CN1201391A - 应用氟吡氨酯预防和治疗与造血细胞系统损伤有关的疾病 - Google Patents
应用氟吡氨酯预防和治疗与造血细胞系统损伤有关的疾病 Download PDFInfo
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Abstract
本发明涉及氟吡氨酯或它的盐作为药物在预防和治疗与造血细胞系统如淋巴细胞损伤有关的疾病中的应用。特别重要的是治疗HIV感染患者/艾滋病患者。
Description
本发明涉及氟吡氨酯(flupirtine)或它的盐类作为药物在预防和治疗与造血细胞系统(例如淋巴细胞)损伤有关的疾病中的应用。
氟吡氨酯是一种已知的、明确的非阿片类镇痛剂，通过中枢神经系统发挥作用。
氟吡氨酯表现出的镇痛作用机制与阿片剂/类阿片镇痛剂不同〔Nickel，B.，《医学研究生杂志》(Postgrad Med J)，63期(增刊第3号)，19页(1987年)；Szelenyi，I.，Nickel，B.，Borke，H.O.，Brune K.，《英国药理学杂志》(Br.J.Pharmacol)，143期，89页(1989年)〕。电生理研究表明，氟吡氨酯能够在脊髓和脊髓上水平影响感受伤害活动〔Carisson，K.H.，Jurna，I.，《欧洲药理学杂志》(Eur.J.Pharmakol)，143期，89页(1987年)；Bleyer，H.，Carlsson，K.H.，Erkel，H.J.，Jurna，I.，《欧洲药理学杂志》151期，259页(1988年)；Nickel，B.，Aledter，A.，《医学研究生杂志》，63期(增刊第3号)，41页(1987年)〕。
氟吡氨酯还可以用于运动系统疾病导致的急性疼痛期间的治疗。
进一步，氟吡氨酯还成功地治疗了变性或风湿性疾病。
除了良好的镇痛作用，氟吡氨酯还具有松驰肌肉的特性。因此它也用于治疗肌肉紧张，或由肌肉紧张导致的疾病(DE 40 22 442)。
在研究氟吡氨酯对大鼠的肌松作用过程中，进一步发现兴奋性氨基酸N-甲基-D-天冬氨酸(NMDR)能够抑制氟吡氨酯的作用。由于这种NMDR拮抗作用，氟吡氨酯也适于治疗一些由NMDR介导的中枢神经系统疾病，例如脑缺血、神经变性疾病和癫痫发作(DE 43 27516)。
氟吡氨酯的化学名称是2-氨基-3-乙氧羰基氨基-6-(对氟苄基氨基)吡啶。氟吡氨酯和其药学适用盐类的合成方法已由专利DE 1795 858、DE 31 33 519和DE 34 16 609说明。
令人惊奇地是，现在发现氟吡氨酯能够抑制造血系统(例如淋巴细胞)细胞的细胞凋亡。
这一发现有希望打开用氟吡氨酯治疗一些与造血细胞系统损伤有关的疾病的希望，特别重要之处是治疗HIV感染患者/艾滋病人。
本发明将通过药理学研究阐述氟吡氨酯的新作用。
药理学研究
材料
马来酸氟吡氨酯〔2-氨基-3-乙氧羰氨基-6-(对氟苄基氨基)吡啶马来酸盐〕，用HIV-1病毒株HTLVIIIB制备的HIV-1-gp120(Popovic等，1984年)。通过聚丙烯酰胺凝胶电泳显示，制备的gp120制备物纯度大于95％〔Muller等，1988年〕。
抗逆转录病毒分析
HIV-1病毒的分析方法已有报道〔Sarin等，1987年〕。人T-淋巴母细胞系CEM(接种浓度：1×105个细胞/ml)的细胞悬浮在培养基中并用HIV-1病毒(HTLVIIIB株)感染，选择一个50％细胞培养感染剂量〔CCID50〕的50倍作为实验中所用的感染量。一个CCID50指悬浮细胞中每毫升细胞的50％被感染所用的感染剂量。1毫升培养液孵育5天。在感染前2小时把不同浓度的氟吡氨酯加至细胞中。通过3-〔4，5-二甲基噻唑-2-基〕-2，5-二苯四唑溴〔MTT〕比色分析法计算活细胞的数目〔Scudiero等，1988年〕，也可以用不久前分布的方法，通过ELISA读数仪测定〔Muller等，1991年〕。孵育后，未感染的CEM细胞进行2.16个，而感染的细胞则进行0.13个细胞分裂周期。
血液样本
人外周血的样本采自：(i)12个HIV-1感染的男性同性恋者〔平均年龄：35岁；年龄范围：22-43岁〕，(ii)8个健康的HIV-1血清学阴性的男性，但与上组患者年龄相近，有同样患病的危险因素〔平均年龄：30岁；年龄范围：23-35岁〕。根据美国疾病控制中心(CDC，1992年)的分类标准将患者分类。用HIV-1血清学阳性的患者与无症状的病毒携带者的血样进行研究(美国疾病控制中心标准：A1，A2意味着CD4细胞数是407个/μl，范围：209-698个/μl)。病史中无一例患者出现过肿瘤、有症状的感染，或者在采集血样10周前曾经接受过免疫抑制剂，例如可的松的治疗。
细胞制备及其处理
