CN1326351A - 应用某些药物治疗神经根损伤 - Google Patents
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Abstract
本发明涉及用于治疗TNF-α释放引起的脊柱病症的药用组合物,该组合物包含有效量TNF-α抑制剂,本发明还涉及治疗这类病症的方法和应用TNF-α抑制剂制备用于所述治疗的药用组合物。
Description
技术领域
本发明涉及使用TNF-α抑制剂制备治疗神经根损伤的药用组合物以及治疗神经根损伤的方法。
本发明的目的是希望可通过阻断椎间盘有关的细胞因子治疗椎间盘突出(disk herniation)引起的神经根损伤,该损伤表现为手臂和腿(坐骨神经痛)的放射性疼痛。
发明背景
椎间盘突出是令人讨厌的病症,它可引起显著的疼痛和肌肉功能障碍并因此丧失工作能力。椎间盘突出可发生于脊柱的任何椎间盘,但腰椎和颈椎椎间盘突出最为常见。颈椎椎间盘突出可引起手臂的放射性疼痛和肌肉功能障碍,而腰椎椎间盘突出可引起腿部放射性疼痛和肌肉功能障碍。腿部放射性疼痛通常称作“坐骨神经痛”。椎间盘突出会引起不同程度的障碍,而疼痛可持续1个月或2个月或在严重情况下长达6个月。因为椎间盘突出发生的手臂或腿部疼痛可能非常强烈并可因此在患病期间影响患者个体的整个生活状况。
US-A-5,703,092公开了异羟肟酸化合物和碳环酸用作金属蛋白酶和TNF抑制剂,而且特别用于治疗关节炎和其它相关炎性疾病。未公开或暗示这类化合物用于治疗神经根损伤。
US-A-4,925,833公开了使用四环素促进骨蛋白的合成以及治疗骨质疏松。
US-A-4,666,897公开了用四环素抑制哺乳动物溶胶原酶。溶胶原活性表现为过度的骨重吸收、牙周病、类风湿关节炎、角膜溃疡或皮肤或其它结缔组织胶原的重吸收。
上述后两个文献均未提及神经根损伤或其治疗。
本发明的描述
目前令人惊奇地证实,使用包含治疗有效量TNF-α抑制剂和药学上可接受的载体的药用组合物能够治疗神经根损伤或至少减轻神经根损伤的症状,所述TNF-α抑制剂选自除外甲泼尼龙的金属蛋白酶抑制剂、四环素类(包括化学修饰四环素)、喹诺酮、皮质类固醇、肽胺哌啶酮、拉扎洛依类(lazaroides)、己酮可可碱(pentoxyphylline)、异羟肟酸衍生物、napthopyrans、可溶性细胞因子受体、抗TNF-α单克隆抗体、氨力农、匹莫苯、维司力农、磷酸二酯酶III抑制剂、乳铁蛋白和乳铁蛋白衍生的类似物以及褪黑激素,它们为碱或加成盐形式。
有效治疗量为使用这类化合物作其它治疗之用时通常使用的剂量。这类药物中许多药物是已知的市售注册药物。
具有这种活性的化合物为四环素类如四环素、多西环素、赖甲四环素、土霉素、米诺环素及化学修饰的四环素类去二甲基氨基四环素(dedimethylaminotetracycline)、异羟肟酸化合物、碳环酸及其衍生物、肽胺哌啶酮、拉扎洛依类(lazaroides)、己酮可可碱、napthopyrans、可溶性细胞因子受体、抗TNF-α单克隆抗体、氨力农、匹莫苯、维司力农、磷酸二酯酶III抑制剂、乳铁蛋白和乳铁蛋白衍生的类似物、褪黑激素、诺氟沙星、氧氟沙星、环丙沙星、gatifloxacine、培氟沙星、洛美沙星(lemefloxacine)及替马氟沙星。这些化合物可以碱或加成盐形式存在,无论哪种形式均具有最佳的药物学作用及最佳的性质以加入适当的药用组合物。
此外,所述活性组分包括抑制TNF-α释放激发产生的化合物的物质,这类物质为碱或加成盐形式,例如γ-干扰素、白介素-1以及一氧化氮(NO)。
本发明还涉及抑制神经根损伤症状的方法。
