响，3(B)显示ACE抑制剂和ARBs对糖尿病eNOSKO小鼠血压的影响。
图4显示ACE抑制剂和ARBs在预防eNOSKO小鼠的糖尿病肾病方面没有效果。糖尿病(DM)可引起糖尿病eNOSKO小鼠肾小球膜肿大，而不能被依那普利(C)和替米沙坦(D)预防。糖尿病eNOSKO小鼠也出现肾小球膜溶解，伴随肾小球毛细管微动脉瘤(E)和细胞外基质沉积增加(F)。依那普利(G)和替米沙坦(H)都不能预防这些严重的病变。柱：20μm，肾小球膜肿大的定量分析(M)确定ACE抑制剂(黑色条)和ARB(灰色条)在野生型糖尿病小鼠体内是有效的，但是在糖尿病eNOSKO小鼠体内无效。柱：20μm。白色柱为没有治疗；黑色柱为依那普利；灰色柱为替米沙坦。按照方法显示数据。
图5为表格，显示ACE抑制剂和ARBs对糖尿病肾病的eNOSKO小鼠的血压和肾功能没有影响。ACE抑制剂和ARBs对野生型糖尿病小鼠的血压和蛋白尿的降低是有效的，并且在非糖尿病eNOSKO小鼠的血压降低也是有效的。然而，ACE抑制剂是无效的，ARAB对血压降低也只是轻微影响，不会显著降低10周糖尿病eNOSKO小鼠的蛋白尿。
图6显示血清醛固酮在糖尿病野生型小鼠(A)体内被抑制，但是在糖尿病eNOSKO小鼠(B)体内没有被ACE抑制剂和ARB抑制。
图7为糖尿病eNOSKO小鼠的肾免疫直方图，显示肾小球内醛固酮增加。eNOSKO小鼠，给药依那普利(10mg/kg体重/天；黑色柱)和替米沙坦(2mg/kg体重/天；灰色柱)4周(从6周到10周岁)，用链脲霉素可诱导其患有糖尿病。
图8显示提供一氧化氮类似物(亚硝酸盐)可更正eNOSKO小鼠的血压异常。
图9为免疫直方图，显示尿酸可引起人大动脉内皮细胞产生氧化应激。绿色荧光是一个采用过氧化物敏感探针，二氯荧光黄乙酰乙酸酯染料测定氧化应激的标记(图9A)。右边是氧化应激的定量分析，对照为开放柱，尿酸(12mg/dl)为黑色柱，右边为含有香英兰乙酮(一种诱导NADPH氧化酶的氧化物抑制剂)的尿酸(图9B)。
图10显示尿酸可引起内皮NO水平降低。显示各种剂量的尿酸对内皮NO的影响(在猪主动脉内皮细胞中采用DAF荧光进行测定，出自Khosla等人30)。
图11为柱状图，显示尿酸可降低人大动脉内皮细胞的ATP水平。尿酸(3.5mg/dl，7mg/dl，12mg/dl)被包含在介质中48小时。没有观测到细胞存活率(锥虫蓝除外)的改变。
图12为图表和图片，显示尿酸可降低人大动脉内皮细胞的线粒体数量。用Mitotracker橙色测定对照细胞(FIG 12A)和UA处理过的细胞(FIG 12B)中线粒体的数量。图12C显示，在48小时时，尿酸12mg/dl对线粒体密度的定量影响。没有观测到对细胞存活率的影响。
发明内容
发明人进行的最近研究表明，可改善内皮功能紊乱和内皮NO的药物应有利于治疗代谢失衡，特别是糖尿病肾病。这些药物通过改善线粒体功能而发挥作用。根据本发明，预计使用的药物包括，但不限于：降低尿酸药物(UALA)，例如：黄嘌呤氧化酶抑制剂(非布索坦、别嘌呤醇)、排尿酸药(苯碘达隆、苯溴马隆、丙磺舒)、尿酸酶衍生物(聚乙二醇尿酸)和基因治疗(尿酸的过度表达)或URAT-1启动子的阻塞(我们已在血管内皮细胞上确定的输送物)；NO类似物例如：长效亚硝酸盐、L-精氨酸和尼可地尔；以及抗氧化剂例如：抗坏血酸盐、N-乙酰半胱氨酸、儿茶素和表儿茶素。
