CN1857715A - 肝硬化治疗药 - Google Patents
肝硬化治疗药 Download PDFInfo
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- CN1857715A CN1857715A CN 200610065168 CN200610065168A CN1857715A CN 1857715 A CN1857715 A CN 1857715A CN 200610065168 CN200610065168 CN 200610065168 CN 200610065168 A CN200610065168 A CN 200610065168A CN 1857715 A CN1857715 A CN 1857715A
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Abstract
本发明公开了抑制慢性肝炎、肝纤维化、肝硬化的药品。该抑制剂以聚普瑞锌为有效成分。
Description
技术领域
本发明是有关抑制慢性肝炎并发产生的进行性肝纤维化和抑制向肝硬化发展的药品。
技术背景
慢性肝炎主要由肝炎病毒引起的慢性肝障碍，急性病毒肝炎经过一段时间治疗没有治愈的肝炎和有相同症状的肝炎。病毒性慢性肝炎有B(乙)型慢性肝炎和C(丙)型慢性肝炎等。慢性肝炎的病因除了病毒外，还有酒精、药物、中毒、肝肪肝、肝豆状核变性，自身免疫性肝炎等。
这些慢性肝炎继续发展就变成肝硬化。肝硬化的病因是肝细胞持续发生变化，通常通过肝细胞再生进行修复；但肝细胞障碍发生强烈的、持续时间长，反复的炎症反应，使肝内纤维增多变硬；残存的肝细胞强烈再生，使肝内形成结节。该结节压迫以肝内静脉为中心的血管系统加重肝内血液循环障碍。由此引起肝门静脉压升高，肝血流量减少等进一步加重肝细胞障碍，产生恶性循环。
由这样的慢性肝炎发展到肝硬化时就产生肝纤维化，由这种可逆状态的慢性肝炎变成不可逆状态的肝硬化。因此，抑制进行性慢性肝炎并发产生的肝纤维化药物作为慢性肝炎治疗药物是非常重要的。
现有已知的慢性肝炎治疗药物有干扰素、拉米夫定和肝保护剂等。但干扰素和拉米夫定是抗病毒剂，肝保护剂是主要对肝细胞障碍有保护作用的药物，对肝纤维化没有抑制作用。
聚普瑞锌(Polaprezinc)【L-肌肽(即β-丙氨酰基-L-组氨酸)锌酸盐，L-carnosine zincate】是已知的早已广泛使用的有效消化性溃疡治疗药物(日本专利1984年-88270公报)，对急性肝炎模型四氯化碳引起的肝功障碍有效(日本专利1988年-14728号公报)。然而聚普瑞锌对慢性肝炎的作用机制完全不了解。
发明内容
本发明的目的是提供治疗肝硬化的药品。
因此本发明者用与已知的四氯化碳诱发肝功障碍的慢性肝炎模型和完成不同作用机制产生肝功能障碍的硫乙酰胺模型探索肝纤维化抑制药物，完成了本发明发现对肝硬化有治疗作用的聚普瑞锌(Polaprezinc)，即本发明提供含有有效成分聚普瑞锌的肝硬化治疗药。
根据本发明的药品能够显著抑制慢性肝炎并发产生肝纤维化，因此它能够防止慢性肝炎向肝硬化发展。
本发明药品有效成分聚普瑞锌即L-肌肽锌酸盐，可以用前述文献资料：
(1)特开昭59(1984年)-88270号公报
(2)特开昭63(1988年)-14728号公报
(3)特公平7(1995年)-116160号公报
(4)特公平3(1991年)-5367号公报等记载的制备方法获得。
后述试验例中的聚普瑞锌对慢性肝炎硫乙酰胺模型有优良治疗效果，尤其是能显著降低肝纤维化标记物组织内羟脯氨酸(Hydroxyproline)量和透明质酸，并且能显著的抑制肝组织纤维化和显著的降低TGF-β量。不仅在硫乙酰胺使用前，而且在硫乙酰胺使用过程中(即慢性肝炎发生后)给予聚普瑞锌都能获得上述的优良治疗效果，这一点是非常重要的。因此，聚普瑞锌作为肝硬化治疗药，特别是作为慢性肝炎肝硬化的治疗是有用的。