已研究了多西环素、可溶性细胞因子受体及单克隆细胞因子抗体的作用,并将所用方法及所获结果公开如下。
实施例研究设计
用免疫组化和记录神经传导速率建立的实验评价髓核(nucleuspulposus)和阻断TNF-α活性而各种治疗的效果。背景资料概述
对观测到的髓核所产生作用的meta-analysis显示,这些作用可能与一种特殊细胞因子即肿瘤坏死因子α(TNF(α))有关。目的
评价猪髓核细胞TNF(α)的存在及观察是否TNF(α)的阻断还阻断髓核引起的神经根传导速率的降低。方法
系列-1:用TNF(α)单克隆抗体对培养的髓核细胞进行免疫组化染色。
系列-2:从13只猪的腰椎间盘收集髓核并将其应用到13只猪的自体骶尾的马尾(sacrococcygeal carda equina)。给4只猪静脉注射100mg多西环素,给5只猪在髓核局部应用阻断性TNF-α单克隆抗体,并保留4只猪不作处理而形成对照。应用3天后通过局部电刺激测定应用区域神经根传导速率。
系列-3:类似于系列2,将13只猪自体髓核置于它们的骶尾马尾。5只猪(体重25kg)术前静脉注射100mg RemicadeR(infliximab),给8只猪在术前皮下注射12.5mg EnbrelR(etanercept),并于术后3天再皮下注射12.5mg EnbrelR。应用髓核后7天按照系列-2通过局部电刺激检测应用区域神经根传导速率。
结果
系列-1:发现TNF-α存在于髓核细胞中。
系列-2:TNF-α选择性抗体限制了神经传导速率的降低,但是与对照系列相比不具有统计学意义。然而,用多西环素治疗显著阻断了髓核诱导的传导速率的降低。
系列-3:用这两种药物治疗后发现两种药物(infliximab和etanercept)有效阻断髓核诱导的神经损伤并观察到正常的平均神经传导速率。结论
首次发现,一种特异性物质即肿瘤坏死因子-α与局部应用髓核后对神经根产生的作用有关。虽然该物质的此类作用可与其它类似物质协同发生,但是本研究的数据可能对继续了解髓核的生物活性具有重要意义,并且可能对将来的坐骨神经痛治疗策略也具有潜在的用途。
以前认为髓核在椎间盘突出处仅作为非生物活性组织组分压迫脊神经根,最近发现它具有高度活性,当在硬膜外应用(24,37,38,41,42)时引起邻近神经根的结构和功能的双重变化。因此确证自体髓核可能诱导轴索变化和特征性髓磷脂损伤(24,38,41,42)、增加血管渗透性(9,44)、血管内凝血作用(24,36),并且确证髓核细胞的膜结合结构或物质与这些作用有关(24,37)。还发现甲基强的松龙和环孢菌素A(2,38)有效阻断这些作用。严格考察这些数据,人们认识到至少有一种细胞因子即肿瘤坏死因子α(TNF-α)与所有这些作用有关。为了判定TNF-α是否参与髓核诱导的神经根损伤,鉴定TNF-α存在于髓核细胞中并研究髓核诱导作用是否能够被多西环素、可溶性TNF-受体以及选择性TNF单克隆抗体所阻断,将后者同时局部应用于髓核和全身应用。材料和方法
系列-1,在猪髓核细胞中存在TNf-α。
从取自一只作它用猪的腰椎和胸椎椎间盘(总数为13)获得髓核(NP)。将NP在Ham’s F12培养基(Gibco BRL,Paisley Scotland)中洗涤一次,然后离心并在37℃下于25cm2组织培养瓶中以5ml胶原酶的Ham’s F12培养基(0.8mg/ml,Sigma Chemical Co.,St Louis,MO,USA)溶液中悬浮40分钟。将分离的NP-细胞团悬浮于补充1%的200mM L-谷氨酰胺(Gibco BRL,Paisley,Scotland)、50μg/ml硫酸庆大霉素(GibcoBRL,Paisley,Scotland)及10%胎牛血清(FCS)的DMEM/F12 1∶1培养基(Gibco BRL,Paisley,Scotland)中。