也已确证刺激NO的药物在糖尿病肾病治疗中将与ACE抑制剂或靶向肾素-血管紧缩素途径的其他药物有直接的协同作用。合用将加强ACE抑制剂对血压、肾结构和肾功能的作用。
根据另一个实例，本发明适合于一项治疗代谢失衡和/或治疗和/或预防糖尿病肾病的联合治疗，包括给药有效治疗量的“RAS抑制剂”，例如一种靶向肾素-血管紧缩素途径的药物，包括但不限于ACE抑制剂、肾素抑制剂或血管紧缩素受体阻滞剂；以及联合给药有效治疗量的“合用药物”，包括但不限于，降低尿酸药物(UALA)，例如黄嘌呤氧化酶抑制剂(非布索坦、别嘌呤醇)、排尿酸药(苯碘达隆、苯溴马隆、丙磺舒)、尿酸酶衍生物(聚乙二醇尿酸)和基因治疗(尿酸的过度表达)或URAT-1启动子的阻塞(我们已在血管内皮细胞上确定的输送物)；NO类似物例如：长效亚硝酸盐、L-精氨酸和尼可地尔；以及抗氧化物例如：抗坏血酸盐、N-乙酰半胱氨酸、硫辛醇、维生素E、儿茶素。有关在此描述的RAS抑制剂或合用药物，应该注意的是也可使用这些药物的药物可接受盐。权利要求中任何涉及RAS抑制剂或合用药物可诠释为包括，或选择性地或额外加入，这些药物对应的药物可接受盐。
在一个特殊实例中，联合治疗包括治疗或预防糖尿病肾病，通过给药一组合物，该组合物包括RAS抑制剂和合用药物，或其药物可接受盐，作为主要活性成分。在更具体的实例中，治疗或预防糖尿病肾病的方法包括给药ACE抑制剂和NO类似物。在更具体的实例中，NO类似物是尼可地尔。
需要的患者是指出现肾脏基金会定义的一种典型期慢性肾病症状和/或出现代谢失衡症状的人。在更具体的实例中，需要的患者出现一种典型期慢性肾病症状和至少两种代谢症状特征。
在本发明的某个方面，代谢失衡选自，包括：糖尿病、妊娠糖尿病、β-细胞功能的遗传缺陷、胰岛素作用的遗传缺陷、胰腺外分泌疾病、内分泌病、药物或化学诱导、感染、与糖尿病、糖尿病前期状态和代谢症状相关的其他遗传症状。一方面，代谢失衡是糖尿病，包括Ⅰ型和/或Ⅱ型。
根据另一方面，代谢失衡是代谢症状。一方面，治疗代谢症状包括治疗一种或一种以上的诊断标准。出现代谢失衡症状的患者包括出现下列诊断标准中两种或两种以上的患者：
-腰围增加：
男性-等于或大于40英尺(102厘米)
女性-等于或大于35英尺(88厘米)
-甘油三酯升高：
等于或高于150mg/dL
-HDL胆固醇降低(好的)：
男性-少于40mg/dL
女性-少于50mg/dL
-血压升高：
等于或高于130/85mm Hg
-空腹血糖升高
等于或高于100mg/dL
在另一个实例中，代谢失衡是糖尿病的前期状态，适合于一种空腹血糖水平过高(等于或高于100mg/dL)或血糖耐受(饮用预先测定的葡萄糖饮料，两小时后高于140mg/dL)
慢性肾病期适合下列：
慢性肾病的第一阶段：肾小球滤过率(GFR)正常或增加；一些肾损伤迹象，出现微蛋白，蛋白尿、血尿或组织改变。
慢性肾病的第二阶段：肾小球滤过率(GFR)轻微减少(定义为89-60ml/min/1.73m2)
慢性肾病的第三阶段：肾小球滤过率(GFR)中等降低(定义为59-30ml/min/1.73m2)
慢性肾病的第四阶段：肾小球滤过率(GFR)严重降低(定义为29-15ml/min/1.73m2)
前面描述的代表慢性肾病的灵床有效期，易于被临床医生辨别，并且在国家肾基金会中详细阐述：K/DOQI肾病结果质量倡议。美国肾病期刊2002；39(增刊)1)：S1-S266.
