CN1265592A - 减少mcp-1蛋白产生的活性药性组合物 - Google Patents
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Abstract
式(Ⅰ)化合物和其与药物可接受的有机或无机碱的盐在制备治疗以MCP-1蛋白产生为特征的疾病的活性药物组合物中的用途。
Description
本发明涉及吲唑氧基链烷酸在制备治疗以MCP-1蛋白产生为特征的疾病的活性药物组合物中的用途。
另外,已知苄达酸和其与药物可接受碱的盐被用于治疗一些异常脂血症(US4352813)、色素性视网膜炎(EP-B-131317)和白内障(US4451477)。
苄达酸和其盐被批露用于预防接触透镜的浑浊化(EP255967)。
现已发现具有式(I)结构的化合物还在减少MCP-1蛋白产生中具有活性。
如所知,MCP-1蛋白(单核细胞趋化性蛋白-1)为属于趋化因子β亚家族的趋化因子。它对单核细胞具有强的趋化活性并作用于T淋巴细胞、肥大细胞和嗜碱性细胞。
属于β亚家族的其它趋化因子为例如MCP-2(单核细胞趋化蛋白-2)、MCP-3、MCP-4、MIP-1α、MIP-1β、RANTES和蛋白1309。
β亚家族在结构上不同于α亚家族;事实上,α亚家族的趋化因子的前面两个半胱氨酸被插入的氨基酸隔开,而β亚家族趋化因子的前面两个半胱氨酸却是彼此相邻的。MCP-1由数种类型的细胞(白细胞、血小板、成纤维细胞和内皮细胞)产生。
在所有已知的趋化因子中,MCP-1对于单核细胞和巨噬细胞显示最高的特异性,它对于它们不仅是一个吸引因子,而且是激活刺激剂,因此诱导产生过氧化物和花生四烯酸的过程,以及刺激吞噬细胞活性的放大。
通常趋化因子尤其是MCP-1的分泌常常由许多因子诱导,如白介素-1(IL-1)、白介素-2(IL-2)、TNFα(肿瘤坏死因子α)、γ-干扰素和细菌脂多糖(LPS)。
在人体中,MCP-1在许多被传统医学分在不同类别中的急性或慢性疾病中发现:例如间质性肺疾病(ILD)、脉管炎和动脉粥样硬化,和肾病,例如肾炎、肾炎综合症、特征为进行性增生的膜性或膜增生性肾小球肾炎的肾病。
在间质性肺疾病中,由肺内皮细胞释放的MCP-1吸引和激活感受态细胞,结果释放损伤肺的肺泡结构的介质。
在脉管炎中,在有害刺激后,MCP-1由脉管的内皮细胞释放,并且吸引和激活导致管壁损伤的单核细胞和其它细胞类型。
在动脉粥样硬化中,在血管平滑肌细胞损伤后,MCP-1由血管内皮细胞产生。MCP-1吸引单核细胞,使其起初粘附于动脉壁、接着迁移穿过血管壁,通过刺激平滑肌细胞的增殖导致动脉粥样化的形成。
在肾病中,致病机理特征是激素和细胞因子的活化,这些因子导致对肾小球和肾小管损伤的开始。尤其是,起始事件几乎总是以白细胞对肠的侵润为特征。这种现象被可溶性因子引发并控制,其中由于对单核细胞和巨噬细胞具有高特异性的趋化蛋白特征,MCP-1在该疾病中发挥重要的作用。
由于它们在病理学现象的上游起作用,目前用于这些疾病的疗法是非特异性,并且经常具有许多有时是非常严重的副作用。
而且上述疗法仅能获得暂时对病理现象的缓和,另一方面它们的高毒性阻碍了它们用于在慢性疾病中所必需的长期治疗。
尤其对于动脉粥样硬化,目前使用的药物仅对一些与形成动脉粥样化有关的因素起作用,如高胆固醇血症或高血压,而对病理过程的靶子即血管壁不起作用。
总的来说趋化因子尤其是MCP-1在手术介入后发生并发症的情况中也非常重要,例如血管成形术、动脉粥样硬化切除术、循环修复术、移植、器官置换、组织置换和假体植入。这些并发症的发生通常使得病人必需进行进一步深入的治疗或甚至是新的手术。
US5571713公开了体外抑制人单核细胞和平滑肌产生MCP-1的包含MCP-1反义寡核苷酸的组合物。
因此,仍强烈需要一种药物组合物,用于有效治疗以MCP-1产生为特征的疾病,例如动脉粥样硬化、脉管炎、间质性肺病、肾病、及心血管手术、移植或器官或组织置换和假体植入中的术后并发症。
以MCP-1蛋白产生为特征的疾病的典型实例为:动脉粥样硬化、脉管炎、间质性肺病、肾病、和心血管手术、移植或器官组织置换和假体植入的术后并发症。
优选地,本发明的药物组合物被制备成适宜的剂型,其中包含有效剂量的至少一种式(I)化合物或其与药物可接受有机或无机碱的盐和至少一种药物可接受的惰性成分。
适宜剂型的实例为用于口服给药的片剂、胶囊、包衣片剂、颗粒剂、溶液剂和糖浆;用于透皮给药的膏药贴片;用于直肠给药的栓剂和通过注射、气雾剂或眼途径给药的溶液剂。
其它适宜的剂型为用于口服或注射途径的缓释和脂质体形式。
制剂中还可包含其它常规成分,例如:稳定保存剂、表面活性剂、缓冲剂、调节渗透压的盐、乳化剂、甜味剂、着色剂、香味剂等。
如果特定的治疗需要,本发明的药物组合物可包含共同给药时对治疗有用的其它药理活性成分。
本发明的药物组合物中的式(I)化合物或其与药物可接受碱的盐的量可在宽范围内变化,其取决于已知的因素,例如所治疗疾病的类型、疾病的严重性、病人的体重、剂型、选择的给药途径、每天给药的次数和选择的式(I)化合物的功效。然而,本领域技术人员可容易地并常规性地确定其最佳量。