将细胞在37℃及5%CO2的空气中培养3-4周,然后直接培养于经组织培养基处理的载玻片上(BectonDickinson & Co Labware,Franklin Lakes,NJ,美国)。在载玻片上培养5天后用丙酮将细胞原位固定10分钟。将不相关抗原用3%H2O2(SigmaChemical Co.,St Louis,MO,美国)封闭30分钟及用马血清(ImmunoPureABC,过氧化酶鼠IgG染色试剂盒nr.32028,Pierce,Rockford,IL)封闭20分钟后,加入1∶10、1∶20及1∶40稀释的一抗(抗猪TNF-α单克隆纯化抗体,Endogen,Cambridge,MA,美国)在+40℃下过夜。作为对照,以同样的方式应用悬于PBS(磷酸盐缓冲盐水,Merck,Darmstadt,德国)中的BSA(牛血清白蛋白,Intergen Co,New York,美国)。次日用含1%BSA的PBS洗涤这些细胞并加入二抗(ImmunoPture ABC,过氧化酶鼠IgG染色试剂盒nr.32028,Pierce,Rockford,IL)处理30分钟。为促进该反应,再使这些细胞与抗生物素蛋白-生物素(Avidin-Biotin)复合物作用30分钟(ImmunoPure ABC,过氧化酶鼠IgG染色试剂盒nr.32028,Pierce,Rockford,IL)。然后将这些细胞在含20mg DAB(3,3-二氨基联苯胺四盐酸盐nr.D-5905,Sigma Chemical Co.,St Louis,MO,美国)和0.033ml3%H2O2的10ml盐水中反应10分钟。将细胞用PBS洗涤,在系列乙醇中脱水,在消除系统误差的情况下置于光学显微镜下由观察者观测,出现褐色着色表明存在TNF-α。系列-2,神经生理学评价:
给13只猪(体重25-30kg)肌内注射20mg/kg体重的KetalarR(氯胺酮50mg/ml,Parke-Davis,Morris Plains,New Jersey)以及静脉注射4mg/kg体重的HypnodilR(methomidate chloride50mg/ml,AB Leo,Helsingborg,瑞典)和0.1mg/kg体重的StresnilR(阿扎哌隆2mg/ml,Janssen Pharmaceutica,Beerse,比利时)。通过额外静脉注射2mg/kg体重HypnodilR和0.05mg/kg体重StresnilR维持麻醉。术后还给这些猪静脉注射0.1mg/kg Stesolid NovumR(安定,Dumex,Helsingborg,瑞典)。
通过腹膜后方法(42)从第5腰椎椎间盘收集髓核。通过对第一尾椎的中线切口及椎板切除术将约40mg髓核应用于骶尾的马尾。4只猪未予进行任何处理(未处理)。给另外4只猪在1小时内静脉滴注含100mg多西环素(Vibramycino,Pfizer Inc.,New York,USA)的100ml盐溶液。对于5只猪,应用髓核前,将其与100gl系列1中所用1,11mg/ml抗TNF-α抗体悬浮液混合。
应用后3天,通过肌内注射20mg/kg体重KetalarR及静脉内注射35mg/kg体重PentothalR(硫喷妥钠,Abbott实验室,芝加哥,IL)将这些猪再麻醉。这些猪利用人工呼吸装置换气。通过静脉大量注射100mg/kg体重氯醛糖(α)-D(+)-葡萄糖-氯醛糖(Merck,Darmstadt,德国)及连续供给30mg/kg/小时氯醛糖维持麻醉。进行第4骶椎至第3尾椎的椎板切除术。将这些神经根用SpongostaneR(Ferrosan,丹麦)覆盖。持续监测局部组织温度并用加热灯将温度保持在37.5-38.0℃。