作为本发明药品，最好用口服制剂给药，特别是片剂、散剂、颗粒剂、糖浆剂和胶囊剂等最适用。
在这些制剂生产中，可以选择适当的辅料例如注射用水，精制水、羧甲基纤维素钙、羧甲基纤维素钠，乳糖、山梨醇、甘露醇、白糖、玉米淀粉、结晶纤维素、乳糖醇、纤维素衍生物、阿拉伯胶、西黄蓍胶浆、明胶、吐温80、滑石粉、硬酯酸镁、水、乙醇、白蜡、甘油、脂肪、脂肪油、乙二醇类。硬酯醇等高级醇类，液体石蜡、石蜡、蜜蜡，聚氧乙烯硬化蓖麻油、糖精、糖浆等，进行组合使用。
可根据年龄，体质，病态症状、疗效、给药方法、给药次数和疗程的不同，酌情增减聚普瑞锌的给药剂量。成人的最佳剂量是1次0.01-10g。最好把1日的剂量分为1-4次给药。
附图说明
图1是显示聚普瑞锌对组织羟脯氨酸量的影响。
图2是显示聚普瑞锌对组织透明质酸量的影响。
图3是显示聚普瑞锌对组织TGB-B1量的影响。
图4是显示聚普瑞锌对肝纤维化影响的肝组织图。上图是HE(苏木精和曙红)染色；右图是硫乙酰胺+聚普瑞锌500mg/kg组、左图是硫乙酰胺20周组。下图是天狼星红染色体：右图是硫乙酰胺+聚普瑞锌500mg/kg组、左图是硫乙酰胺20周组。
具体实施方式
列举下面实验例子更详细地说明本发明。但不局限于该实例。
实施例1：
将大鼠分组，每组15只。300mg/L硫乙酰胺水溶液作为对照组大鼠饮用水，连续饮用10周或20周。300mg/L硫乙酰胺水溶液亦作为实验组大鼠饮用水，连续饮用20周，但在第10周后增加口服200mg/day/kg或500mg/day/kg聚普瑞锌。
对照组和实验组大鼠，按规定给完药后将他们杀死，取出肝脏。用乳汁凝集免疫比浊法测定肝纤维化血清中标记物透明质酸。用盐酸处理过的氯胺和埃利希溶液吸收光度法测定肝组织纤维化标记物羟脯氨酸。用ELISA法测定对促进肝纤维化有特殊作用的、肝组织内增加的TGF-β1。进行把肝组织染色为目的天狼星红染色，用α-SMS免疫染色法鉴定出对纤维化起主要作用的活性化星形细胞。此外，用生物学方法测定肝障碍标记物中血清中转移酶和碱性磷酸酶。
这些测定结果表示于图1、图2、图3、图4和表1中。
表1
| 组 | 血清ALP(u/L)* |
| 硫乙酰胺10周组 | 964±34 |
| 硫乙酰胺20周组 | 1429±137a |
| 硫乙酰胺20周+聚普瑞锌200mg/kg组 | 728±28b |
| 硫乙酰胺20周+聚普瑞锌500mg/kg组 | 829±28b |
| 对照组(非给药组) | 525±26c |
*ALP：碱性磷酸酶
a：p＜0.01(与对照组、硫乙酰胺10周组、硫乙酰胺+聚普瑞锌组有显著差异)
b：p＜0.01(与对照组有显著差异)
c：p＜0.01(与硫乙酰胺10周组、20周组、硫乙酰胺+聚普瑞锌组有显著的差异)。
图1、图2、图3、图4明显地显示：即使是在硫乙酰胺服用10周后才开始口服聚普瑞锌，但肝纤维化标记物羟脯氨酸量、透明质酸和TGF-B1量显著降低，可见聚普瑞锌对肝组织纤维化有明显抑制作用，作为肝组织纤维化抑制剂是有用的。此外，表1亦显示：肝功能障碍标记物碱性磷酸酶(ALP)值有明显改善、慢性肝炎症状亦有明显改善。
Claims (2)
1.一种制剂，其特征是用聚普瑞锌作为有效成分的肝硬化治疗药。
2.一种制剂，其特征是用聚普瑞锌作为有效成分的肝硬化和慢性肝炎肝纤维化治疗药。
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| CN104083751A (zh) * | 2014-07-18 | 2014-10-08 | 大连大学 | 一种用于肝硬化治疗的药物组合物及其用途 |
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