CN1073844C - 肝脏再生的治疗剂 - Google Patents
肝脏再生的治疗剂 Download PDFInfo
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Abstract
含有缬氨酸为活性成分的肝脏再生治疗剂可通过促进肝脏再生和恢复肝脏正常功能来有效治疗肝炎、脂肪肝和药物诱发的肝脏疾病，它还可通过诱导早期肝再生而使那些因胆囊癌、肝癌和转移性肝癌而进行肝切除的病人术后迅速恢复。
Description
本发明涉及用于肝脏再生的治疗剂，该治疗剂中含有作为活性成分的支链氨基酸缬氨酸。更确切地说，本发明涉及含有缬氨酸的制剂，该制剂能在肝病、肝炎和肝硬变等症的肝切除后再生肝细胞。
已知了一些具有肝细胞再生活性的因子和药物。例如，Archive ofPathology,16,226-231(1993)中阐述了如果在部分肝切除后连续服用含有重量百分比为1％的干甲状腺粉剂的食物，从肝脏部分切除的第七天时肝的重量比对照组有明显的增加。
生物化学杂志，247,1757-1766(1972)中报道了三碘甲状腺氨酸、混合氨基酸溶液、胰高血糖素和肝素的液体混合物可引发肝脏中DNA的合成。
另外，生物化学和生物物理研究通讯，122,1450-1459(1984)中描述了可从70％部分肝切除后24小时的大鼠血清中纯化出用于成熟大鼠肝细胞原代培养的的一种生长因子，该因子被称作HGF(肝细胞生长因子)或亲肝素。
Advances in Enzyme Regulation,13,281-293(1975)中描述了胰岛素和胰高血糖素也是肝脏再生的重要因子，同时自从Okita等人在胃肠学，日本，14,453(1979)中报道了应用胰岛素-胰高血糖素的治疗诱发肝炎后，日本已将其广泛用于临床。
已报道了支链氨基酸-缬氨酸、异亮氨酸和亮氨酸可改善肝脑病和腐败性脑病或者在发病过程中保护蛋白质，可市售得到的氨基酸溶液有Hepatoamine(已注册商标)、Hepan(已注册商标)、Aminoleban(已注册商标)、Amiparen(已注册商标)、Amizet(已注册商标)和Aminic(已注册商标)。然而，无人知道缬氨酸具有肝细胞再生能力。
近几年来，从大鼠和人类纯化出肝细胞生长因子(HGF)后，已可成功地将其cDNA克隆，鉴于HGF具有增殖原代培养肝细胞的能力以及所导致的肝脏病生理中血浆HGF活性增高及诱导HGF mRNA的表达，预计HGF将可用于临床，尽管到目前为止，HGD还没有商品化。
目前日本实施的具有肝脏再生效应的唯一治疗方法是胰高血糖素-胰岛素治疗(GI治疗)。然而，这种GI治疗的效果尚未得到欧洲和美国的认可。
本发明的目的是提供一种用于不同程度肝病的安全并且具有强效肝脏再生作用的药物。
为达到此目的，将不同浓度的缬氨酸静脉内给予hyperelimented大鼠。详细分析了缬氨酸对肝脏重量的影响及组织病生理结果。结果发明者发现，缬氨酸可引起显著的肝脏再生，从而达到了本发明的目的。
本发明中所用的缬氨酸可买到或合成制得，任何形式的缬氨酸均可使用，不考虑其制备的方法。另外，可使用D-,L-和DL-形式的缬氨酸。
当本发明缬氨酸用作肝脏再生的治疗剂时，通常优选静脉注射，但也可采用诸如口服、非胃肠道给药等其它给药途径。缬氨酸可作为主要成分而单独用于制剂中，但优选将其与用于输液的制剂如高卡路里药物合用于输液或者将其加入到用于输液的制剂中。
可能的给药剂型包括：液体、悬浮液、乳剂、片剂、胶囊、颗粒剂、细颗粒、微粒、粉剂和栓剂。为了制备这些液体或固体的可药用剂型，优选加入适当辅剂，例如：赋形剂、填充剂、填料、溶剂、乳化剂、润滑剂、矫味剂、甜味剂、染料和缓冲剂。
本发明的用于肝脏再生的治疗剂适用于由于诸如肝炎、肝硬化和肝癌等而切除肝脏的患者，给药剂量随患者的性别、体格、状况、年龄和症状以及所用剂型的不同而不同；如果治疗剂是以氨基酸输注剂形式通过周围或中枢静脉给药，缬氨酸浓度优选在0.5-5.0％的范围，如果将安瓿加入到输注剂中时，缬氨酸浓度优选为1.0-10.0％范围，如果将悬浮液、乳剂、片剂、胶囊、颗粒剂、细颗粒、微粒、粉剂、栓剂及其它剂型口服或经肠道给药时，缬氨酸的浓度范围是5.0-100％。
需要提到的是本发明中当缬氨酸是液体时，它的百分比浓度是指重量/体积百分比，当它是固体时，其百分比浓度是指重量/重量百分比。
下列实施例进一步说明本发明。
实施例1
增高缬氨酸剂量对70％肝切除大鼠肝再生的影响