用两个与Grass SD9刺激器(Grass Instrument Co.,Quincy,MA)相连的E2皮下铂针电极(Grass Instrument Co.,Quincy,MA)刺激马尾,所述电极轻轻地首先置于马尾的颅侧前10mm,然后间断性置于尾侧距暴露区10mm处。为确保只记录源自暴露神经纤维的脉冲,切断源自两个刺激位点之间的椎管神经根。通过置入尾部脊柱旁肌肉的两个相距约10mm的皮下铂针电极记录EMG。该方法具有可重复性并测量马尾神经根运动神经纤维机能。使用带有Superscope软件和MacAdiosII AID转换器(GW Instrument,Sommerville,MA)及Grass P18前置放大器(Grass Instrument Co.,Quincy,MA)的MacintoshIIci计算机观察EMG。测定两次记录的第一EMG峰之间的距离,并用卡钳测量马尾上两个刺激位点间的距离。由此从这两个测量值计算这两个刺激位点之间的神经传导速率。
进行神经生理学分析的人员不知道各动物的实验方案,并在完成全部研究后将数据分成三个实验组并通过Student’s t检验判定各组间统计学差异。该实验的实验方案得到当地动物研究伦理委员会许可。
系列-3:类似系列-2,将13只猪自体髓核置于其骶尾的马尾。5只猪(体重25kg)在术前静脉注射100mg人/鼠单克隆抗体RemicadeR(infliximab,Immunex Coporation,Seattle,WA98101,美国),给8只猪术前皮下注射12.5mg EnbrelR(etanercept,Centocor B.V.,Leiden,荷兰)及在术后3天再皮下注射12.5mg EnbrelR。应用髓核后7天按照系列-2通过局部电刺激检测应用区域神经根传导速率。为作双盲研究,神经生理学评价与另外一个研究并列进行,并且进行所述分析的人员不知道每只特定动物接受哪种研究及何种处理。由于预先已知应用髓核或脂肪(对照)7天后的神经传导速率,所以在系列-3中不包括未处理动物。通过使用ANOVA和Fisher’s PLSD评价infliximab和etanercept、未治疗的髓核(源自先前数据的阳性对照)以及腹膜后应用脂肪(源自先前数据的阴性对照)的各组之间的5%的统计学差异。结果
系列-1,在猪髓核细胞中存在TNF-α
染色载玻片的光学显微镜观察实例。在以溶于PBS的BSA作为“一抗”(对照)的切片中未观察到染色,证实没有标记或显现不相关抗原。当以1∶40稀释液应用抗TNF-α抗体时只有较弱的染色。然而随抗体稀释度的减少染色增强。染色见于细胞体中,而无法区分TNF-α是位于胞浆、还是在细胞表面结合于细胞膜或两种并存。
系列-2,神经生理学评价
与上述试验相似,应用未修饰的髓核而且未作任何处理时引起神经传导速率的降低(表1),而用多西环素处理完全阻断了这种降低(Student’s t检验,p<0.01)。局部应用抗TNF-α抗体也部分阻止这种减少,但是不象多西环素完全阻断且与未处理系列相比无统计学意义。
系列-3,因为这两个处理组的平均神经传导速率与先前研究中所见的脂肪-应用系列的平均传导速率(表2)接近,所以用这两种药物治疗似乎阻止了髓核诱导的神经根传导速率的降低。这两种药物与应用髓核但是没有作任何治疗的组相比,均具有统计学意义。表1-系列-2治疗 n NCV(m/s+SD)局部应用抗TNF-α 5 64±28多西环素 4 76±9未治疗 4 46±12表2-系列-3治疗 n NCV(m/s+SD)脂肪* 5 76±11EmbrelR 8 78±14RemicadeR 5 79±15未治疗* 5 45±19*包括参考文献第42条Olmarker等,1993数据讨论
