CN1108818C - 活化免疫球蛋白 - Google Patents
活化免疫球蛋白 Download PDFInfo
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- CN1108818C CN1108818C CN96109428A CN96109428A CN1108818C CN 1108818 C CN1108818 C CN 1108818C CN 96109428 A CN96109428 A CN 96109428A CN 96109428 A CN96109428 A CN 96109428A CN 1108818 C CN1108818 C CN 1108818C
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- immunoglobulin
- histamine
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- immune globulin
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Abstract
本发明提供了作为嗜酸性白细胞增多抑制剂、免疫调整剂、自身免疫疾病治疗剂、抗炎剂、抗过敏剂的有用的活化免疫球蛋白。本发明涉及把天然型免疫球蛋白原来不具有的新的药理活性赋与免疫球蛋白的方法、及由该方法得到的活化免疫球蛋白、及将该活化免疫球蛋白作为有效成份的医药组合物。本发明活化免疫球蛋白具有与先有免疫抑制剂不同的免疫调整作用,也作为慢性关节风湿病、全身性红斑狼疹、多发性硬化症等自身免疫疾病和各种免疫不全症等免疫系统异常疾病的治疗剂。
Description
本发明涉及得到活化免疫球蛋白的方法、由该方法得到的活化免疫球蛋白及将该活化免疫球蛋白作为有效成份的医药组合物,得到活化免疫球蛋白的方法是把天然型免疫球蛋白原来所不具有的嗜酸性白细胞增多抑制作用、免疫调整作用、自身免疫疾病改善作用、抗炎症作用、抗过敏作用等新的药理活性赋与天然型免疫球蛋白的方法。
如果异物侵入生物体内,则在生物体内引起要排除那些异物的各种反应。其中之一就是免疫反应,对该异物(抗原)会产生特异的蛋白质(抗体)。免疫反应即:当自身以外的异物如病原体、其他各种蛋白质、多糖类等侵入时,为了保护自身而引起的生物反应,其本质是基于抗体和抗原特异结合的抗原抗体反应。
抗体的主要活性是和异物(抗原)的特异结合活性。抗原是细菌等粒子状时,抗体在粒子间随交联的形成而引起凝集反应,抗原具有毒性、酶活性等时,抗体由于结合而引起中和反应,或抗原抗体复合体和血液中的补体成份结合后活化由此引起溶血反应、溶菌反应、免疫附着反应、免疫吞噬反应等,进行针对侵入异物的生物体内的免疫反应。
免疫球蛋白是抗体蛋白质及和它结构、功能类似的蛋白质的总称。从性状上分共分5类,如:IgG是免疫球蛋白的主要成份,IgG的产生量、血中浓度都最高,而且随抗原刺激的持续产生,血液中的半衰期也长,所以被认为是持续地维持免疫的重要抗体成份。IgM即使在微量抗原刺激的早期也能产生,但量少而且是一过性的,被认为是形成早期防御中心的抗体。还有IgA,大半分泌在唾液,消化道和气管的分泌液、乳汁等中,是对从外界经过气管、口腔感染的第一道防御主体。
基于如上所述免疫球蛋白本来的抗体活性,由人血浆调制的免疫球蛋白制剂已经作为医药品使用。仅由血浆精制浓缩的天然型免疫球蛋白制剂因它含有对各种感染症病原体及这些病原体产生物的抗体,作为适应症,它不仅仅适用于没有或低γ-球蛋白血症而且能予防和减轻麻疹、A型肝炎、脊髓灰质炎等病毒性疾病,在重症感染中也可和抗生素并用。也有把特殊血浆作为原料用于抗破伤风、B型肝炎等特殊疾病的天然型免疫球蛋白制剂。
如果要使天然型免疫球蛋白能够从静脉给药,就要除去作为产生休克症状的原因的球蛋白分子凝集体。可将天然型免疫球蛋白利用酶、化学方法处理或修饰,得到静脉注射用的处理型免疫球蛋白制剂。例如有在胃蛋白酶、血纤维蛋白溶酶、聚乙二醇、离子交换树脂、PH4的条件下处理过的制剂和利用烷基化或磺基化形成的免疫球蛋白制剂等。这些处理型制剂的药理作用也和天然型免疫球蛋白一样,免疫球蛋白本来具有的抗体活性没变。