用乙醚麻醉重约250克，八至九周龄的Donryu雄性大鼠(每组5-7只)，麻醉时插入导管并固定于中央静脉，对其实施剖腹术，切除70％肝脏制成70％肝切除大鼠模型。该导管穿过皮下管道而跨越两根扁骨，它套有保护套并通过一保护性旋管与旋转点相连。将大鼠转入代谢笼，用lactated Ringer’s注射剂(LACTEC是Otsuka药品有限公司的注册商标)使其适应于输注，以非蛋白群体组计算得到的剂量220kcal/kg/天连续三或五天给予大鼠高卡路里输注液(见下)，泵式给药速率设定为250ml/kg/天：给予100％组(对照组)的高卡路里输注液含有10％氨基酸复合剂(MORIPRON，孟山都有限公司的注册商标)以及葡萄糖、电解质、痕量金属和维生素(缬氨酸浓度为2.25g/L)；给予0％组除不含缬氨酸(缬氨酸浓度为0g/L)外与对照组相同的液体；给予200％组除另外含有L-缬氨酸(日本药典)(缬氨酸浓度为4.50g/L)外与对照组相同的液体；给予400％组除另含有L-缬氨酸(日本药典)(缬氨酸浓度为9.00g/L)外与对照组相同的液体。
每次输注完毕后，计算每只动物体重。乙醚麻醉后腹主动脉放血，然后摘除肝脏并称重。随后将肝脏标本用于病理组织学检验。根据所得的肝脏及动物体重计算肝脏与动物体重的比值。另外，用福尔马林填充肝脏并用苏木精-曙红二次染色制备用于病理组织学检测的标本。检测结果用平均值±标准偏差(SD)表示，并用学生T检验进行统计处理，其中P＜0.05为结果是“显著性差异”。肝脏重量和肝脏和体重的重量比数据如表1所示。
表1
#：高卡路里输注液中缬氨酸的浓度括号中的数据是与作为整体的对照组相比的相对值。学生T检验的统计学分析平均值±SD*:p＜0.05 **p＜0.01(与对照组相比)
| 组 | 持续给药3天 | 持续给药5天 | ||||
| 病例数 | 肝重(g) | 肝与体重比(％) | 病例数 | 肝重(g) | 肝与体重比(％) | |
| 0％(0g/L)# | 5 | 5.6±0.5[1.00] | 2.2±0.1[0.96] | 7 | 6.3±0.2[1.03] | 2.4±0.1[1.04] |
| 100％(对照组)(2.25g/L) | 5 | 5.6±0.3[1.00] | 2.3±0.2[1.00] | 6 | 6.1±0.3[1.00] | 2.3±0.1[1.00] |
| 200％(4.50g/L) | 5 | 6.8±0.3**[1.21] | 2.6±0.2*[1.13] | 6 | 7.6±0.3**[1.25] | 2.9±0.2**[1.26] |
| 400％(9.00g/L) | 5 | 7.5±0.3**[1.34] | 2.9±0.1*[1.26] | 7 | 8.6±0.3**[1.41] | 3.1±0.1**[1.35] |
给药3天后，对照组动物肝重为5.6±0.3克，而200％组动物肝重为6.8±0.3克，400％组动物肝重为7.5±0.3克，这两组动物的数据显著提高(p＜0.01)；给药5天后，对照组动物肝重为6.1±0.3克，而200％组动物肝重为7.6±0.3克，400％组动物肝重为8.6±0.3克，这两组动物的数据显著提高(p＜0.01)。
给药3天后，对照组动物肝脏与体重比为2.3±0.2％，而200％组动物肝脏与体重比为2.6±0.2％，这一数值显著增高(p＜0.05),400％组动物肝脏与体重比为2.9±0.1％，这一数值也显著增高(p＜0.01)；给药5天后，对照组动物肝脏与体重比为2.3±0.1％，而200％组动物肝脏与体重比为2.9±0.2％,400％组动物肝脏与体重比为3.1±0.1％，这两个数值均显著增高(p＜0.01)。
在肝脏病理组织性检验中，0％组中肝细胞糖原域的扩大及空泡形成明显；而在其它组中未观察到任何异常，且其肝细胞的外形正常。
实施例2
缬氨酸对前脂肪细胞生长的影响
将从C3H雌性大鼠皮肤中得到的前脂肪细胞用于研究缬氨酸对细胞生长的影响。在96孔平底板培养浓度为1×104个细胞/孔或2.5×104个细胞/孔的前脂肪细胞，缬氨酸的浓度为80mg/L,160mg/L或320mg/L。注入3H-胸苷后，用闪烁计数器计算胸苷的摄取。培养基是RPMI 1640。结果如表2所示。
表2
*：液体培养基中缬氨酸的浓度。
| 组 | [3H]-胸苷摄取(cpm) | |
| 细胞计数：1×104细胞胞 | 细胞计数：2.5×104个细 | |
| 100％(80mg/L)* | 1203.3 | 2771.1 |
| 200％(160mg/L)* | 1314.4 | 3441.1 |
| 400(320mg/L)* | 3180.0 | 4678.9 |
从表2可明显地看出，胸苷的摄取随缬氨酸浓度的增大而增高。
实施例3
缬氨酸对原代培养的肝细胞生长的影响
在乙醚麻醉下将八至九周龄重约250克的Donryu雄性大鼠沿腹壁切开后摘除70％肝脏。三天后，用胶原蛋白灌注麻醉大鼠的肝脏并收集游离的肝细胞。将肝细胞以2×104个细胞/孔的浓度接种在涂有胶原蛋白的92孔平底板上。将缬氨酸浓度设定为50mg/L,100mg/L或200mg/L，孵育36小时后，注入3H-胸苷并用闪烁计数器计算胸苷的摄取。培养基是Williams Media E,该培养基含有10％FCS,10-6M地塞米松和10-7M胰岛素。胸苷摄取的数据如表3所示。
表3
*：液体培养基中缬氨酸的浓度。