在另一个实例中，对出现慢性肾病症状和代谢症状诊断标准的患者进行治疗。
ACE抑制剂被认为是治疗糖尿病肾病的最好治疗方法——然而，最近的研究表明，它们可能是唯一对糖尿病肾病有害的。发明者可能发现了原因，并也找到了解决方法。换句话说，如果内皮功能紊乱可以被改善，ACE抑制剂可将更好地发挥作用。
在另一个实例中，治疗组合物可以通过传统方法进行相应的制备。上述配方通常可通过将活性组分，RAS抑制剂和合用药物，和非活性添加剂，例如辅料，稀释剂和载体进行混合/捏合而制备。在本说明书中，胃肠道外给药包括皮下注射、静脉注射、肌肉注射、腹腔内注射或滴注等。对于注射剂配方，例如无菌液体混悬液或注射用油性混悬液，可通过本领域已知的方法，采用适当的分散剂或润湿剂以及混悬剂进行制备。上述注射用无菌配方可以是无菌注射溶液或混悬液在稀释剂或溶剂中，此稀释剂或溶剂应是无毒的，并通过胃肠道外途径给药，包括水溶液。可以用的可接受载体或溶剂可以是，例如，水、林格氏溶液、等渗调节剂等。无菌非挥发性油也可被用来作为溶剂或混悬媒介。出于上述目的，也可采用任何非挥发性油或脂肪酸，包括天然的或合成的或半合成的脂肪油或脂肪酸，以及天然的或合成的或半合成的甘油单酯或甘油双酯或甘油三酯。
适当的基质(例如：丁酸聚合物、羟基乙酸聚合物、丁酸和羟基乙酸共聚物、丁酸聚合物和羟基乙酸聚合物的混合物、脂肪酸聚甘油酯等)可以被合用形成缓释配方。
在另一个实例中，口服固体剂型可以是，例如，粉剂、颗粒剂、片剂、丸剂、胶囊剂等，正如上述描述的。上述剂型的配方可通过将活性化合物，RAS抑制剂或合用药物，和至少一种非活性添加剂混合和/或捏合而制成，非活性添加剂包括蔗糖、乳糖、纤维素多糖类、甘露醇、麦芽糖醇、环糊精、淀粉(例如：玉米淀粉)、微晶纤维素、琼脂、海藻酸盐、酪素、白蛋白、合成或半合成聚合物或甘油酯。上述剂型通常可再加入添加剂，包括惰性稀释剂、润滑剂，例如硬酯酸镁，防腐剂，例如苯甲酸酯类和山梨酸，抗氧化剂，例如抗坏血酸，α-生育酚和半胱氨酸，崩解剂(例如：交联羧甲基纤维素钠)，粘合剂(例如：羟丙甲纤维素)，增稠剂、缓冲物质、甜味剂、矫味剂、香料等。片剂和丸剂可进行进一步包衣。口服液体配方可以是，例如，药物可接受的乳剂、糖浆剂、酏剂、混悬剂、溶液等，可含有药物常用的惰性稀释剂，例如水，如果需要，可含有添加剂。上述口服液体配方可通过将活性成分、惰性稀释剂，必要的话和其他添加剂混合制成，与传统方法一致。口服配方通常含有约0.01～99％(重量)，优选含有约0.1～90％(重量)，通常是约0.5～50％(重量)的所发明的活性化合物，数量可依据剂型变化。
在一个可替代的实例中，直肠用栓剂可将活性化合物和适当的非刺激性辅料混合制成，栓剂在常温下是固体，但在肠道温度下变成液体，在直肠内融解，由此释放活性成分，例如可可豆脂和聚乙二醇。
确定某个患者的剂量可根据年龄、体重、一般状况、性别、饮食、给药时间、给药方式、排除率、药物合用、当前治疗疾病的程度，以及其它因素进行考虑。
本发明的糖尿病肾病治疗组合物为低毒性，可安全使用，日剂量可依据患者的状态和体重、化合物类型和给药途径变化，例如，当用作糖尿病肾病预防和治疗时，在口服配方中，活性成分[1]可以是约1～500mg，典型的约为10～200mg；在成人(60kg)的胃肠道外配方中，活性成分[1]可以是约0.1～100mg，典型的约为1～50mg，通常是约1～20mg，在上述剂量范围内无毒。
适合用于治疗组合物的黄嘌呤氧化酶抑制剂的实例，包括，但不局限于别嘌呤醇、羟基乙酸、TEI-6720、卡洛芬、非布索坦和y-700。美国专利号5,614,520和美国专利公开号2005/0090472在此引用，无限制性地列出其它实例。代表性的RAS抑制剂包括：卡托普利、西拉普利、依那普利、福辛普利、赖诺普利、喹那普利、雷米普利、佐芬普利、坎地沙坦西酯、依普沙坦、厄贝，依贝沙坦，氯沙坦，他索沙坦，替米沙坦和缬沙坦，或其药物可接受盐。
在另一个实例中，本发明适合于一种治疗糖尿病或胰岛素非敏感患者慢性肾病阶段的方法，方法包括给药有效治疗量的RAS抑制剂或其药物可接受盐，以及同时给药有效治疗量的合用药物或其药物可接受盐，其中所述合用药物或其药物可接受盐的有效治疗量包括足以改善内皮紊乱和/或内皮NO水平的量。
术语“联合给药”或“同时给药”，使用时，例如，对于给药合用药物连同给药RAS抑制剂，是指给药合用药物和RAS抑制剂，以便两者可以同时达到一种生理效应。但是，这两种药物不必同时给药。在某个实例中，一种药物可先于另一种药物给药，但是，这种联合给药一般导致两种药物以所给剂量的最大血清浓度显著分数(例如20％或更高，优选30％或40％或更高，更优选为50％或60％或更高，最优选为70％或80％或90％或更高)同时出现在体内(例如血浆)。
