CN1155406C - 一氧化氮生成抑制剂 - Google Patents

一氧化氮生成抑制剂 Download PDF

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CN1155406C
CN1155406C CNB981039146A CN98103914A CN1155406C CN 1155406 C CN1155406 C CN 1155406C CN B981039146 A CNB981039146 A CN B981039146A CN 98103914 A CN98103914 A CN 98103914A CN 1155406 C CN1155406 C CN 1155406C
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大野耕作
小西甚右卫门
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末广诚之
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Abstract

本发明公开了一种含有痘苗病毒接种炎症组织提取物为有效成分的药物组合物，该组合物对内毒素诱发的细胞致死和一氧化氮过量生成有抑制作用，对内毒素诱发低血压有改善作用，可以作为一氧化氮生成抑制剂、败血症治疗剂、抗内毒素剂、内毒素休克治疗剂等。此外，由于本发明物质对于病态时异常的一氧化氮生成有抑制作用，所以它可用作为与过量一氧化氮生成有关的疾病，例如急性低血压等的治疗和预防药物。

Description

一氧化氮生成抑制剂
本发明涉及痘苗病毒接种炎症组织提取物的新药理作用，具体地说就是涉及以痘苗病毒接种炎症组织提取物为有效成分的一氧化氮生成抑制剂、败血症治疗剂、抗内毒素剂、内毒素休克治疗剂等医药品。
已知，针对病毒等外界而来的侵袭或内在的病理状态的进行，机体具有对过度反应的抑制作用和对机能降低的增强作用的两重性。机体为了维持稳定性、调节机体机能使之正常化，会生成各种机体机能调节物质。例如，接种痘苗病毒后炎症组织产生的机体机能调节物质，从病变组织提取该物质的方法及其药理活性都已有种种报告(特公昭63-39572号公报、特公昭63-25600号公报、特公平3-43279号公报等)。
此外，作为实际的药品有痘苗病毒接种家兔炎症皮肤提取物制剂。这种制剂例如《医疗药日本医药品集》(1994年8月版，日本医药情报中心编，药业时报社发行)1434页所记载的，为含有从接种了痘苗病毒的家免炎症皮肤组织提取分离的非蛋白性活性物质的制剂，其适应症有腰痛病、颈肩腕综合症、肩周炎、变形性关节病、综合性神经痛、伴有皮肤病(湿疹、皮炎、荨麻疹)的搔痒、变态反应性鼻炎、亚急性脊髓视神经症后遗症的无感觉、疼痛、感觉异常等，作为上市的制剂成品有皮下、肌肉、静脉注射用的注射剂和片剂等。
对于上述痘苗病毒接种炎症组织提取物来说，已知其有镇痛作用、镇静作用、抗变态反应作用、改善微循环作用等种种药理作用，但对于一氧化氮生成抑制作用、败血症治疗作用、抗内毒素作用以及内毒素休克治疗作用等涉及到本发明的新药理作用方面迄今却完全未见报道。
在败血症和其它严重细菌感染症中，产生了大量内毒素(细胞内毒素)，其作用是引起休克的症状。内毒素对机体具有发热、白细胞增多、补体和激肽系统活化、诱发弥散性血管内凝血综合症(DIC)、骨髓抑制等多种多样的作用。内毒素引起的休克症状如果持续进行，则使机体血压过度下降，心输出量过分降低，产生无尿、意识障碍等，使机体陷入极其危险的状态。由于发生内毒素休克时血压急剧下降，暗示内毒素作用于血管内皮细胞，使之异常产生过量的一氧化氮，因而已有讨论将例如精氨酸衍生物等一氧化氮合成酶抑制剂作为内毒素休克时的低血压症治疗剂。
本发明人等对关于痘苗病毒接种炎症组织提取物的药理活性进行了种种的实验研究，结果发现该物质对内毒素诱发的细胞致死和一氧化氮的过度产生有抑制作用，对内毒素诱发的低血压症有改善作用，从而完成了本发明。
本发明的目的在于提供以痘苗病毒接种炎症组织提取物为有效成分的一氧化氮生成抑制剂、败血症治疗剂、抗内毒素剂、内毒素休克治疗剂等新型药物组合物。
本发明药物组合物的有效成分为从痘苗病毒接种炎症组织提取的非蛋白性机体机能调节物质，这可以使用前述《医疗药日本医药品集》记载的已得到生产许可市售的痘苗病毒接种家兔炎症皮肤的提取物制剂。此外，上述特许公报等文献记载的各种痘苗病毒接种炎症组织提取物也可作为本发明的有效物质而使用，其制造方法和优选给药量等文献中也都有说明。
至于对患者的给药方法，市售药剂中对注射剂来说有皮下、肌注和静注给药等，对片剂来说有口服给药，但是对于其他种类的疾病来说，则也可能有最适合其治疗的上述剂形及方法之外的给药方法。给药量应因痘苗病毒接种炎症组织提取物种类的不同而适当设定；市售制剂认可的给药量，根据前述《医疗药日本医药品集》(1434页)，基本上为内服每日16个神经促进素(neurotropin)单位，注射剂为每日3.6至7.2个神经促进素单位不过根据疾病种类、严重程度、患者个体差异、给药方法、给药时间等的不同，可以作适当的增减。
以下为涉及痘苗病毒接种炎症组织提取物新药理作用的药理实验结果。
(1)细胞保护作用
每个3.5cm培养皿中有2×104个移植的人脐带血管内皮细胞，分别加入各种浓度的内毒素(脂多糖：LPS)，然后进行内皮细胞培养。7天后，用血细胞计算盘对细胞计数，以锥虫蓝染色法测定细胞的生死。以此实验系统进行在本发明物质共存下LPS对内皮细胞的致死作用的研究，从而考查本发明物质的效果，图1所示为一例结果。