本研究的数据证实,TNF-α可见于猪的髓核细胞。如果局部应用选择性单克隆抗体阻断TNF-α,则部分阻断所述髓核诱导的神经根传导速率的降低,但是与未治疗动物系列相比无统计学意义。然而,如果用多西环素、infliximab及etanercept全身治疗以抑制TNF-α,则显著阻止神经传导速率的降低。
近几年,已证实局部应用自体髓核可损伤邻近的神经根。因此椎间盘突出中所见到的神经根损伤显然不可能仅仅是由于神经根的机械变形,而且也可能由于未知的与硬膜外存在的髓核突出相关的“生化作用”所致。虽然这一新的研究领域进行了许多实验研究,但是对所涉及的机理和物质尚未完全了解。已发现局部应用自体髓核可诱导轴索损伤(24,37,38,40-42)、髓磷脂鞘的特征性损伤(24,38,40-42)、局部血管渗透性增加(9,36,44)、血管内凝血作用、神经内血流减少(43)以及白细胞趋向性(36)。已发现髓核相关作用可被甲泼尼龙(38)和环孢菌素A(2)有效阻断,以及被消炎痛(3)和利多卡因(69)轻度有效阻断。此外,已知这些作用由髓核细胞介导(37),尤其是由与细胞膜结合的物质或结构介导(25)。当严格考察这些数据时,显然至少一种特异的细胞因子,即肿瘤坏死因子α(TNF-α)可能与所观察的这些作用相关。TNF-α可诱导神经损伤(29,31,45,50,66),主要表现为特征性髓磷脂损伤,该损伤与髓核诱导的髓磷脂损伤(29,47,51,54,62,64,66,70)非常相似。TNF-α还可导致血管渗透性增加(47,66)及启动凝血反应(22,34,63)。此外,TNF-α可被类固醇(4,8,21,61,68)及环孢菌素A(11,55,67,68)阻断。然而NSAID对TNF-α的阻断作用不是如此显著(14,17,20),而利多卡因的阻断作用非常弱或相反(5,32,46,60)。最近观察到局部应用髓核可引起大鼠疼痛相关性作用,尤其是热痛觉过敏(23,40)。还发现TNF-α与这类疼痛作用的变化相关(12,35,56,66),并且还与一般神经病相关(30,54,56,57)。然而没有评价TNF-α可能存在于髓核细胞的研究。
为了评价TNF-α是否与所观察到的髓核诱导的神经根传导速率的降低相关,有必要首先分析髓核细胞中是否存在TNF-α。所述数据清楚地表明TNF-α存在于这些细胞中。TNF-α作为与膜结合的前体(前TNF)产生,该前体由锌依赖性金属内肽酶(TNF-α转化酶,TACE)裂解细胞膜激活(6,15,16,48,49)。因此这可能与仅应用自体髓核细胞的细胞膜诱导神经传导速率降低的实验结果密切相关,此结果表明该作用通过膜结合物质介导。其次,TNF-α的作用得以调控的方式阻断。那么应用前我们首先选择将与系列-1免疫组化所用抗体相同的选择性抗体用于髓核,已知该抗体还可阻断TNF-α的作用。我们还选择用多西环素治疗所述猪,已知多西环素阻断TNF-α(26,27,33,52,53)。然而由于多西环素制剂的pH值低,所以选择它通过静脉注射治疗这些猪,而不是局部加入应用于髓核,因为发现低pH髓核加强髓核的作用(38,39)。
本研究还包括两种最近开发的特异性抑制TNF-α的药物。Infliximab是由人抗体恒定区和鼠抗体的可变区组成的单克隆抗体,它特异性结合人TNF-α。与在系列-2中3天观察期内所使用的单克隆抗体相反,Infliximab不是局部应用于自体移植的髓核,而是以临床推荐剂量(4mg/kg)全身给予。Etanercept是由人IgG Fc部分组成的二聚体二融合蛋白。该药物以与小儿科推荐使用剂量(0.5mg/kg,一周两次)相当的剂量给药。
