CN1207042A - 用于治疗自身免疫性疾病的药物组合物 - Google Patents
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Abstract
一种包含可抑制细胞因子生成的抗炎药(CSAID),免疫抑制剂和药学允许的填充剂的药物组合物。
Description
本发明涉及一种包含可抑制细胞因子生成的抗炎药(CSAID),免疫抑制剂和药学允许的填充剂的药物组合物。
众所周知,自身免疫性疾病具有炎症和在免疫系统作用下机体自身的抗体产生导致的组织损伤等一系列病理特征。在自然界中认定为自身免疫的疾病有:风湿性关节炎,肾小球性肾炎,淋巴瘤性甲状腺肿,全身性红斑狼疮,重症肌无力,自身免疫性溶血性贫血,自身免疫性血小板减少性紫癜,自身免疫性紊乱和1型糖尿病。
目前,在自身免疫性疾病的治疗中应用甾体和非甾体抗炎药,金化合物,青霉素和免疫抑制剂。
非甾体抗炎药(NSAID)在具有抗炎活性的同时,也具有解热和非麻醉性止痛的效果。它们广泛应用于治疗急性炎症和慢性炎症。因此它们目前应用于治疗自身免疫性疾病,这类疾病中炎症过程是非常重要的。即便不排除其它的作用机制,它们的活性主要在于能够抑制用于合成前列腺素(PG)和白三烯的酶,尤其是环氧合酶和脂氧酶的活性。这个作用机制也是在不同的组织(主要是胃肠的和肾的)中产生副作用的主要原因,这些副作用是上述药物长期使用的必然结果。
此外,对于自身免疫性疾病的急性期中抗炎药物对主要症状的影响,非甾体类药物例如,环磷酰胺,具有最重要的疗效。
然而这种药物不能长时间持续使用,因为不同类型副作用的出现会导致严重的副作用。
实际上,由于对组织或全身的毒性,20%的病人需要在12个月内停止治疗。停药持续的时间可大不相同(平均1~18个月)。而且,尽管第二个及通常第三个治疗周期能有积极的效果,超过50%的最初进行治疗的病人由于复发和/或后来的毒性必须在3~6年后停止治疗。最常见的受损伤的组织是肾、肝、血液和生殖器官。
因此,在自身免疫性疾病的治疗中毒性对于药物的应用是一个严重的障碍,所以很需要一种能够降低在上述治疗中应用的药物的非期望的副反应的产品,从而减少给药剂量或数量。
最近,已发现一些化合物在转录或翻译水平上能以不同的作用机制通过调节免疫应答细胞产生细胞因子的能力影响免疫系统的活性。此外,众所周知细胞因子,特别是称作前炎性细胞因子(肿瘤坏死因子,白细胞介素-1和6)参与了维持以及有时是诱导炎症。上面提到被称作CSAID(抗炎性抑制细胞因子药物)的化合物与传统的抗炎药不同,因为它对那些调节花生四烯酸代谢的酶没有活性,而且不抑制免疫应答细胞的增殖和B细胞中免疫球蛋白的分泌(1,2)。再有,它们在炎症急性期活性并不很高而主要在炎症过程的第二期有活性。
典型的CSAID有SK和F 86002(2,3),普尼达替(tenidap)(4),BB 2284(5),GI 129471(6),已酮可可碱(7),vivigrol(8),苏拉明(9),酞胺哌啶酮(反应停)(10),罗扎利特(romazarit)(11)和又被称作AF 2838或2-((1-苄基-吲唑-3-基)-甲氧基)-2-甲基丙炔酸(12)的宾达利特(bindarit)。
现在,我们意外地发现CSAID能降低在自身免疫性疾病的长期治疗中免疫抑制剂的用量,而不降低治疗效果并由此提高了耐受性。
因而,本发明的第一个目的是提供一种包含可抑制细胞因子生成的抗炎药(CSAID),免疫抑制剂和药学允许的填充剂的药物组合物。
此外,本发明的第二个目的是提供一种治疗自身免疫性疾病的方法,其特征在于同时应用能抑制细胞因子生成的抗炎药(CSAID)和免疫抑制剂。
本发明中典型的免疫抑制剂有环孢菌素,硫唑嘌呤,氨甲嘌呤,环磷酰胺,FK506,氢化可的松,倍他米松,可的松,地塞米松,9-去氟肤轻松,泼尼松龙,甲基泼尼松龙,去氢可的松,去炎松,阿氯米松,安西奈德丙缩羟强龙和去氧米松。
可以用CSAID和免疫抑制剂同时治疗的典型的疾病有风湿性关节炎,肾小球性肾炎,淋巴瘤性甲状腺肿,全身性红斑狼疮,重症肌无力,自身免疫性溶血性贫血,自身免疫性血小板减少性紫癜,自身免疫性肝炎和1型糖尿病及类似的疾病。
CSAID的用量范围依赖于本领域技术人员所熟知的因素例如,自身免疫性疾病的类型,上述疾病的严重程度,病人的体重,药物的剂型,给药方式,每日给药的次数及所用化合物的药效。然而,理想的用量可以通过常规的“剂量寻找(dose-finding)”程序很方便地测定出来。
通常,CSAID化合物的用量应该保持给药水平在0.01~100mg/kg/日之间。
例如,以Bindarit为例,为1~50mg/kg/日,更优选4~35mg/kg/日。
免疫抑制剂的用量范围也依赖于本领域技术人员所熟知的因素例如,自身免疫性疾病的类型,上述疾病的严重程度,病人的体重,药物的剂型,给药方式,每日给药的剂量及所用化合物的药效。然而,理想的用量可以通过常规的程序很方便地测定出来,尤其应参考文献(Goodman andGilman第8版)中大家熟知的免疫抑制剂的通常的用量。
一般来说,免疫抑制剂的用量也应该保持给药水平在0.01~100mg/kg/日之间。
例如,以环磷酰胺为特例,它应比通常用量低30%~40%。因此,优选0.01~10mg/kg/日。更优选0.05~5mg/kg/日。
对于泼尼松,用量也应该比通常用量低30%~40%。因此,优选0.01~1mg/kg/日。更优选,0.05~0.5mg/kg/日。
合适的剂型有片剂、胶囊剂、包衣片剂、颗粒剂、溶液剂和口服糖浆、凝胶剂、软膏剂、霜剂和局部给药用贴剂、直肠给药的栓剂和灭菌的注射液、气雾剂和滴眼剂。
除常用的赋形剂外,组合物还可包含药用的合适的添加剂,如防腐剂、稳定剂、表面活性剂、乳化剂、调节渗透压的盐、缓冲剂、香料和色素。
