CN1642574A - 用于肾小球疾病的治疗剂 - Google Patents

用于肾小球疾病的治疗剂 Download PDF

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CN1642574A
CN1642574A CNA038072033A CN03807203A CN1642574A CN 1642574 A CN1642574 A CN 1642574A CN A038072033 A CNA038072033 A CN A038072033A CN 03807203 A CN03807203 A CN 03807203A CN 1642574 A CN1642574 A CN 1642574A
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中川隆
丰泉茶谷香
伊菅昌子
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Nissan Chemical Corp
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Abstract

本发明涉及肾小球疾病的预防或治疗剂，它包含作为活性成分的抗凝血细胞药和HMG－CoA还原酶抑制剂。上述药剂用于预防和治疗包括慢性肾小球肾炎在内的各种肾小球疾病。

Description

用于肾小球疾病的治疗剂
发明领域
本发明涉及肾小球疾病的预防性或治疗剂。
发明背景
由肾小球损伤引起的肾小球疾病(原发性肾小球肾炎)在临床上可分为以下七种疾病中的任何一种：感染溶血性链球菌后的急性肾炎、新月体肾小球肾炎(进行性迅速的肾炎)、IgA肾病、膜性肾病、膜增生性肾病、局灶性肾小球肾炎和最小变化肾病综合征。其中，感染溶血性链球菌后的急性肾炎、新月体肾小球肾炎和最小变化肾病综合征通常称为慢性肾小球肾炎，其发作原因和时间在许多情况下相对不明显。此外，肾小球的损伤过程大多数是进行性的，并在许多情况下导致肾衰竭。
目前尚未打到以治疗这种肾小球疾病为基本目标的药物，为了抑制或延迟向透析转变，常用类固醇药、抗凝血细胞药、抗凝药和免疫抑制剂等进行药物治疗。
其中，抗凝血细胞药有抑制血小板中各种介体释放的作用，如血栓烷A2、组胺、白细胞迁移因子、细胞因子和增殖因子。因此，用这种药剂据认为可以抑制由肾小球膜细胞增殖引起的肾小球疾病进行性增加，和由各种介体引起的肾小球SNARE壁中屏障机制的失灵(Cameron JS等.：肾病综合征中的凝血和血栓栓塞并发症Adv Nephrol 13：75，1984)。
另据报道，在肾病中，高脂血的程度与肾功能中蛋白尿恶化和加重的程度有统计学的相关性。为清除高脂血肾病的增强因子，人们采用HMG-CoA还原酶抑制剂等高脂血治疗剂。
但是，抗凝血细胞药和高脂血治疗剂产生的改善肾病的效果有限，且仍不能令人满意。
本发明的目标是提供一种药物，它对预防或治疗肾小球疾病具有优异的效果。
发明概述
考虑到上述问题，本发明者经反复研究发现，当联合采用抗凝血细胞药和作为高脂血治疗剂的HMG-CoA还原酶抑制剂时，对肾病的治疗效果明显好于它们各自独立使用时的效果，可用作肾小球疾病的预防或治疗剂。
也就是说，本发明提供了一种肾小球疾病的预防或治疗剂，它包含作为活性成分的抗凝血细胞药和HMG-CoA还原酶抑制剂。
此外，本发明提供了一种预防或治疗肾小球疾病的药物组合物，它包含抗凝血细胞药、HMG-CoA还原酶抑制剂和药学上可接受的载体。
本发明还提供了用抗凝血细胞药和HMG-CoA还原酶抑制剂生产肾小球疾病的预防或治疗剂的方法。
此外，本发明提供了治疗肾小球疾病的方法，它包括施用抗凝血细胞药和HMG-CoA还原酶抑制剂。
附图简述
图1所示为单独施用匹伐他汀钙时观察到的尿中蛋白质总量。图中每个值为平均值±标准误差。
图2所示为单独施用盐酸地拉齐普时观察到的尿中蛋白质总量。图中每个值为平均值±标准误差。
图3所示为联合施用匹伐他汀钙和盐酸地拉齐普时观察到的尿中蛋白质总量。图中每个值为平均值±标准误差。
本发明的最佳实施方式