用Ficoll-Hypaque密度梯度液离心肝素化的血液，从中分离出单核细胞(MNC)并且浓缩〔Rossol等，1990年〕。0.5×106个细胞置于终容量为500μl的培养基中，所用的培养基是MEM-培养基，内含10mM HEPES缓冲液、2.6％碳酸氢钠、100单位/L青霉素、100μg/ml链霉素、10％胎牛血清(FCS)和1mM谷氨酸。需强调的是，分离之后要用化学物质立刻处理细胞。
用反应活性氧诱导细胞调亡
通过次黄嘌呤〔HX〕和黄嘌呤氧化酶〔XOD〕系统产生反应活性氧基〔Bruck等，1994年〕。
单核细胞在总容量为500μl的MEM培养基中悬浮24小时(如上描述)。
0-80mU/ml的黄嘌呤氧化酶和1mM次黄嘌呤加入这份细胞中。黄嘌呤氧化酶(Sigma公司，德国慕尼黑)浓度为90mU/ml时，90％以上的淋巴细胞出现凋亡。
除非特别地指出，下列试验中用的是10mU/ml黄嘌呤氧化酶和1mM次黄嘌呤。在这样的孵育条件下，大约50％的细胞出现凋亡。当检查某种化合物是否是一种潜在的细胞凋亡的抑制剂和/或刺激剂时，最好能保持这个50％的细胞凋亡比率。氟吡氨酯加主细胞中之前6小时加入产生氧基的系统，孵育1天后中止反应。
连续流式细胞仪做细胞分析
根据已经发表的方法(Schmid等，1994年)，用FACScan(Becton-Dickinson产品)连续流式细胞仪分析细胞的凋亡，细胞仪以488nm波长的氩激光激发。通过光学方法，结合前光散射检查细胞的大小〔FSC〕和垂直散射光检查细胞表面的成分〔SSC〕，来区分并且确定淋巴细胞。为了染色凋亡的单核细胞，要把这些细胞孵育在含20μg/ml的7-氨基放线菌素D(7-AAD)(Sigma产品)的PBS溶液中，置4℃黑暗中20分钟。然后，在染液中用连续流式细胞仪分析细胞。用650nm波长的滤过器检查7-氨基放线菌素D发出的红色荧光。
由于细胞膜的裂解，7-氨基放线菌素D穿透凋亡的细胞，通过插入过程进-步将DNA染色。用LYSIS II程序分析数据。
均道数转化成平均荧光强度、细胞大小和表面组成成分。
用TdT法和表面标记进行原位荧光标记
为了明确某一细胞亚群正在发生细胞的凋亡，以末端转移酶系统(TdT)处理细胞，应用Gorczyca等(1993年)的方法并稍做改进。悬浮细胞用PBS(Gibco产品)冲洗二次，然后用1％强度的多聚甲醛(Riedel de Haen产品)4℃下固定10分钟。用PBS液(已加入5％AB血清和0.5％牛血清白蛋白)冲洗二次后，将细胞沉集，并重新悬浮于加了0.5nM生物素-16-dUTP和25U末端转移酶系统的50μl的2.5mM氯化钴溶液中，再加入200mM卡可酸钾、25mM Tris-HCl和0.25mg/ml牛血清白蛋白成为缓冲液。根据制造商的用户指南(Boehringer Mannheim，Mannheim，FRG)，37℃下孵育30分钟。然后用PBS缓冲液(内含5％AB血清和0.5％牛血清白蛋白)冲洗二次，再悬浮于100μl含有5μg/ml荧光异硫氰酸盐(FITC)标记的生物素(细胞分析试剂纯度)的缓冲染液中。细胞另外用20μg/ml藻红素标记的单克隆抗CD3抗体(Becton-Dickinson产品)处理作同时的表面标记。
通过Halliwell(1987年)介绍的方法，用连续流式细胞仪确定荧光数量。
结果
用氟吡氨酯处理HIV-1感染的CEM细胞
CEM细胞用氟吡氨酯预处理2小时，然后保持非感染态；或者用HIV-1感染作为平行试验。
5天后就可以测得相关试验的细胞数目。图1显示，用氟吡氨酯处理后，非感染态细胞与感染培养基中的细胞浓度无显著性差异(P＞0.1)。
试验中加入氟吡氨酯的终浓度是0.1-30μg/ml。非感染试验组中的细胞浓度是446,880±31,020个/ml，而HIV-1感染组的细胞浓度是108,420±6,710个/ml。
该结果说明，氟吡氨酯对细胞无毒性作用，而且在所实施的孵育条件下，体外不影响HIV-1的感染。
次黄嘌呤/黄嘌呤氧化酶系统的调节
要选择合适的黄嘌呤氧化酶的浓度，使凋亡的细胞比率大约为50％。
凋亡的细胞显示出的荧光强度大于10个任意均道数。黄嘌呤氧化酶浓度为0时，只有6.6±2.1％的细胞超过这个大于10个任意均道数的界线，即6.6％的细胞出现凋亡。随着黄嘌呤氧化酶浓度的增加，凋亡细胞的比率也增加。当黄嘌呤氧化酶浓度为80mU时，凋亡的细胞达到93.2±6.8％；当黄嘌呤氧化酶浓度为10mU时，大约有50％(准确说是54.6±6.1％)的细胞出现凋亡。
缺乏黄嘌呤氧化酶时，细胞出现以下细胞大小/表面组成(FSC/SSC)的分布形式：细胞大小是349±27(任意均道数)，表面组成是112±15。当黄嘌呤氧化酶浓度是80mU时，细胞变小到256±22，而表面组成则增加至180±29。这种基于细胞形态学的改变表明了一种特征性的细胞凋亡。当黄嘌呤氧化酶浓度是10mU时，细胞出现的分布形式则介于上述提到的2个极端数值之间。除非特别地指出，一般使用黄嘌呤氧化酶的浓度是10mU。