剂型中还包括脂质体、囊泡和其它用于控制释放具有药理活性的化合物的剂型。此外,还可以将它们做成包含各个具有不同崩解速度的片层的复压片剂。
根据特殊治疗的需要,本发明涉及的组合物还可以包含其它同时给药时有治疗用途的组分。
药物组合物可以按照药物化学家的常规技术进行生产,包括混合、造粒和压缩,需要时可根据所需的化合物来混合和溶解各种适当的组分。
实施例
1.Bindarit用作CSAID
Bindarit对炎症细胞因子的产物的影响已在小鼠模型上进行了评价。其中,在注射了伴刀豆球蛋白A(0.3毫克/小鼠静注)后,分别测量对照组和口服200mg/kg bindarit组动物的血浆中白细胞介素-6(IL-6)的浓度。实验结果(表1)显示服用bindarit的动物IL-6血浆浓度比未服用的对照组低大约40%(10.2±2.1vs.16.5±6.4ng/ml,每组6只动物)。
由于Bindarit的具有降低炎症因子产物的能力,它可以作为CSAID药物,我们已经知道bindarit缺乏免疫抑制活性并且对环氧合酶和脂氧酶也没有活性(13)。
2.Bindarit和环磷酰胺在红斑狼疮的小鼠模型中
NZB/W F1杂交小鼠能自发产生一种在临床和免疫学上与人全身性红斑狼疮(SLE)相似的自身免疫性疾病。这个SLE的动物模型似乎是高度预测性的并且通常用作研究新治疗方法的临床前模型。用于人体治疗的常规药物,实际上在这一动物模型上具有活性。模型的特征是具有严重的蛋白尿,存在自身抗体和循环免疫复合物以及肾小球性肾炎的增加。它们是这些动物主要的致死因素。免疫抑制剂如环磷酰胺和泼尼松能够延缓病理过程,然而它们的治疗效能受到它们通常的毒性和高肿瘤生成率以及用药导致的病毒感染的限制。
以药用食物的方式对NZB/W F1雌性小鼠(每组26只)给药,其中bindarit的含量为0.5%,bindarit的血药浓度可达50~200微克/ml(通过反相HPLC检测),同时给予低剂量的环磷酰胺bola(2×22.5和2×45mg/kg腹膜给药),证实与使用大剂量环磷酰胺时的活性相同,因此可以减少免疫抑制治疗中的毒性现象。实际上,bindarit和环磷酰胺一起使用,可以显著延长动物的生命(表2)并且可以加强环磷酰胺对这一动物模型中免疫学参数的影响(表3),明显改善对照组和给予大剂量(2×90mg/kg腹膜给药)环磷酰胺bola组动物的病理过程。
这些结果证明bindarit可以降低免疫抑制剂的用量并由此减少限制它们在这类病理学中应用的毒性现象。
3.Bindatir和皮质甾醇应用于人体
10名患有III类和IV类(依WHO分类)狼疮性肾炎的患者(8男2女,17至60岁),用一天两次的bindarit(600mg)和泼尼松(5mg,一天两或三次)治疗8周。在治疗开始和结束时测量尿中UAE(尿白蛋白分泌物)和白细胞介素-6(IL-6)的含量。在研究结束时,UAE浓度是开始时的60%左右,而开始时尿中的IL-6的浓度为200和500pg/ml的患者的IL-6浓度为10pg/ml左右。这些结果显示bindarit可显著降低使用皮质甾醇的全身性红斑狼疮患者的肾炎并发症的严重程度。
表1
Bindarit对伴刀豆球蛋白A诱导的IL-6生成的影响
治疗 | ng/ml | 抑制率 |
伴刀豆球蛋白A | 16.5±6.4 | |
bindarit | 10.2±2.1 | 38.2 |
表2
对存活期限的影响
治疗 | 平均值(天) | 增加天数(天) |
对照组 | 254 | |
环磷酰胺(22.5) | 259 | 4 |
环磷酰胺(45) | 294 | 40 |
环磷酰胺(90) | 330 | 76* |
bindarit | 387 | 133* |
bindarit+环磷酰胺(22.5) | 408 | 154* |
bindarit+环磷酰胺(45) | 403 | 149* |
*P值小于0.001,LogRank试验测定Kaplan-Meier值
表3
对蛋白尿峰值的影响
治疗 | 平均值(月) | p-值vs.对照组* |
对照组 | 7 | |
环磷酰胺(22.5) | 8 | n.s. |
环磷酰胺(45) | 9 | 0.0018 |
环磷酰胺(90) | 10 | 0.00006 |
bindarit | 9 | 0.0078 |
bindarit+环磷酰胺(22.5) | 9 | 0.0168 |
bindarit+环磷酰胺(45) | 10 | 0.00006 |
*以Mann-Whitney校正试验进行多重比较
文献目录1.Lee J.C.et al.Ann.N.Y.Acad.Sci.696:149-170,1993.2.Lee J.C.et al.Nature 372:739-746,1994.3.Griswold D.E.et al. Drugs Exp.Chim.Res.19:243-248,1993.4.Mcniff P.A.et al.Cytokine 7:196-208,1995.5.Gearing A.J.H.et al.Nature 370:555-557,1994.6.Mcgeehan G.M.et al.Nature 370:558-561,1994.7.Dezabe B.J.et al.Cancer Immun.Immunother.36:57-60.1993.8.WO 91/07953.9.EP-A-O 486 809.10.Moreira A.L.et al.J.Exp.Med.177:1675-1680,1993.11.Self C.R.et al.J.Med.Chem.34:772-777,1991.12.US-A-5 278 183.13.Cioli V.et al.J.Rheumatol.19:1735-1742,1992.
Claims (8)