通常,本发明的药物组合物中的式(I)化合物或其与药物可接受碱的盐的量为确保给药水平为1-100mg/kg/天的量。优选给药水平为5-50mg/kg/天或更优选2-20mg/kg天。
本发明药物组合物的剂型可根据药剂师已知的技术制备,包括混合、成粒、压制、溶解、灭菌等。
本发明组合物的活性可通过下面的试验评价。
试验I
药物对MCP-1产生的影响
评价了药物降低LPS刺激的白细胞(PBMC)产生MCP-1的能力。通过在Ficoll梯度中离心分离白细胞,接着在存在或不存在标量浓度的待评价药物下用LPS刺激。最后收集上清液并通过特异性免疫酶试验测定MCP-1的水平。
试验II
药物对小鼠“气囊”中的细胞吸引的影响
在小鼠实验模型中研究了药物的作用,所述模型特征在于产生MCP-1、细胞浸润和渗出物的形成。用啮齿动物标准食物或用加入了待评价药物的相同食物以随意食水方式喂养小鼠。醚麻醉下,将无菌空气注射至小鼠的背侧皮肤以形成一个囊。将无菌的生理溶液或刺激剂注射至如此形成的囊中。所述刺激剂可为角叉菜或IL-1。用CO2窒息杀死小鼠。收集产生的渗出液并用于白细胞计数以及所产生介质的测定。
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Application Number | Priority Date | Filing Date | Title |
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IT97MI001788A IT1293794B1 (it) | 1997-07-28 | 1997-07-28 | Farmaco attivo nel ridurre la produzione di proteina mcp-1 |
ITMI97A01788 | 1997-07-28 |
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CN1265592A true CN1265592A (zh) | 2000-09-06 |
Family
ID=11377641
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN98807694A Pending CN1265592A (zh) | 1997-07-28 | 1998-07-22 | 减少mcp-1蛋白产生的活性药性组合物 |
Country Status (15)
Country | Link |
---|---|
US (1) | US6191158B1 (zh) |
EP (1) | EP0999836A1 (zh) |
JP (1) | JP2001510802A (zh) |
KR (1) | KR20010022333A (zh) |
CN (1) | CN1265592A (zh) |
AU (1) | AU9160298A (zh) |
BG (1) | BG104162A (zh) |
CA (1) | CA2298507A1 (zh) |
EA (1) | EA200000168A1 (zh) |
HU (1) | HUP0004936A3 (zh) |
IL (1) | IL134050A0 (zh) |
IT (1) | IT1293794B1 (zh) |
SK (1) | SK1332000A3 (zh) |
TR (1) | TR200000244T2 (zh) |
WO (1) | WO1999004791A1 (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ITMI20062254A1 (it) | 2006-11-24 | 2008-05-25 | Acraf | Uso di un acido metossi-alcanoico dell'indazolo per preparare una composizione farmaceutca |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3970194A (en) * | 1975-01-08 | 1976-07-20 | Philip Morris Incorporated | Razor blade cartridge and display article |
IT1147079B (it) * | 1980-05-30 | 1986-11-19 | Sigma Tau Ind Farmacuetiche Ri | Esteri di alcossi-acil derivati della carnitina procedimento per la loro preparatione e composizioni farmaceutiche che li contengono |