关于神经传导速率的数据表明,所述神经传导速率的降低完全被全身性治疗阻断,并且这些系列中的神经传导速率与先前研究中应用对照物质(腹膜后脂肪)后的传导速率(42)接近。将抗TNF-α抗体应用于髓核还部分阻止了神经传导速率的降低,然而不如多西环素显著,并且由于数据的标准差较大,该系列中的速率与未处理动物系列中的速率无统计学差异。
局部抗TNF-α抗体治疗只部分阻断髓核诱导的神经传导速率的降低以及这些数据标准差高的事实可能至少有三种不同的解释。首先,如果看一下该组内的具体数据,发现2只动物神经传导速率低(平均37.5m/s)而3只动物神经传导速率高(平均81.3m/s)。因此在抗TNF-α治疗系列中有两组明显不同的数据。这将说明高标准差的原因并可能提示在3只动物中阻断作用是充分的而在2只动物中阻断作用是不充分的。这些动物中阻断作用的缺乏可能只是基于与TNF-α分子相关的抗体量不充足,而且使用更高剂量的抗体时,甚至在这些动物中TNF-α作用会因此被阻断。那么这种情况理论上可能提示TNF-α单独与所观察的髓核诱导作用有关,并且由于抗体量太低以至这一点不能由实验证实。
其次,还已知四环素如多西环素和米诺环素可阻断许多细胞因子和其它物质。例如它们可阻断IL-1(1,28,58)、IFNγ(27)、NO合成酶以及金属蛋白酶(1,53,58)。尤其是已知IL-1和IFγ与TNF-α协同作用,而且已知它们或多或少具有神经毒性(7,10,13,18,19,56,59)。类固醇和环孢菌素A也阻断这些物质,这与先前对髓核诱导的神经根损伤的观察结果非常一致,证实髓核诱导的作用可被这些物质阻断(8,67)。因此还可以考虑选择性阻断TNF-α可能不足以完全阻断髓核诱导的对神经功能的作用的可能性,从而其它协同物质的同时阻断也是必要的。因此,另一方面,该情况提示不仅仅是TNF-α影响髓核诱导的作用,而且被多西环素阻断的其它协同物质可能是必需的。
第三种解释可能是髓核中TNF含量可能足以启动神经根局部病理生理级联反应,包括血管渗透性增加和全身白细胞的聚集以及募集作用。然而正是这些白细胞含有大量TNF-α,而足够剂量的全身治疗阻断这些白细胞的作用,并由此也阻断导致神经损伤的过程是必需的。
TNF-α可具有各种病理生理作用。它可直接作用于组织如神经组织和血管,它可触发其它细胞生成其它致病物质,并可触发炎性细胞和神经组织局部的Schwann细胞释放更多的TNF-α(65)。因此就是这个原因使人们相信即使少量TNF-α可能足以启动这些过程,以及存在着细胞因子生成细胞的局部募集,然后使其它细胞因子以及TNF-α的产生和释放增加。因此TNF-α可能起作病理生理过程的“点火键”作用并对髓核诱导神经损伤之后的病理生理级联反应的启动起重要作用。然而TNF-α的主要作用可能来自募集、聚集甚至可能是渗出的白细胞,并且只有通过全身治疗才可能实现成功的药理阻断。
总之,虽然从所述实验结果不能完全了解TNF-α的确切作用,但是我们可以得出的结论是:首次提出一种特异性物质(TNF-α)与髓核诱导的神经根损伤有关。这一新的信息可能对继续了解髓核诱导的神经损伤以及提出干预TNF-α和相关物质的药理作用以治疗坐骨神经痛在将来临床使用中的潜力问题是非常重要的。
因此,免疫组化证实在猪髓核细胞中存在TNF-α。局部应用单克隆抗体阻断TNF-α部分限制了髓核诱导的神经根传导速率的降低,而用多西环素、infliximab及etanercept静脉内注射治疗显著阻断这种降低作用。这些数据首次将一特异性物质TNF-α与髓核诱导的神经损伤联系起来。