如果本发明的化合物和合用药物被联合给药时，没有特别限制本发明的合用配方的给药模式。上述给药模式可以是，例如，(1)同时给药RAS抑制剂和合用药物组成的单一配方，(2)通过相同的途径同时给药分别由RAS抑制剂和合用药物制备的两种配方，(3)通过相同的途径连续和间断给药分别由RAS抑制剂和合用药物制备的两种配方，(4)通过不同的途径同时给药分别由RAS抑制剂和合用药物制备的两种配方，(5)通过不同的途径连续和间断给药分别由RAS抑制剂和合用药物制备的两种配方(例如，先给药联合制剂或它的药物组合物，接着给药RAS抑制剂或它的药物组合物，或者相反)等等。
本发明的糖尿病肾病治疗组合物具有低毒性，因此，RAS抑制剂和合用药物可根据本身已知的方法与药理上可接受的载体混合，形成药物组合物，例如，片剂(包括糖衣片和薄膜衣片)、粉剂、颗粒剂、胶囊(包括软胶囊)、溶液剂、注射剂、栓剂、缓释制剂等，可经口服或非胃肠道安全给药(例如：局部、直肠、静脉)。注射剂可通过静脉、肌肉、皮下注入器官或直接注入病变处。
用来制备本发明复方制剂的药理上可接受载体可以是，例如通常被用作药物材料的各种有机和无机载体材料，例如固体制剂中的辅料、润滑剂、粘合剂和崩解剂，液体制剂中的溶剂、助溶剂、悬浮剂、等渗剂、缓冲剂和止痛剂。而且，也可以加入适量的其他添加剂，例如：一般防腐剂、抗氧化剂、着色剂、甜味剂、吸收剂、润湿剂。
辅料可以是，例如乳糖、食糖、甘露醇、淀粉、玉米淀粉、结晶纤维素、无水轻质硅酸盐等。润滑剂，可以是例如硬脂酸镁、硬脂酸钙、滑石粉、胶态硅等。
粘合剂可以是，例如结晶纤维素、食糖、甘露醇、环糊精、羟丙基纤维素、羟丙甲纤维素、聚乙烯吡咯烷酮、淀粉、蔗糖、凝胶、甲基纤维素、羧甲基纤维素钠等。
崩解剂可以是，例如淀粉、羧甲基纤维素、羧甲基纤维素钙、羧甲基淀粉钠、低取代羟丙基纤维素等。
溶剂可以是，例如注射用水、乙醇、丙二醇、聚乙二醇、麻油、玉米油、橄榄油等。
助溶剂，可以是例如聚乙二醇、丙二醇、甘露醇、苯甲酸苄酯、乙醇、三羟甲基氨基甲烷(tris溶液)、胆固醇、三乙醇胺、碳酸钠、柠檬酸钠等。
混悬剂可以是，例如表面活性剂，如硬脂酸三乙醇胺、月桂醇硫酸钠、十二烷基丙氨酸、卵磷脂、苯扎氯铵、氯化苄甲乙氧胺、单硬脂酸甘油酯等；亲水聚合物例如：聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素等。
等渗剂可以是，例如葡萄糖、山梨醇、氯化钠、甘油、甘露醇等。
缓冲剂可以是，例如磷酸、醋酸、碳酸、柠檬酸等的缓冲溶液。
止痛剂可以是例如苯甲醇。
防腐剂可以是，例如对羟基苯甲酸酯、三氯叔丁醇、苯甲醇、苯乙醇、脱氧乙酸、山梨酸等。
抗氧化剂可以是，例如亚硫酸、抗坏血酸、硫辛酸、α-生育酚、儿茶素等。
在本发明的复方制剂中，RAS抑制剂和合用药物的比例可依照目的和途径进行适当地筛选。例如，ACE抑制剂在整个配方中的量通常是约0.01～100％(重量)，一般是约0.1～50％(重量)，更具体的是约0.5～20％(重量)，虽然ACE抑制剂可依照剂型发生改变。尼可地尔在根据整个配方中的量通常是约0.01～100％(重量)，一般是约0.1～50％(重量)，更具体的是约0.5～20％(重量)，尼可地尔的剂量可依照剂型发生改变。
本发明复方制剂中含有的添加剂的量，例如：载体，根据整个配方，通常是约1～99.99％(重量)，优选是10～90％(重量)，虽然添加剂的量可依照剂型发生改变。
本发明的化合物和合用药物分开制备时，也可采用相似用量。
可以采用制药工艺中常用的本身已知的方法制备上述配方。
例如，本发明的化合物和合用药物可与以下成分制成注射用液体配方：分散剂(例如：吐温80(ATLAS POWDER，美国)、HCO60(NIKKO化学)、聚乙二醇、羧甲基纤维素、海藻酸钠、羟丙甲纤维素、环糊精)，稳定剂(例如：抗坏血酸、焦亚硫酸钠)，表面活性剂(例如：聚山梨酸酯80、聚乙二醇)，增溶剂(例如：甘油、乙醇)，缓冲物质(磷酸和其碱金属盐、柠檬酸和其碱金属盐等)，等渗剂(例如：氯化钠、氯化钾、甘露醇、山梨醇、葡萄糖)，pH调节剂(例如：盐酸、氢氧化钠)，防腐剂(例如：对羟基苯甲酸乙酯、苯甲酸、羟基苯甲酸甲酯、尼泊金丙酯、苯甲醇)，增溶剂(例如：浓缩甘油、葡糖胺)，助溶剂(例如：丙二醇、食糖)，止痛剂(例如：葡萄糖、苯甲醇)，或者溶解、混悬或乳化在植物油中，例如：橄榄油、麻油、棉花籽油和玉米油，以及助溶剂中，例如：丙二醇，从而形成油性配方，制成注射制剂。
为了获得一种口服剂型，采用本身已知的方法，将本发明的化合物或合用药物与以下成分压制成所需形状，例如：辅料(如：乳糖、糖粉、淀粉)，崩解剂(如：淀粉、碳酸钙)，粘合剂(如：淀粉、阿拉伯胶、羧甲基纤维素、聚乙烯吡咯烷酮、羟丙基纤维素)，或助流剂(如：滑石粉、硬脂酸镁、聚乙二醇6000)，那时，必要的话，可用本身已知方法进行包衣以便掩盖味道、获得肠溶性质或缓释特性，从而获得口服剂型。上述包衣，可以是，例如羟丙甲纤维素、乙基纤维素、羟甲基纤维素、羟丙基纤维素、聚乙二醇、吐温80、泊洛沙姆F68、醋酸邻苯二甲酸纤维素、羟丙基甲基纤维素邻苯二甲酸酯、羟甲基纤维素醋酸酯，尤特奇(丙烯酸树脂)(Rohm，德国，甲基丙酸烯/丙酸烯共聚物)，和着色剂(如：氧化铁红、二氧化钛)。口服剂型可以是速释制剂或缓释制剂。