1.一种包含可抑制细胞因子生成的抗炎药-CSAID,免疫抑制剂和药学允许的填充剂的药物组合物。
2.如权利要求1中所述的药物组合物,其特征在于,CSAID化合物选自SK & F86002,普尼达替,BB2284,GI129471,己酮可可碱,vivigrol,苏拉明,反应停,罗扎利特和宾得利特。
3.如权利要求1和2中任何一项所述的药物组合物,其特征在于免疫抑制剂选自环孢菌素,硫唑嘌呤,氨甲嘌呤,环磷酰胺,FK506,氢化可的松,倍他米松,可的松,地塞米松,9-去氟肤轻松,泼尼松龙,甲基泼尼松龙,去氢可的松,去炎松,阿氯米松,安西奈德丙缩羟强龙和去氧米松。
4.如权利要求1至3中任何一项所述的药物组合物,其特征在于含有的CSAID的用量能保持给药浓度为0.01~100mg/kg/日。
5.如权利要求1至4中任何一项所述的药物组合物,其特征在于含有的免疫抑制剂的用量能保持给药水平为0.01~100mg/kg/日。
6.如权利要求2所述的药物组合物,其特征在于含有的宾得利特的用量能保持给药水平为1~50mg/kg/日。
7.如权利要求3所述的药物组合物,其特征在于含有的环磷酰胺的用量能保持给药水平为0.01~10mg/kg/日。
8.如权利要求3所述的药物组合物,其特征在于含有的泼尼松的用量能保持给药水平为0.01~10mg/kg/日。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT95MI002242A IT1276031B1 (it) | 1995-10-31 | 1995-10-31 | Composizione farmaceutica per il trattamento delle malattie autoimmuni |
ITMI95A002242 | 1995-10-31 |
Publications (2)
Publication Number | Publication Date |
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CN1207042A true CN1207042A (zh) | 1999-02-03 |
CN1229113C CN1229113C (zh) | 2005-11-30 |
Family
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Application Number | Title | Priority Date | Filing Date |
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CNB96199472XA Expired - Lifetime CN1229113C (zh) | 1995-10-31 | 1996-10-26 | 用于治疗自身免疫性疾病的药物组合物 |
Country Status (27)
Country | Link |
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US (1) | US6020356A (zh) |
EP (1) | EP0858337B1 (zh) |
JP (1) | JP4007615B2 (zh) |
KR (1) | KR19990067237A (zh) |
CN (1) | CN1229113C (zh) |
AT (1) | ATE326965T1 (zh) |
AU (1) | AU721841B2 (zh) |
BR (1) | BR9611320B1 (zh) |
CA (1) | CA2236256C (zh) |
CZ (1) | CZ292258B6 (zh) |
DE (1) | DE69636167T2 (zh) |
DK (1) | DK0858337T3 (zh) |
EA (1) | EA000826B1 (zh) |
ES (1) | ES2264144T3 (zh) |
HK (1) | HK1018219A1 (zh) |
HU (1) | HU228051B1 (zh) |
IL (1) | IL124291A (zh) |
IT (1) | IT1276031B1 (zh) |
MX (1) | MX9803478A (zh) |
NO (1) | NO324130B1 (zh) |
NZ (1) | NZ321580A (zh) |
PL (1) | PL186377B1 (zh) |
PT (1) | PT858337E (zh) |
SK (1) | SK284069B6 (zh) |
TR (1) | TR199800765T2 (zh) |
WO (1) | WO1997016185A2 (zh) |
ZA (1) | ZA969060B (zh) |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
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US6323201B1 (en) | 1994-12-29 | 2001-11-27 | The Regents Of The University Of California | Compounds for inhibition of ceramide-mediated signal transduction |
IT1293795B1 (it) | 1997-07-28 | 1999-03-10 | Angelini Ricerche Spa | Farmaco attivo nel ridurre la produzione di proteina mcp-1 |