已证实氨基胍通过抑制可诱导的一氧化氮合成酶从而抑制在神经根损伤部位释放一氧化氮(NO),因此氨基胍是抑制TNF-α的释放激发产生的化合物的一种化合物。
本发明的化合物可以各种剂型给予,如以片剂、胶囊剂、糖或膜包衣片剂、液体溶液剂的形式口服;以栓剂形式由直肠给药;胃肠外给药如肌肉内或静脉内注射或滴注。对不同临床综合症的治疗方案必须适合于通常需要考虑的病理类型,还有给药途径、所述化合物的给药形式以及受治患者的年龄、体重及病情。
通常对需要这类化合物的所有疾病采用口服途径。在紧急情况下优选静脉内注射。为此本发明的化合物可以约20-1500mg/天的剂量口服给药。当然可调节这些剂量方案以获得最佳的治疗反应。
当然,包含本发明化合物与药学上可接受的载体或稀释剂的药用组合物的性质取决于所需要的给药途径。该组合物可用常用成分以常规方式配制。例如本发明的组合物可以水溶液剂或油溶液剂或悬浮剂、片剂、小丸剂、明胶胶囊剂(硬胶囊或软胶囊)、糖浆剂、滴剂或栓剂的形式给予。
因此,对于口服给药,包含本发明化合物的药用组合物优选为片剂、小丸剂或明胶胶囊剂,它们含有所述活性物质以及稀释剂,例如乳糖、葡萄糖、蔗糖、甘露醇、山梨醇、纤维素;润滑剂如二氧化硅、滑石、硬脂酸、硬脂酸镁或硬脂酸钙和/或聚乙二醇;或者它们也可包含粘合剂如淀粉、明胶、甲基纤维素、羧甲基纤维素、阿拉伯胶、黄芪胶、聚乙烯吡咯烷酮;崩解剂如淀粉、海藻酸、海藻盐、淀粉羟乙酸钠、微晶纤维素;泡腾剂如碳酸盐和碳酸;染料;甜料;湿润剂如卵磷脂、聚山梨醇酯、十二烷基硫酸盐以及用于配制药用组合物的基本无毒的药学惰性物质。所述药用组合物可以已知的方式生产,例如通过混合、成粒、制片、糖包衣或膜包衣工艺方法。在膜包衣情况下可选择化合物以在肠道吸收的适当部位释放并获得最大功效。因此可用pH依赖性膜形成剂以使其照此在肠道内吸收,所以通常使用不同的邻苯二甲酸盐或丙烯酸/甲基丙烯酸衍生物以及聚合物。
用于口服给药的液体分散剂可以是如糖浆剂、乳剂及悬浮剂。
所述糖浆剂可包含如蔗糖、蔗糖和甘油和/或甘露醇和/或山梨醇作为载体。
所述悬浮剂和乳剂可包含例如天然胶,如阿拉伯胶、黄原胶、琼脂、藻酸钠、果胶、甲基纤维素、羧甲基纤维素、聚乙烯醇作为载体。
所述肌肉内注射的悬浮剂或溶液剂可包含所述活性化合物以及药学上可接受的载体如无菌水、橄榄油、油酸乙酯、二元醇如丙二醇,而且如果有此需要,可包含适当量的利多卡因盐酸盐。也可加入激发注射效果的辅助剂。
所述静脉内注射或滴注的溶液剂可包含如无菌水或最好是无菌等渗盐溶液作为载体以及用于活性化合物注射剂领域的辅助剂。
所述栓剂可包含所述活性化合物以及药学上可接受的载体如可可油聚乙二醇、聚乙烯脱水山梨醇脂肪酸酯表面活性剂或卵磷脂。
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Claims (8)
1. TNF-α抑制剂的用途,用于制备通过抑制椎间盘TNF-α治疗脊柱病症的药用组合物,所述病症例如为TNF-α释放以及TNF-α释放或存在激发产生的化合物引起的神经根损伤,所述TNF-α选自碱或其加成盐形式的除外甲泼尼龙的金属蛋白酶抑制剂、包括化学修饰四环素的四环素类、喹诺酮、皮质类固醇、肽胺哌啶酮、拉扎洛依类、己酮可可碱、异羟肟酸衍生物、碳环酸、napthopyrans、可溶性细胞因子受体、抗TNF-α单克隆抗体、氨力农、匹莫苯、维司力农、磷酸二酯酶III抑制剂、乳铁蛋白和乳铁蛋白衍生的类似物以及褪黑激素。
2. 按照权利要求1的用途,其中所述活性组分选自碱或加成盐形式的四环素、多西环素、赖四甲环素、土霉素、米诺环素及化学修饰的四环素类去二甲基氨基四环素。