IT1131779B (it) * | 1980-07-29 | 1986-06-25 | Acraf | Sale dell'acido (1-benzil-1h-indazol-3-il)-ossiacetico con la lisina e procedimento per la sua preparazione |
IT1189052B (it) * | 1981-11-27 | 1988-01-28 | Acraf | Trattamento della cataratta |
IT1197805B (it) * | 1986-08-01 | 1988-12-06 | Acraf | Metodo per il tratamento di lenti a contatto |
-
1997
- 1997-07-28 IT IT97MI001788A patent/IT1293794B1/it active IP Right Grant
-
1998
- 1998-07-22 CA CA002298507A patent/CA2298507A1/en not_active Abandoned
- 1998-07-22 IL IL13405098A patent/IL134050A0/xx unknown
- 1998-07-22 EP EP98943863A patent/EP0999836A1/en not_active Withdrawn
- 1998-07-22 HU HU0004936A patent/HUP0004936A3/hu unknown
- 1998-07-22 KR KR1020007000912A patent/KR20010022333A/ko not_active Application Discontinuation
- 1998-07-22 CN CN98807694A patent/CN1265592A/zh active Pending
- 1998-07-22 SK SK133-2000A patent/SK1332000A3/sk unknown
- 1998-07-22 AU AU91602/98A patent/AU9160298A/en not_active Abandoned
- 1998-07-22 JP JP2000503846A patent/JP2001510802A/ja active Pending
- 1998-07-22 US US09/463,665 patent/US6191158B1/en not_active Expired - Fee Related
- 1998-07-22 EA EA200000168A patent/EA200000168A1/ru unknown
- 1998-07-22 WO PCT/EP1998/004925 patent/WO1999004791A1/en not_active Application Discontinuation
- 1998-07-22 TR TR2000/00244T patent/TR200000244T2/xx unknown
-
2000
- 2000-02-17 BG BG104162A patent/BG104162A/xx unknown
Also Published As
Publication number | Publication date |
---|---|
HUP0004936A3 (en) | 2002-01-28 |
TR200000244T2 (tr) | 2000-09-21 |
KR20010022333A (ko) | 2001-03-15 |
EP0999836A1 (en) | 2000-05-17 |
IL134050A0 (en) | 2001-04-30 |
ITMI971788A1 (it) | 1999-01-28 |
BG104162A (en) | 2000-12-29 |
IT1293794B1 (it) | 1999-03-10 |
HUP0004936A2 (hu) | 2001-11-28 |
SK1332000A3 (en) | 2000-12-11 |
AU9160298A (en) | 1999-02-16 |
EA200000168A1 (ru) | 2000-08-28 |
WO1999004791A1 (en) | 1999-02-04 |
JP2001510802A (ja) | 2001-08-07 |
US6191158B1 (en) | 2001-02-20 |
CA2298507A1 (en) | 1999-02-04 |
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