ES2335008T3 (es) * | 2003-04-24 | 2010-03-18 | Jagotec Ag | Comprimido con nucleo coloreado. |
US20080076743A1 (en) | 2006-08-03 | 2008-03-27 | Nitec Pharma Ag | Delayed-Release Glucocorticoid treatment of Rheumatoid Disease |
ITMI20062254A1 (it) * | 2006-11-24 | 2008-05-25 | Acraf | Uso di un acido metossi-alcanoico dell'indazolo per preparare una composizione farmaceutca |
EP2391369A1 (en) * | 2009-01-26 | 2011-12-07 | Nitec Pharma AG | Delayed-release glucocorticoid treatment of asthma |
EP2462119B1 (en) | 2009-08-03 | 2014-06-11 | Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.p.A. | Process for the preparation of 1-benzyl-3-hydroxymethyl-1H-indazole and its derivatives and required Magnesium intermediates |
UA108742C2 (uk) | 2009-09-23 | 2015-06-10 | Фармацевтична композиція для лікування запальних захворювань, опосередкованих mcp-1 | |
US8999292B2 (en) | 2012-05-01 | 2015-04-07 | Translatum Medicus Inc. | Methods for treating and diagnosing blinding eye diseases |
CA3095012C (en) * | 2012-05-01 | 2023-02-07 | Translatum Medicus Inc. | Methods for treating and diagnosing blinding eye diseases |
CA3144861A1 (en) | 2019-06-25 | 2020-12-30 | Translatum Medicus, Inc. | Processes of making 2-((1-benzyl-1h-indazol-3-yl)methoxy)-2-methylpropanoic acid and its derivatives |
Family Cites Families (6)
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JPH04506066A (ja) * | 1989-06-16 | 1992-10-22 | ジ・アップジョン・カンパニー | 脈管形成を抑制するためのスラミン・タイプの化合物および脈管形成抑止ステロイド類 |
IT1253703B (it) * | 1991-04-22 | 1995-08-23 | Angelini Francesco Ist Ricerca | Uso di acidi metossi alcanoici dell'indazolo per preparare un farmaco attivo nel trattamento di malattie autoimmunitarie |
US5770589A (en) * | 1993-07-27 | 1998-06-23 | The University Of Sydney | Treatment of macular degeneration |
WO1995004533A2 (en) * | 1993-08-04 | 1995-02-16 | Andrulis Pharmaceuticals Corporation | Treatment of rheumatoid arthritis with thalidomide alone or in combination with other anti-inflammatory agents |
US5434170A (en) * | 1993-12-23 | 1995-07-18 | Andrulis Pharmaceuticals Corp. | Method for treating neurocognitive disorders |
JPH10506632A (ja) * | 1995-05-10 | 1998-06-30 | ファイザー・インコーポレーテッド | 慢性関節リウマチを治療するためのメトトレキセートとテニダップとの組合せ物 |
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1995
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- 1996-10-26 KR KR1019980703195A patent/KR19990067237A/ko not_active Application Discontinuation
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