本发明的抗凝血细胞药指抑制血小板的粘连和凝固的药物，包括(例如)噻氯匹定、西洛他唑、奥扎格雷、贝前列素、沙格雷酯、双嘧达莫、阿加曲班、阿司匹林、地拉齐普、二十碳戊酸盐(icosapentate)乙酯、利马前列素α-环糊精、前列地尔、前列地尔α-环糊精、曲美他嗪、曲匹地尔和氯吡格雷(日本专利申请待公开号955/1979)、CS-747(日本专利号2683479)、AT1015(日本专利申请待公开号3135/1996)、SR-46349(日本专利号2562503)及其盐。其中，优选那些具有腺苷增强功能或磷脂酶抑制功能的药物，如地拉齐普、双嘧达莫、曲美他嗪、曲匹地尔及其盐，特别优选地拉齐普及其盐(盐酸盐等)。
本发明的HMG-CoA还原酶抑制剂包括所有的所谓斯达汀型化合物，它们具有胆固醇合成抑制活性，是已知的高脂血治疗剂。它优先包括具有3，5-二羟基庚酸或3，5-二羟基-6-庚酸的化合物。具体而言，优选的化合物描述于日本专利申请待公开号2240/1982、163374/1982、122374/1981、500015/1985(通过PCT)、216974/1989、58967/1991、279866/1989和178841/1993。其中包括内酯化合物、开环内酯化合物或它们的盐。其中还包括这些化合物的水合物、它们的盐和其具有可作为药物接受的溶剂的溶剂合物。当这些化合物中存在不对称碳原子，和当它们含不饱和键且存在立体异构体时，所有的异构体都包含在其中。
合适的HMG-CoA还原酶抑制剂包括(例如)普伐他汀((+)-(3R，5R)-3，5-二羟基-7-[(1S，2S，6S，8S，8aR)-6-羟基-2-甲基-8-[(S)-2-甲基丁氧基]-1，2，6，7，8，8a-六氢-1-萘基]庚酸，日本专利申请待公开号2240/1982)、洛伐他汀((+)-(1S，3R，7S，8S，8aR)-1，2，3，7，8，8a-六氢-3，7-二甲基-8-[2-(2R，4R)-四氢-4-羟基-6-氧-2H-吡喃-2-基]乙基)-1-萘基(S)-2-甲基丁酸酯，日本专利申请待公开号163374/1982)、辛伐他汀((+)-(1S，3R，7S，8S，8aR)-1，2，3，7，8，8a-六氢-3，7-二甲基-8-[2-(2R，4R)-四氢-4-羟基-6-氧-2H-吡喃-2-基]乙基-1-萘基-2，2-二甲基丁酸酯，日本专利申请待公开号122375/1981)、氟伐他汀((±)-(3R*，5S*，6E)-7-[3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基]-3，5-二羟基-6-庚酸，日本专利申请待公开号(通过PCT)500015/1985)、西立伐他汀((+)-(3R，5S，6E)-7-[4-(4-氟苯基)-2，6-二-(1-甲基乙基)-5-甲氧基甲基吡啶-3-基]-3，5-二羟基-6-庚酸，日本专利申请待公开号216974/1989)、阿伐他汀((3R，5R)-7-[2-(4-氟苯基)-5-(1-甲基乙基)-3-苯基-4-苯基氨基羰基-1H-吡咯-1-基]-3，5-二羟基庚酸，日本专利申请待公开号58967/1991)、匹伐他汀((3R，5S，6E)-7-[2-环烷基-4-(4-氟苯基)-3-喹啉基]-3，5-二羟基-6-庚酸，日本专利申请待公开号279866/1989)和罗素他汀(7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲基磺酰氨基)-嘧啶-5-基]-(3R，5S)-二羟基-(E)-6-庚酸，日本专利申请待公开号178841/1993)及其盐。
其中，优选阿伐他汀、罗素他汀、匹伐他汀及其盐，更优选匹伐他汀及其盐(钠盐、钙盐等)。
除了上述已公布的专利申请中所述的方法外，上述抗凝血细胞药和HMG-CoA还原酶抑制剂可用众所周知的方法产生。
本发明的药物组合使用上述抗凝血细胞药和HMG-CoA还原酶抑制剂。如后面的实施例所述，与各自单独施用抗凝血细胞药和HMG-CoA还原酶抑制剂的情况相比，药物的功效是能显著抑制肾小球疾病模型的进行性抗Thy-1肾病大鼠尿中的总蛋白量。
因此，本发明的药物能有效预防或治疗动物的肾小球疾病，特别是预防或治疗包括人在内的哺乳动物的肾小球疾病。这种肾小球疾病的例子包括慢性肾小球肾炎如IgA肾病、局灶性肾小球肾炎、膜性肾病和膜增生性肾病。
用来预防或治疗肾小球疾病的本发明抗凝血细胞药和HMG-CoA还原酶抑制剂的使用形式不受特别限制，二者可同时施用，也可隔一段时间分开施用。