虽然本发明的复方制剂的剂量可发生变化，根据本发明化合物的类型、受试者的年龄、体重、状况和剂型，以及给药方式和周期，例如，糖尿病和/或胰岛素耐受和/或ckd阶段(成年人的体重约60kg)患者的每日剂量中本发明的化合物约为0.01～1000mg/kg，优选约为0.01～100mg/kg，更优选约为0.1～100mg/kg，特别是约0.1～50mg/kg，尤其约为1.5～30mg/kg，可通过静脉一次或多次给药。正如上述所描述的，剂量当然可根据各种因素发生变化，有时少量是足够的，有时需要过量。
合用药物(例如：尼可地尔)在不引起副作用的范围内可采用任何剂量。合用药物的每日剂量没有特殊限制，可依据以下发生变化，如：疾病的严重程度、受试者年龄、性别、体重和敏感性，以及给药时间和间隔、和制剂的性质、组成、剂型和活性成分，作为药剂，哺乳动物中单位体重(kg)的每日口服剂量约为0.001～2000mg，优选为0.01～500mg，更优选约为0.1～100mg，通常以1～4次给药。
当使用本发明的复方制剂时，可以同时给药，但是也可能先给药合用药物，然后给药本发明的化合物，或先给药本发明的化合物，然后给药合用药物。当采用上述间断给药方式时，时间间隔可依据所给药的活性成分、剂型和给药方式发生变化，例如，先给药合用药物时，本发明的化合物可在给药合用药物之后1分钟至3天之内给药，优选是10分钟～1天，更优选是15分钟～1小时内给药。例如，先给药本发明的化合物时，然后合用药物可在本发明的化合物给药后1分钟至1天之内给药，优选是10分钟～6小时，更优选是15分钟～1小时内给药。
在优选的给药方式中，例如，作为口服制剂制成的合用药物按照每日剂量口服给药约0.001～200mg/kg，15分钟后，给药口服制剂的本发明化合物约0.005～100mg/kg，作为每日剂量。
采用主要活性成分，RAS抑制剂和合用药物的同时，也可给药其它药理活性成分。在一种实例中，其它药理活性成分包括，但不局限于β-阻滞剂、他汀类和阿司匹林。适当的他汀类是在本领域所熟知的，上述他汀类包括，但不局限于阿托伐他汀(LIPITOP
辉瑞)、辛伐他汀(ZOCOR
默克)、普伐他汀(PRAVACHOL
美国百时美施贵宝)、氟伐他汀(LESCOL
诺华)、洛伐他汀(MEVACOR
默克)、瑞舒伐他汀(Crestor
阿斯利康)、匹伐他汀(三共制药)等。合适的β-阻滞剂包括，但不局限于心选择性(选择性β1-阻滞剂)，例如：醋丁洛尔、阿替洛尔、倍他洛尔、比索洛尔、美托洛尔等。合适的非选择性阻滞剂(阻滞β1和β2相当)包括，但不局限于卡替洛尔、纳多洛尔、喷布洛尔、心得乐、心得安、噻吗洛尔、拉贝洛尔等。
下面的实施例进一步支持本发明，但并不限制本发明。
除另有规定外，表示溶剂混合物的数值为每种溶剂的体积比。除另有规定外，A％为a％(重量)。除另有规定外，硅胶柱的色谱分析法中洗脱液的比值是体积比。这里采用室温(常温)通常是指温度约为20～30℃。
具体实施方式
实施例证明联合治疗糖尿病肾病和/或代谢症状相关结果的治疗价值
图1显示ACE抑制剂在野生糖尿病型(DM)小鼠中可有效地降低血压。图1所显示的是不进行治疗(无TX)、ACE抑制剂依那普利(DM依那普利)，和ARB替米沙坦(DM替米沙坦)的治疗效果。ACE抑制剂依那普利和ARB可显著降低野生型糖尿病小鼠的血压。图2表明给药ACE抑制剂(依那普利)和ARBs(替米沙坦)也可改善野生糖尿病型(DM)小鼠的肾小球膜肿大(A)和肾小球Ⅳ型胶原沉积(B)。这些被认为是糖尿病肾病的早期变化。
相反，给予不能产生内皮一氧化氮的糖尿病小鼠ACE抑制剂和ARBs时，惊奇地发现这些药物的作用是最小的(图3-5)。图3显示给予缺乏内皮NO的糖尿病小鼠ACE抑制剂和ARBs，不能很有效地降低血压。在内皮NO合成缺乏的非糖尿病小鼠(eNOSKO)体内，ACE抑制剂和ARBs可有效地降低血压(图3A)。相反，在8周的糖尿病eNOSKO小鼠体内，虽然最初观测到血压下降，但是血压下降并没有维持(图3C)。这与其他抗高血压药物相反，后者非常有效的(例如：肼酞嗪)。没有效果也可能由于剂量，正如我们所发现的，尽管50mg/kg剂量的依那普利，在内皮NO合成缺乏的糖尿病小鼠体内不能降低血压(图3C)。