3. 按照权利要求2的用途,其中所述活性组分为多西环素。
4. 按照权利要求1的用途,其中所述活性组分选自碱或加成盐形式的异羟肟酸化合物、碳环酸及其衍生物、肽胺哌啶酮、拉扎洛依类、己酮可可碱、napthopyrans、可溶性细胞因子受体、抗TNF-α单克隆抗体、氨力农、匹莫苯、维司力农、磷酸二酯酶III抑制剂、褪黑激素。
5. 按照权利要求1的用途,其中所述活性组分选自碱或加成盐形式的诺氟沙星、氧氟沙星、环丙沙星、gatifloxacine、培氟沙星、洛美沙星及替马氟沙星。
6. 按照权利要求1的用途,其中所述活性组分为碱或加成盐形式的金属蛋白酶抑制剂。
7. 按照权利要求1的用途,其中所述活性组分包括抑制由TNF-α的释放激发产生的化合物的物质,该物质为碱或加成盐形式,例如γ-干扰素、白介素-1及一氧化氮(NO)。
8. 治疗包括人类在内的哺乳动物脊柱病症如TNF-α释放引起的神经根损伤的方法,包括给予药学有效量的TNF-α抑制剂,该抑制剂选自碱或其加成盐形式的除外甲泼尼龙的金属蛋白酶抑制剂、包括化学修饰四环素的四环素类、喹诺酮、皮质类固醇、肽胺哌啶酮、拉扎洛依类、己酮可可碱、异羟肟酸衍生物、碳环酸、napthopyrans、可溶性细胞因子受体、抗TNF-α单克隆抗体、氨力农、匹莫苯、维司力农、磷酸二酯酶III抑制剂、乳铁蛋白和乳铁蛋白衍生的类似物以及褪黑激素。
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SE98032766 | 1998-09-25 | ||
SE9803276A SE9803276D0 (sv) | 1998-09-25 | 1998-09-25 | Use of certain drugs for treating nerve root injury |
SE9803710A SE9803710L (sv) | 1998-09-25 | 1998-10-29 | Användning av vissa substanser för behandling av nervrotsskador |
SE98037104 | 1998-10-29 |
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CN99813548A Pending CN1326351A (zh) | 1998-09-25 | 1999-09-23 | 应用某些药物治疗神经根损伤 |
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US (4) | US6649589B1 (zh) |
EP (3) | EP1115405B1 (zh) |
JP (3) | JP4832641B2 (zh) |
CN (1) | CN1326351A (zh) |
AT (1) | ATE362363T1 (zh) |
AU (1) | AU772036B2 (zh) |
BR (1) | BR9913926A (zh) |
CA (2) | CA2342200C (zh) |
CZ (1) | CZ2001983A3 (zh) |
DE (1) | DE69936102T2 (zh) |
ES (1) | ES2288319T3 (zh) |
HU (1) | HUP0103839A3 (zh) |
NZ (1) | NZ510122A (zh) |
PL (1) | PL347469A1 (zh) |
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