如图1所示，LPS在超过0.1μg/ml的浓度显示出浓度依赖性的内皮细胞损伤和细胞死亡。对于这种LPS诱发的细胞致死，依照特公昭63-39572号公报中实施例1记载方法所得的本发明物质具有优良的细胞保护作用，可以显著地改善细胞的生存率。
(2)一氧化氮生成抑制作用
将人脐带血管内皮细胞(2×104个/孔)在96孔的多凹孔培养皿中加入200ml培养基进行培养，直到细胞生长汇合。然后除去培养基，加入含有LPS(0.001～100mg/ml)及上述本发明物质的新鲜培养基，24小时后用Griess试剂以发色分析法对一氧化氮生成量进行测定。也就是分别从各培养皿中取100ml，加入100ml的Griess试剂(1％磺胺及0.1％N-1-萘替乙撑二胺盐酸盐的2％磷酸溶液)，在25℃下温育10分钟后，测定540nm处的吸光度。以亚硝酸钠水溶液为标准溶液，考察本发明物质的一氧化氮生成抑制作用，图2所示为一例结果。
作为本发明物质对上述LPS诱发的细胞损害的细胞保护作用的作用机制之一，研究其对LPS引起的一氧化氮生成所具有的抑制作用。如图2所示，LPS浓度在0.1μg/ml以上时一氧化氮生成显著增加，本发明物质对这种LPS引发的一氧化氮生成有显著的抑制作用。此外，对于LPS处理的小鼠肺、肝脏及肾脏的NADPH-硫辛酰胺脱氢酶阳性物质及诱导型一氧化氮合成酶的增加，本发明物质(在LPS给与的同时给与)显示出对这种增加的抑制作用。因此提示本发明物质对一氧化氮生成的抑制作用是基于对诱导型一氧化氮合成酶出现的抑制。
(3)LPS诱发致死的抑制作用
雄性ddy系小鼠(25～30g)，LPS(0.75mg/只)和本发明物质溶液或磷酸缓冲化生理盐水共同腹腔内给药。在这次给药后五天内每隔12小时再给与本发明物质溶液(40单位/千克)或磷酸缓冲化生理盐水(对照组)，每天2次测定死亡数。图3所示为一例结果。
如图3所示，给与LPS后，小鼠生存率随时间推移而降低，但本发明物质(痘苗病毒接种炎症皮肤提取物制剂、商品名为“神经促进素”Neurotropin)给药组可观察到明显的对LPS诱发致死的抑制作用。和图1所示的培养内皮细胞培养实验一样，通过动物实验确证了本发明物质对LPS诱发致死的抑制作用。
(4)对LPS诱发低血压的改善作用
雄性费歇尔系大鼠(230～250g)以戊巴比妥(40mg/kg)腹腔给药麻醉，为测定血压和心跳以及给与本发明物质，作动脉插管。血压和心跳次数稳定以后，静脉给与本发明物质(60mg/kg)或生理盐水(对照组)。30分钟后给与LPS(15mg/kg)，3小时内每隔10分钟测定一次血压。
暴露在LPS下的大鼠平均动脉血压在给与LPS后40分钟左右开始下降，1小时半至2小时半时约下降20％，与此相对，痘苗病毒接种炎症皮肤提取物制剂的给药组不发生血压下降，并仅观察到5％程度的血压上升。
从上述药理实验结果可以看出，针对内毒素(脂多糖：LPS)引起的细胞和动物致死，作为本发明医药组合物的有效成分的痘苗病毒接种炎症组织提取物具有优良的防御作用；此外对于内毒素诱发的一氧化氮过量生成，本品也有显著的抑制作用。发生内毒素休克时血压急剧下降，提示内毒素诱发血管内皮细胞产生过量的一氧化氮；从上述LPS诱发低血压的药理实验来看，对一氧化氮生成有抑制作用的本发明物质对LPS给与后的血压下降有对抗作用，确认具有维持正常血压的良好作用。虽以上述药理实验(内毒素诱发致死抑制作用、一氧化氮生成抑制作用、LPS诱发低血压的改善作用)中的一例实验结果进行说明，但可以确认除市售痘苗病毒接种炎症皮肤提取物制剂之外，特公昭63-39572号公报中实施例记载的提取物、特公昭63-25600号公报实施例记载的提取物、特公平3-43279号公报实施例记载的提取物等其它各种的痘苗病毒接种炎症组织提取物等也具有这种同样的作用。
在败血症和其它严重细菌感染中产生了内毒素(细胞内毒素)，由于其作用引起休克症状。因此，如上所述对内毒素诱发毒性有优良抑制作用的本发明物质对于内毒素为诱因的休克症状、败血症以及伴随着的其它症状的治疗和预防非常有价值。此外，由于本发明物质对于病态时异常的一氧化氮生成有抑制作用，所以它作为与过量一氧化氮生成有关的疾病，例如急性的低血压等的治疗和预防药物是有用的。
[实施例]
作为本发明药品组成物有效成分的痘苗病毒接种炎症组织提取物，可以和适当的药用载体或稀释剂组合制成药品，可以以通常的生产方法使之制剂化，可以用于口服或非口服给药而以固体、半固体、液体或气体剂形处方。在处方的时候，可以单独应用本发明物质或以适当组合应用，此外也可以和其它药物活性成分组成复方应用。
制作注射剂时，可以和水性溶剂或非水性溶剂，例如注射用蒸馏水、生理盐水、Ringer’s液、植物油、合成脂肪酸甘油酯、高级脂肪酸酯、丙二醇等作成溶液或混悬液，从而使之制剂化。
作为口服给药制剂，可以以原型或适当干燥或者加入适当的添加剂，例如乳糖、甘露糖醇、玉米淀粉、马铃薯淀粉等常用的赋形剂，同时与结晶纤维素、纤维素衍生物、阿拉伯胶、玉米淀粉、明胶等粘合剂，玉米淀粉、马铃薯淀粉、羧早基纤维素钾等崩解剂，滑石、硬脂酸镁等润滑剂，其它的填充剂、湿润化剂、缓冲剂、防腐剂、香料等适当组合，作成片剂、散剂、颗粒剂或胶囊剂。此外，与疾病种类相适应，也可作成对其最适治疗的上述之外的剂形，例如栓剂、吸入剂、气雾剂、点眼剂、软膏、泥敷剂等。
附图的简要说明
[图1]
表示本发明物质对LPS所致内皮细胞致死抑制效果图。
[图2]
表示本发明物质对LPS所致一氧化氮过量生成抑制作用图。
[图3]
表示本发明物质对LPS给药引起的小鼠致死的抑制作用的图。