图4为组织切片，显示ACE抑制剂和ARBs不能有效地预防eNOSKO小鼠的糖尿病肾病。糖尿病可引起糖尿病eNOSKO小鼠的肾小球肿大(b)，这不能用依那普利(c)和替米沙坦(d)进行预防。糖尿病eNOSKO小鼠也出现肾小球膜溶解伴随肾小球毛细管微动脉瘤(e)和细胞间基质的大量沉积(f)。依那普利(g)和替米沙坦(h)都不能预防这些高级病变。柱状：20μm.肾小球膜的定量分析确证了ACE抑制剂(黑色柱)和ARBs(灰色柱)在野生型糖尿病小鼠中是有效的，但在糖尿病eNOSKO小鼠体内是无效的。柱状：20μm.白色柱表示没有治疗；黑色柱表示依那普利；灰色柱表示替米沙坦。图5与提供ACE抑制剂和ARBs对糖尿病肾病eNOSKO小鼠血压和肾功能影响结果的表格相适应。ACE抑制剂和ARBs在降低野生型糖尿病小鼠的血压和蛋白尿方面是有效的，在降低非糖尿病eNOSKO小鼠的血压也是有效的。但是，在10周的糖尿病eNOSKO小鼠体内，ACE抑制剂是无效的，ARAB仅有最小的降血压作用，并不能显著降低蛋白尿。
这些数据提供了依据，即关于ACE和ARB的疗效，内皮NO缺失和糖尿病之间有具体的联系，这个证据并不能根据糖尿病或eNOS缺乏的研究进行预测，这些后面的药物仅在eNOS缺乏中是有效的。
ACE抑制剂和ARBs不能预防内皮功能紊乱(缺少内皮NO)下的糖尿病肾病，可能是由于醛固酮突释以及内源性肾素-血管紧缩素系统的抑制作用。与本次观测到的一致，发明者发现ACE抑制剂和ARB治疗可抑制野生型糖尿病小鼠的血清醛固酮，但是不能抑制糖尿病eNOSKO小鼠的血清醛固酮(图6)。而且，在用ACE抑制剂治疗的糖尿病eNOSKO小鼠体内，确定醛固酮在肾小球内(图7)。
图6显示ACE抑制剂和ARB治疗并不能抑制糖尿病eNOSKO小鼠的血清醛固酮，但是可以抑制野生型糖尿病小鼠的血清胆固醇。图7为免疫直方图，显示糖尿病eNOSKO小鼠肾小球内的醛固酮增加。用链脲霉素诱导eNOSKO小鼠产生糖尿病，用依那普利(10mg/kg体重/天；黑色柱)或替米沙坦(2mg/kg体重/天；灰色柱)治疗4周(从6周岁到10周岁)22。用依那普利治疗的糖尿病eNOSKO小鼠肾中的醛固酮的免疫组织化学可采用兔抗醛固酮多克隆抗体进行测定(Thermo Fisher Scientific，Rockford，IL)。正如图中所显示的，在这个模型中，醛固酮存在于肾小球中。虽然数据并不一定意味着醛固酮在肾小球中合成，醛固酮可在血管，特别是内皮细胞中23，24。阳性绿色染色表示醛固酮的存在。
这些研究证明内皮NO的缺失或严重减少可导致ACE抑制剂和ARBs在糖尿病肾病的治疗中是无效的，机制类似于醛固酮突释。研究还表明，虽然ACE抑制剂和ARBs没有响应，不能根据单独糖尿病或单独内皮功能紊乱(内皮NO缺失)进行猜测，但是可特定为它们之间的相互作用。虽然内皮功能紊乱在糖尿病中很普遍，尽管使用ACE抑制剂25-27，但是没有人提出内皮功能紊乱和糖尿病之间有具体的相互作用，可导致ACE抑制剂发挥作用。因为eNOSKO小鼠体内唯一异常(与野生型相比)的是缺乏内皮NO，所以这些数据表明一氧化氮的取代应该扭转这种小鼠体内的缺点。
在这方面，eNOSKO小鼠较野生型小鼠具有较高的基线血压。正如图8显示的，如果给予eNOSKO小鼠亚硝酸盐(NO提供者)，可将血压下降为与野生型小鼠相同的水平。图8显示，一氧化氮类似物(亚硝酸盐)的供应可更正eNOSKO小鼠体内的血压异常。由于亚硝酸盐是NO的代谢物，可在体内转换成NO(参考于28)，检测亚硝酸钠以观测亚硝酸钠是否可预防eNOSKO小鼠的高血压。用亚硝酸盐治疗4周(50/l饮用水)可将eNOSKO小鼠的血压下降到与野生型小鼠体内观测的类似。
考虑到内皮功能紊乱是造成ACE抑制剂和ARB治疗对糖尿病肾病没有响应的关键作用，如果在糖尿病肾病的治疗中联合使用ACE抑制剂，增加内皮NO水平将是有效的。糖尿病肾病中内皮NO减少的主要原因是氧化应激29，因此，抗氧化物在糖尿病肾病中联合使用ACE抑制剂和ARBs，有独特的好处。氧化应激的另一个来源是尿酸；已经显示尿酸可以刺激内皮细胞产生氧化应激(图9)，也可引起内皮一氧化氮减少30，31(图10)。因此，降低尿酸的药物，例如，黄嘌呤氧化酶抑制剂(非布索坦和别嘌呤醇)，以及排尿酸药(例如：丙磺舒、苯碘达隆和苯溴马隆)，在糖尿病肾病中联合使用ACE抑制剂和ARBs也是有利的，特别是在尿酸水平＞6mg/dl的受试者体内，内皮功能被认为是普遍受损32。的确，最近发现，尿酸是1型糖尿病受试者中明显糖尿病肾病的强有力预测者33。
尿酸引起内皮功能紊乱的关键机制之一是引起线粒体和线粒体DNA缺失，导致ATP储存的耗尽，而后者对内皮功能是必需的(图11和12)。图11显示，尿酸可降低人大动脉内皮细胞的ATP水平。而且，图12显示，尿酸可降低人大动脉内皮细胞的线粒体数量。
NO提供者，例如尼可地尔，在氧化应激反应中可预防线粒体的缺失。这个观察提供了一个机制，通过这个机制，NO可改善糖尿病患者体内的内皮功能和加强ACE作用。同时，意识到与NO缺失和糖尿病肾病相关的状况，例如尿酸升高，已经显示与线粒体缺失有关。