也就是说，抗凝血细胞药和HMG-CoA还原酶抑制剂可与药用稀释剂、填充剂等混合，制成单一制剂或药物，也可以分别制成制剂以制备一组(试剂盒)。当两种药物分开制成制剂时，其剂量形式可彼此不同。
根据其用途，本发明的预防或治疗肾小球疾病的药剂可具有各种剂量形式。例子有粉剂、颗粒剂、微粒、干糖浆、片剂、胶囊和注射剂形式。
这些制剂可根据传统方法制备，如适当混合、稀释或用医用添加剂溶解，如赋形剂、分解剂、粘合剂、抛光剂、稀释剂、缓冲液、等渗剂、防腐剂、湿润剂、乳化剂、分散剂、稳定剂和根据其制剂形式药学上许可的溶解助剂。
例如，粉剂可如下制备：在活性组分(抗凝血细胞药和/或HMG-CoA还原酶抑制剂)加入合适的赋形剂(如果需要的话)、抛光剂等，充分混合。片剂可如下制备：加入合适的赋形剂(如果需要的话)、分解剂、粘合剂、抛光剂等，制成片剂。此外，可提供包衣片剂，制成涂薄膜衣片剂和糖衣片剂。
另外，注射剂的形式可以是液体制剂(无菌溶液或非水溶液)、乳液和悬浊液，所用非水载体、稀释剂、溶剂或载体包括(例如)丙二醇、聚乙二醇、植物油(如橄榄油)、有机酸酯(如可注射的油酸乙酯)。此外，上述组合物可适当与辅剂混合，如防腐剂、湿润剂、乳化剂和分散剂。
抗凝血细胞药和HMG-CoA还原酶抑制剂在本发明肾小球疾病的预防或治疗剂中的含量可根据制剂适当选择，抗凝血细胞药约1-50质量％，优选约10-50质量％，HMG-CoA还原酶抑制剂约0.1-10质量％，优选约0.5-5质量％。
在本发明中，如上所述分开配制的抗凝血细胞药和HMG-CoA还原酶抑制剂可同时施用，也可间隔一段时间分开施用。在后一种情况下，各组分的施用频率可不同。
本发明肾小球疾病的预防或治疗剂的剂量可根据肾小球疾病的类型和症状恰当选择，抗凝血细胞药一般一天服用1-1000mg，优选10-500mg；HMG-CoA还原酶抑制剂一般一天服用0.1-100mg，优选1-50mg。此剂量可分为一天1次或数次服用。
实施例
下面将结合实施例更详细地解释本发明。
实施例1：对患有进行性抗Thy-1肾病大鼠的药理测试
对Wistar雌鼠(5周龄，购于日本SLC有限公司)进行检疫，并适应环境4天，然后用于试验。首先，用戊巴比妥麻醉后，通过胁腹切开，取出大鼠的右肾。2周后，将抗Thy-1抗体(单克隆抗体1-22-3；购自Panafarm实验有限公司)注射(500μg/鼠)到尾部静脉，从而引起进行性肾损伤，立即进行以下试验1-3：
试验1：悬浮在0.5％羧甲基纤维素钠水溶液中的匹伐他汀钙(10mg/kg，N＝7)连续口服10周。
对照组(抗体处理的和未施用化合物的组)：N＝8；未经抗体处理的组：N＝6。
试验2：将溶解在生理盐水中的盐酸地拉齐普(10mg/kg)注射到腹膜内，连续10周。
对照组(抗体处理的和未施用化合物的组)：N＝8；未经抗体处理的组：N＝6。
试验3：联合施用两种药物10周，即口服悬浮在0.5％羧甲基纤维素钠水溶液中的匹伐他汀钙(5mg/kg，N＝10)，然后立即将溶解在生理盐水中的盐酸地拉齐普(5mg/kg，N＝10)注射到腹膜内。
对照组(抗体处理的和未施用化合物的组)：N＝10；未经抗体处理的组：N＝6。
在各试验中，通过代谢笼(Sugiyama Gen有限公司)取尿液18小时，测定尿液中排泄的蛋白质总量。结果示表1-3所示。
施用匹伐他汀钙(10mg/kg)10周后，尿液中排泄的蛋白质总量几乎与未施用化合物的对照组相同，没有观察到匹伐他汀钙的效果(图1)。另外，施用盐酸地拉齐普(10mg/kg)10周后，尿液中排汇的蛋白质总量几乎与未服用化合物的对照组相同，没有观察到盐酸地拉齐普的效果(图2)。
与此相反，联合施用匹伐他汀钙(5mg/kg)和盐酸地拉齐普(5mg/kg)10周后，观察到尿液中排泄的蛋白质总量与未施用化合物的对照组相比，明显受到抑制(图3)。
实施例1中片剂的配制
具有以下组成的片剂按如下方法生产：
           表1
匹伐他汀钙 2mg
盐酸地拉齐普 100mg
乳糖 70mg
低取代羟丙基纤维素 20mg
羟丙基纤维素 6mg
硬脂酸镁 2mg
总计 200mg
混合匹伐他汀钙和羟丙基纤维素，制备均匀粉末混合物，加入适量的纯净水，用搅拌造粒法使混合物形成颗粒，由此制备片状颗粒。混合硬脂酸镁和这种片状颗粒，将此混合物压片得到含匹伐他汀钙和盐酸地拉齐普的片剂。
工业应用
本发明肾小球疾病的预防或治疗剂用于预防和治疗各种肾小球疾病，包括慢性肾小球肾炎如IgA肾炎、病灶肾小球肾病、局性性肾病和膜增生性肾病。