| 组 | [3H]-胸苷摄取(cpm) |
| 细胞计数：2×104细胞 | |
| 100％(50mg/L)* | 1276.2 |
| 200％(100mg/L)* | 1339.2 |
| 400(200mg/L)* | 1991.5 |
从表3可明显地看出，原代培养的肝细胞对胸苷的摄取随缬氨酸浓度的增大而增高，这表明缬氨酸对培养的肝细胞的生长有作用。
工业适用性
本发明的肝脏再生治疗剂可通过促进肝脏再生和恢复肝脏正常功能来有效治疗肝炎、脂肪肝和药物引起的肝脏疾病。它还可通过诱导早期肝再生从而使那些因胆囊癌、肝癌和转移性肝癌而进行肝切除的病人术后迅速恢复。如果将该治疗剂与高卡路里输注液联合使用，该治疗剂的疗效会进一步提高，即使对于那些因慢性肝炎或肝硬变而实施肝切除的病人，该治疗剂也可通过迅速的肝脏再生而确保手术的安全并使病人术后迅速恢复。
Claims (4)
1．用于肝脏再生的治疗剂，该治疗剂含有作为活性成分的缬氨酸，并且不含有除缬氨酸以外的其它氨基酸。
2．权利要求1的肝脏再生治疗剂，其中缬氨酸是L-缬氨酸。
3．权利要求1或2的肝脏再生治疗剂，该治疗剂是一种用于输注的制剂。
4．权利要求1或2的肝脏再生治疗剂，其为输注剂形式，并且其中缬氨酸的浓度是0.5-5.0重量/体积％。
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| US20040022827A1 (en) * | 1997-09-30 | 2004-02-05 | Chugai Seiyaku Kabusiki Kaisha | Remedy for hepatopathy |
| WO2001013912A1 (fr) * | 1999-08-23 | 2001-03-01 | Chugai Seiyaku Kabushiki Kaisha | Medicaments destines a la regeneration d'un foie transplante |
| CA2413149A1 (en) | 2000-06-14 | 2001-12-20 | Medarex, Inc. | Prodrug compounds with isoleucine |
| US6864242B2 (en) * | 2001-03-05 | 2005-03-08 | Stephen P. Ernest | Enteral formulation |
| WO2003063853A1 (fr) * | 2002-01-31 | 2003-08-07 | Chugai Seiyaku Kabushiki Kaisha | Compositions de reduction de la graisse mesenterique |
| CN101720222B (zh) | 2007-06-21 | 2016-09-07 | 学校法人城西大学 | 具有促进肝细胞增殖作用的药物 |
| KR100943577B1 (ko) | 2009-08-28 | 2010-02-23 | 서울대학교산학협력단 | 베타인을 함유하는 부분적으로 절제된 간의 재생 촉진용 조성물 |
| FR2989032B1 (fr) | 2012-04-05 | 2015-04-10 | Michelin & Cie | Pneumatique et ensemble pneumatique-roue a mobilite etendue |
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| EP0769295A1 (en) | 1997-04-23 |
| CN1154064A (zh) | 1997-07-09 |
| WO1996000059A1 (fr) | 1996-01-04 |
| AU2629895A (en) | 1996-01-19 |
| CA2193363C (en) | 2004-07-13 |
| KR970703763A (ko) | 1997-08-09 |
| US5916921A (en) | 1999-06-29 |
| KR100322404B1 (ko) | 2002-05-09 |
| EP0769295A4 (en) | 1999-11-10 |
| ATE289809T1 (de) | 2005-03-15 |
| CA2193363A1 (en) | 1996-01-04 |
| ES2238680T3 (es) | 2005-09-01 |
| DE69534039D1 (de) | 2005-04-07 |
| DE69534039T2 (de) | 2005-12-29 |
| EP0769295B1 (en) | 2005-03-02 |
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