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Claims (25)
1.一种用于治疗出现至少一种代谢失衡症状的患者的慢性肾病的治疗组合物，所述的组合物包括RAS抑制剂和NO类似物。
2.根据权利要求1的组合物，其中所述的NO类似物是尼可地尔。
3.根据权利要求1的组合物，其中所述的至少一种代谢失衡症状包括腰围增大、甘油三脂升高、HDL胆固醇降低、血压升高或空腹血糖升高。
4.根据权利要求1的组合物，其中所述的至少一种代谢失衡症状是血压升高和空腹血糖升高。
5.根据权利要求1的组合物，制成固体剂型，包括：粉剂、颗粒剂、片剂、丸剂或胶囊剂。
6.根据权利要求1的组合物，制成液体混悬液或溶液。
7.根据权利要求1的组合物，其中所述的慢性肾病是慢性肾病(CKD)的第一阶段、第二阶段或第三阶段。
8.一种治疗出现至少一种代谢失衡症状的患者的慢性肾病的方法，所述方法包括联合给药有效治疗量的RAS抑制剂和合用药物。
9.根据权利要求8的方法，其中所述的RAS抑制剂是ACE抑制剂或血管紧缩素受体阻滞剂。
10.根据权利要求8的方法，其中所述的合用药物是降低尿酸的药物。
11.根据权利要求10的方法，其中所述降低尿酸的药物是黄嘌呤氧化酶抑制剂。
12.根据权利要求11的方法，其中所述的黄嘌呤氧化酶抑制剂是别嘌呤醇或非布索坦。
13.根据权利要求8的方法，其中所述的合用药物是NO类似物。
14.根据权利要求13的方法，其中所述的NO类似物是左旋精氨酸或尼可地尔。
15.根据权利要求8的方法，其中所述的RAS抑制剂和所述的合用药物是通过口服给药。
16.根据权利要求8的方法，其中所述的RAS抑制剂和所述的合用药物是通过肠道外途径给药。
17.根据权利要求8的方法，其中所述的RAS抑制剂和所述的合用药物是以固体制剂形式同时给药，剂型包括粉剂、颗粒剂、片剂、丸剂或胶囊剂。
18.根据权利要求8的方法，其中所述的RAS抑制剂是以第一种给药模式给药，所述的合用药物是以不同于第一种给药模式的另外一种给药模式给药。
19.根据权利要求8的方法，其中所述的至少一种代谢失衡症状包括腰围增大、甘油三脂升高、HDL胆固醇降低、血压升高或空腹血糖升高。
20.根据权利要求8的方法，其中所述的至少一种代谢失衡症状是空腹血糖升高。
21.根据权利要求8的方法，其中所述的慢性肾病是慢性肾病(CKD)的第一阶段、第二阶段、第三阶段、第四阶段、第五阶段或第六阶段。
22.根据权利要求8的方法，其中所述的慢性肾病是第一阶段、第二阶段、第三阶段或第四阶段。
23.一种治疗出现至少一种代谢失衡症状的患者的慢性肾病的方法，所述方法包括给药有效治疗量的尼克地尔。
24.根据权利要求23的方法，进一步包括同时给药尼可地尔和ACE抑制剂和/或血管紧缩素受体阻滞剂。
25.一种用于治疗糖尿病肾病的组合物，包括有效治疗量的RAS抑制剂和降低尿酸的药物或抗氧化剂，或降低尿酸的药物和抗氧化剂的组合。
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| US6218411B1 (en) * | 1997-08-08 | 2001-04-17 | Chugai Seiyaku Kabushiki Kaisha | Therapeutics for diabetic complications |
| US20020019360A1 (en) * | 2000-06-28 | 2002-02-14 | Merck & Co., Inc. | Treatment for cardiovascular disease |
| US20030216384A1 (en) * | 2002-05-16 | 2003-11-20 | Northern Sydney Area Health Service | Composition and method for treating hypertension |
| US20080255101A1 (en) * | 2005-02-24 | 2008-10-16 | Nitromed, Inc. | Nitric oxide donating diuretic compounds, compositions and methods of use |
-
2009
- 2009-10-19 CN CN2009801513897A patent/CN102256488A/zh active Pending
- 2009-10-19 US US13/124,978 patent/US20110257202A1/en not_active Abandoned