氟吡氨酯对人淋巴细胞自发凋亡率的影响
检查健康人和HIV-1感染患者的外周血中单核细胞的的自发凋亡。采集血样一天后进行细胞分析。正如图2所示，此时对照组非感染者的单核细胞有6.32±0.82％出现凋亡，而HIV-1感染患者的细胞则有28.42±7.84％出现凋亡。两组的单核细胞均用0.1-30μg/ml浓度的氟吡氨酯处理了24小时。如图2的总结，对健康人和HIV-1感染患者来说，氟吡氨酯并不能明显改变淋巴细胞自发凋亡率(p＞0.1)。
氟吡氨酯减少单核细胞的诱导凋亡
用次黄嘌呤/黄嘌呤氧化酶系统(形成氧基)处理健康人和HIV-1感染患者的单核细胞来诱导细胞的凋亡。在诱导之前6小时，把不同浓度的氟吡氨酯加入细胞培养基中。正如图3所示，0.1-3.0μg/ml浓度的氟吡氨酯明显减少了细胞的凋亡(p＜0.001)。氟吡氨酯浓度为10μg/ml时，仅仅对HIV-1患者的淋巴细胞有明显的保护作用。氟吡氨酯浓度为0.3-3.0μg/ml时，药物的保护作用最显著，对细胞诱导凋亡的抑制作用也最强。本实验中，对健康人的淋巴细胞大约减少了40％诱导的凋亡，而对HIV-1感染患者则减少了大约60％。
应用DNA-断裂法也可以检测到淋巴细胞的凋亡。细胞与黄嘌呤/黄嘌呤氧化酶(HX/XOD)系统孵育后，提取细胞中的DNA，根据分子大小在琼脂糖凝胶中分离并进一步转移到印迹上。
DNA断裂为180及其成倍碱基对的梯形片断模式，这种片断模式是细胞凋亡过程中DNA遭到破坏的典型结构(Wyllie，1980年)。相反，用1μg/ml氟吡氨酯处理过的细胞未出现任何DNA片断。
同样得到了代表性的斑点印迹，表明了氟吡氨酯对进行自发凋亡和诱导凋亡的细胞的作用效果。
为了完成这一系列的实验，要使用次黄嘌呤/20mU黄嘌呤氧化酶系统诱导单核细胞凋亡。在没有经过氟吡氨酯处理时，有64.2±7.9％的细胞出现凋亡。然而，当细胞用氟吡氨酯处理24小时以后，凋亡细胞的比率明显下降至18.3±5.8％。
这些结果清楚地表明：氟吡氨酯是一种很有希望地可用于治疗艾滋病患者淋巴细胞诱导凋亡的药物。
DE-A-43 27 516阐明了氟吡氨酯的神经保护作用，例如在脑缺血、早老性痴呆、帕金森氏病和由于感染如AIDS脑病或Creutzfeld-Jakob综合征导致的神经变性疾病中的作用。
伴有进行性痴呆的AIDS脑病是艾滋病的一种神经系统并发症。认为AIDS脑病的发病原因之一是HIV(gp-120)诱导NMDR激动性神经毒素如喹啉酸从感染的巨噬细胞中释放，最终导致神经细胞坏死。
AIDS脑病和艾滋病本身(获得性免疫缺陷综合征)可以累及不同的器官系统。前者已如上所述，是艾滋病的一种神经系统并发症(神经细胞的凋亡)，后者则是基于细胞免疫功能紊乱而出现了T细胞数目的明显减少(造血细胞系统中一种细胞成分的凋亡)。
本发明的氟吡氨酯的作用，即抑制造血细胞系统如淋巴细胞的诱导凋亡的最引人惊异之处在于，迄今为止尚未报告存在于中枢神经系统之外的NMDA受体。因此，即使是本领域熟练技术人员也不可能由氟吡氨酯对神经细胞的保护作用，而预知到它对造血细胞系统的细胞也有保护作用。
根据本发明中氟吡氨酯的作用，它还可以预防或治疗其它疾病，例如：
-药物(如细胞生长抑制剂和可的松类)、毒物、射线或其它疾病导致的中性粒细胞减少症/淋巴细胞减少症，
-药物或感染(如HIV感染)导致的血小板减小症。
氟吡氨酯用于预防和治疗给药可以采取已知的下面一些剂型：
片剂、膜衣片剂、硬胶囊、软胶囊、丸剂、颗粒剂、糖衣片剂、栓剂、微胶囊、水质或油质悬液、油质溶液、肌肉注射液和静脉内注射液。
用于制备药物的适用盐是所有可与氟吡氨酯生理匹配的盐类，例如氟吡氨酯的盐酸盐、马来酸盐、硫酸盐和葡萄糖酸盐。
本发明的药品中氟吡氨酯的含量是0.1mg-3000mg，最好是10mg-500mg。所述药物的单一剂量可分每日1-5次给药，最好1-3次。
指定的给药剂量都是指氟吡氨酯的量，如果使用的是氟吡氨酯的盐类化合物，则必须考虑到分子量的转换。
根据本发明的化合物可以通过常规的制药标准方法制备，例如，氟吡氨酯与赋形剂和/或辅助剂一般在20℃-80℃，最好是20℃-50℃温度下通过搅拌或均质化完全地混合。
附图说明
图1
将非感染的〔○表示〕和HIV-1感染的CM细胞〔●表示〕与不同浓度的氟吡氨酯孵育。给出的是10次平行试验得到的平均值，标准差不超过10％。
图2
氟吡氨酯对未感染者〔空白条形图表示〕与HIV-1感染患者〔斜线条形图表示〕的淋巴细胞自发凋亡的影响。采集血样1天后，通过连续流式细胞仪做细胞分析。检查的淋巴细胞来自12个HIV-1感染患者和8个未感染者。平均值和标准差已标明。
图3