Claims (11)

1.一种肾小球疾病的预防或治疗剂，它包含作为活性成分的抗凝血细胞药和HMG-CoA还原酶抑制剂。
2.权利要求1所述的肾小球疾病的预防或治疗剂，其特征在于抗凝血细胞药具有腺苷增强功能或磷脂酶抑制功能。
3.权利要求1或2所述的肾小球疾病的预防或治疗剂，其特征在于抗凝血细胞药选自地拉齐普、双嘧达莫、曲美他嗪、曲匹地尔及其盐。
4.权利要求1或2所述的肾小球疾病预防或治疗的剂，其特征在于抗凝血细胞药是地拉齐普及其盐。
5.权利要求1-4中任一项所述的肾小球疾病的预防或治疗剂，其特征在于HMG-CoA还原酶抑制剂选自洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、西立伐他汀、阿伐他汀、罗素他汀和匹伐他汀及其盐
6.权利要求1-4中任一项所述的肾小球疾病的预防或治疗剂，其特征在于HMG-CoA还原酶抑制剂是匹伐他汀及其盐。
7.权利要求1-6中任一项所述的肾小球疾病的预防或治疗剂，其特征在于它在单一制剂中含有抗凝血细胞药和HMG-CoA还原酶抑制剂。
8.权利要求1-6中任一项所述的肾小球疾病的预防或治疗剂，其特征在于一种试剂盒包含以独立制剂形式的抗凝血细胞药和HMG-CoA还原酶抑制剂。
9.预防或治疗肾小球疾病的药物组合物，其特征在于它包含抗凝血细胞药、HMG-CoA还原酶抑制剂和药学上可接受的载体。
10.抗凝血细胞药和HMG-CoA还原酶抑制剂在生产肾小球疾病的预防或治疗剂中的应用。
11.一种治疗肾小球疾病的方法，它包括施用抗凝血细胞药和HMG-CoA还原酶抑制剂。
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