- 2009-10-19 JP JP2011532310A patent/JP2012505925A/ja active Pending
- 2009-10-19 EP EP09821384A patent/EP2398319A4/en not_active Withdrawn
- 2009-10-19 WO PCT/US2009/061157 patent/WO2010045636A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6218411B1 (en) * | 1997-08-08 | 2001-04-17 | Chugai Seiyaku Kabushiki Kaisha | Therapeutics for diabetic complications |
| US20020019360A1 (en) * | 2000-06-28 | 2002-02-14 | Merck & Co., Inc. | Treatment for cardiovascular disease |
| US20030216384A1 (en) * | 2002-05-16 | 2003-11-20 | Northern Sydney Area Health Service | Composition and method for treating hypertension |
| US20080255101A1 (en) * | 2005-02-24 | 2008-10-16 | Nitromed, Inc. | Nitric oxide donating diuretic compounds, compositions and methods of use |
Non-Patent Citations (5)
| Title |
|---|
| BAYLIS CHRIS: "Nitric oxide deficiency in chronic kidney disease", 《AMERICAN JOURNAL OF PHYSIOLOGY RENAL PHYSIOLOGY》 * |
| BELLA KOIFMAN ET AL: "Effects of Losartan L-Arginine on Nitric Oxide Production,Endothelial Cell Function, and Hemodynamic Variables in Patients With Heart Failure Secondary to Coronary Heart Disease", 《THE AMERICAN JOURNAL OF CARDIOLOGY》 * |
| ISHMAIL ASHAB ET AL: "Oral administration of L-arginine and captopril in rats prevents chronic renal failure by nitric oxide production", 《KIDNEY INTERNATIONAL》 * |
| TAKAHASHI KEIKO ET AL: "Effect of Angiotensin-Converting Enzyme Inhibitors and Nitroxy Groups on Human Coronary Resistance Vessels In Vitro", 《JOURNAL OF CARDIOVASCULAR PHARMACOLOGY》 * |
| YVES LACOURCIE` RE ET AL: "Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy", 《KIDNEY INTERNATIONAL》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021239106A1 (zh) * | 2020-05-28 | 2021-12-02 | 杭州起岸生物科技有限公司 | 钾atp通道调节剂在制备抗糖尿病肾病药物中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2398319A4 (en) | 2012-11-14 |
| JP2012505925A (ja) | 2012-03-08 |
| US20110257202A1 (en) | 2011-10-20 |
| WO2010045636A1 (en) | 2010-04-22 |
| EP2398319A1 (en) | 2011-12-28 |
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