Claims (20)

1.痘苗病毒接种炎症组织提取物在制备一氧化氮生成抑制剂中的应用。
2.根据权利要求1记载的应用，所说的炎症组织为皮肤组织。
3.根据权利要求2记载的应用，所说的炎症动物组织为哺乳动物的皮肤组织。
4.根据权利要求1至3中任一项记载的应用，所述抑制剂为注射剂。
5.根据权利要求1至3中任一项记载的应用，所述抑制剂为口服制剂。
6.痘苗病毒接种炎症组织提取物在制备败血症治疗剂中的应用。
7.根据权利要求6记载的应用，所说的炎症组织为皮肤组织。
8.根据权利要求7记载的应用，所说的炎症动物组织为哺乳动物的皮肤组织。
9.根据权利要求6至8中任一项记载的应用，所述的治疗剂为注射剂。
10.根据权利要求6至8中任一项记载的应用，所述的治疗剂为口服制剂。
11.痘苗病毒接种炎症组织提取物在制备抗内毒素剂中的应用。
12.根据权利要求11记载的应用，所说的炎症组织为皮肤组织。
13.根据权利要求12记载的应用，所说的炎症动物组织为哺乳动物的皮肤组织。
14.根据权利要求11至13中任一项记载的应用，所述的药剂为注射剂。
15.根据权利要求11至13中任一项记载的应用，所述的药剂为口服制剂。
16.痘苗病毒接种炎症组织提取物在制备的内毒素休克治疗剂中的应用。
17.根据权利要求16记载的应用，所说的炎症组织为皮肤组织。
18.根据权利要求17记载的应用，所说的炎症动物组织为哺乳动物的皮肤组织。
19.根据权利要求16至18中任一项记载的应用，所述的治疗剂为注射剂。
20.根据权利要求16至18中任一项记载的应用，所述的治疗剂为口服制剂。
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