用氟吡氨酯处理后的淋巴细胞减少了诱导凋亡。通过次黄嘌呤/黄嘌呤氧化酶系统诱导未感染者〔空白条形图表示〕和HIV-1感染患者〔斜线条形图表示〕的单核细胞凋亡，在加入这一氧基产生系统前6小时把氟吡氨酯加至细胞中，1天后通过连续流式细胞仪分析细胞。先确定总的凋亡细胞比率，从中减去的是自发凋亡的细胞比率。因此图中所示的数值表明了诱导凋亡的程度。检查的淋巴细胞来自12个HIV-1感染的患者和8个未感染者，平均值和标准差已标明。
Claims (3)
1.活性化合物氟吡氨酯或其药学上适用的盐在制备一种治疗与造血细胞系统损伤有关的疾病的药物中的应用。
2.根据权利要求1的活性化合物氟吡氨酯或其药学上适用盐的应用，所述药物用于治疗HIV-1感染患者/艾滋病患者。
3.根据权利要求1的应用，其特征在于氟吡氨酯或其盐与药学上适宜的赋形剂和/或辅助物结合形成一种合适的给药形式。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19625582A1 (de) * | 1996-06-27 | 1998-01-02 | Asta Medica Ag | Verwendung von Flupirtin zur Prophylaxe und Therapie von Erkrankungen die mit einer unphysiologisch hohen Zellsterberate einhergehen |
| US6821995B1 (en) | 1999-12-01 | 2004-11-23 | Duke University | Method of treating batten disease |
| DE10327674A1 (de) | 2003-06-20 | 2005-01-05 | Awd.Pharma Gmbh & Co. Kg | Injizierbare Darreichungsform von Flupirtin |
| EP1688141A1 (en) * | 2005-01-31 | 2006-08-09 | elbion AG | The use of flupirtine for the treatment of overactive bladder and associated diseases, and for the treatment of irritable bowel syndrome |
| US20080279930A1 (en) * | 2007-05-07 | 2008-11-13 | Bernd Terhaag | Controlled-Release Flupirtine Compositions, Compacts, Kits and Methods of Making and Use Thereof |
| DE102009023162B4 (de) * | 2009-05-29 | 2011-07-07 | Corden PharmaChem GmbH, 68305 | Verfahren zur Herstellung von Flupirtin |
| EP2462253B1 (en) * | 2009-08-07 | 2021-04-07 | Swagelok Company | Low temperature carburization under soft vacuum |
| DE102010030053A1 (de) | 2010-06-14 | 2011-12-15 | Awd.Pharma Gmbh & Co.Kg | Injizierbare Darreichungsform von Flupirtin |
| MX2014010460A (es) * | 2012-03-02 | 2014-10-13 | Meda Pharma Gmbh & Co Kg | Formulaciones farmaceuticas que contienen flupirtina. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IN172468B (zh) * | 1990-07-14 | 1993-08-14 | Asta Medica Ag | |
| DE4327516A1 (de) * | 1993-08-17 | 1995-02-23 | Asta Medica Ag | Primäre und sekundäre neuroprotektive Wirkung bei neurodegenerativen Erkrankungen von Flupirtin |
-
1995
- 1995-11-07 DE DE19541405A patent/DE19541405A1/de not_active Ceased
-
1996
- 1996-10-18 ZA ZA968783A patent/ZA968783B/xx unknown
- 1996-10-23 JP JP9517734A patent/JPH11514652A/ja active Pending
- 1996-10-23 DE DE59611327T patent/DE59611327D1/de not_active Expired - Lifetime
- 1996-10-23 BR BR9611588A patent/BR9611588A/pt not_active Application Discontinuation
- 1996-10-23 RU RU98111152/14A patent/RU2200555C2/ru not_active IP Right Cessation
- 1996-10-23 KR KR10-1998-0703376A patent/KR100512673B1/ko not_active IP Right Cessation
- 1996-10-23 ES ES96945822T patent/ES2257755T3/es not_active Expired - Lifetime
- 1996-10-23 PT PT96945822T patent/PT859613E/pt unknown
- 1996-10-23 WO PCT/DE1996/002009 patent/WO1997017072A2/de active IP Right Grant
- 1996-10-23 CN CN96198131A patent/CN1116037C/zh not_active Expired - Fee Related
- 1996-10-23 CZ CZ0128398A patent/CZ298115B6/cs not_active IP Right Cessation
- 1996-10-23 AT AT96945822T patent/ATE316789T1/de active
- 1996-10-23 PL PL96326629A patent/PL186537B1/pl not_active IP Right Cessation
- 1996-10-23 DK DK96945822T patent/DK0859613T3/da active
- 1996-10-23 UA UA98062946A patent/UA51682C2/uk unknown
- 1996-10-23 SK SK586-98A patent/SK284601B6/sk not_active IP Right Cessation
- 1996-10-23 HU HU9901659A patent/HU225742B1/hu not_active IP Right Cessation
- 1996-10-23 EP EP96945822A patent/EP0859613B1/de not_active Expired - Lifetime
- 1996-10-23 NZ NZ330414A patent/NZ330414A/en unknown
- 1996-10-23 AU AU17165/97A patent/AU711207B2/en not_active Ceased
- 1996-11-04 TW TW085113437A patent/TW393317B/zh not_active IP Right Cessation
- 1996-11-06 CA CA002189705A patent/CA2189705C/en not_active Expired - Fee Related
- 1996-11-07 US US08/744,953 patent/US6034111A/en not_active Expired - Lifetime
-
1998
- 1998-04-16 US US09/061,099 patent/US6034112A/en not_active Expired - Lifetime
- 1998-04-24 BG BG102404A patent/BG63149B1/bg unknown
- 1998-04-27 NO NO19981898A patent/NO315074B1/no not_active IP Right Cessation
- 1998-05-07 MX MX9803610A patent/MX9803610A/es not_active IP Right Cessation
-
1999
- 1999-04-21 HK HK99101726A patent/HK1016508A1/xx not_active IP Right Cessation
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