现在应用的免疫球蛋白制剂具有基于上述抗体本身生理活性的治疗效果,但还没有有关天然型免疫球蛋白经什么样的处理后能被赋与新的药理活性的报告。
本发明的目的是提供一种免疫球蛋白的活化方法及将该活化免疫球蛋白作为有效成份的医药组合物,该免疫球蛋白的活化方法是将天然型免疫球蛋白原来所不具有的嗜酸性白细胞增多抑制作用、免疫调整作用、自身免疫疾病改善作用、抗炎作用及抗过敏作用等药理活性赋与天然型免疫球蛋白的方法。
本发明活化免疫球蛋白可通过将免疫球蛋白和组胺成份适当地混合处理后,再除去组胺成份的活化处理得到。作为人用医药品当然最好把人免疫球蛋白作为原料,人免疫球蛋白可由血清或胎盘血浆等利用通常的方法得到。为了确保作为医药品的安全性,血浆分级分离制剂必须满足通常规定的标准。例如:作为原料血浆要用HBs抗原、HCV抗体和HIV抗体阴性的人血浆,而且要进行加热处理,避免肝炎病毒和艾滋病毒等的混入。加热处理一般地是利用病毒的不活性,在血浆分级分离制剂中常用的方法有:60℃-10小时的液态加热处理、60℃-10小时的蒸气化热处理、65℃-96小时的干燥热处理等。
在适用于人以外的情况下,根据作为使用对象的动物种类,可以使用由人以外的动物调制的免疫球蛋白,组胺成份可用游离的组胺及其盐酸盐、磷酸盐、苦味酸盐等药学上容许的盐类。
通过将免疫球蛋白和组胺成份混合处理后,再除去组胺成份,使原来不具有嗜酸性白细胞增多抑制作用、免疫调整作用、自身免疫疾病改善作用、抗炎作用和抗过敏作用等药理活性的天然型免疫球蛋白活化。混合处理是把免疫球蛋白和组胺成份溶解在水或生理盐水等水性溶液中,在溶液即不冻结、免疫球蛋白也不热变性的适当温度下,例如在室温下适当地搅拌或搅拌后放置,不需要特别的操作。免疫球蛋白和组胺成份混合处理的比率,是组胺成份的添加量能使免疫球蛋白活化即可,例如,相对于1g的免疫球蛋白,组胺成份(换算成组胺)一般是0.015至150μg,优选0.075至75μg,但本发明并不局限于上述比例。
上述混合处理后,除去组胺成份即可得到本发明的活化免疫球蛋白。作为除去组胺成份的方法,常用的有透析法、凝胶过滤法等,简便且易实施,也可用其它的吸附柱色谱、离子交换色谱、亲和性色谱等,只要能够使活化免疫球蛋白和组胺分离的方法都可以采用。以下用实施例进一步详细地说明本发明活化免疫球蛋白的制造方法。
〔实施例〕
以下所述的药理实验中使用的实验动物是小鼠和大白鼠,所以这里用实验对象动物的免疫球蛋白代替人免疫球蛋白,即采用小鼠免疫球蛋白和大白鼠免疫球蛋白。以下的实施例是活化小鼠免疫球蛋白的制法。
实施例1,活化小鼠免疫球蛋白的制法
把50μl组胺二盐酸盐溶液(0.25mg/ml)添加到50ml小鼠免疫球蛋白溶液(20mg/ml)中,把该混合溶液在室温下缓慢地搅拌2小时。然后把该溶液在4℃下用分级分离的分子量12000~14000的透析膜,透析3天。然后除去组胺成份即可得到本发明活化小鼠免疫球蛋白溶液。具体为,用21的生理食盐水透析10~50ml的溶液,透析外液一天换3次,即可完全地除去组胺成份。透析结束后,经冷冻干燥处理以后保存。用时溶解到水或生理盐水中。
实施例2、残存的组胺成份的测定
采用放射免疫测定方法(商品名:ヒスタミンキツト〔荣研〕)测定上述实施例调制的本发明活化小鼠免疫球蛋白中残存的组胺。该免疫法是酰基化标准组胺和检体以后,把125I标记的组胺和组胺抗体试管同时保温,然后除去未反应的125I标记的组胺,然后用孔型闪烁计数器测定在组胺抗体试管中结合的放射能。由作成的标准曲线求检体中组胺浓度。这个测定方法的灵敏度是0.2nM,结果未测出上述本发明活化小鼠免疫球蛋白中有残存的组胺。
另外,用HPLC-萤光法等其他的组胺检测系统,也没测出有残存的组胺。把用氚标记的组胺和免疫球蛋白和实施例1一样混合以后透析,除去组胺,测定最终透析内液的放射能,结果和用非标记的组胺(对照)一样,没有残存组胺的痕迹。总之,用任意的测定方法都没测出有残存的组胺,所以可以确定用上述透析处理方法可完全除去组胺。
〔作用〕
下面叙述本发明的活化免疫球蛋白的药理实验结果。
1.嗜酸性白细胞增多抑制作用
根据Kaneko等人的方法(Int、Archs Allergy Appl.Immunol.,96卷、41~45页、1991年),用生理盐水稀释1000倍的豚草花粉提取物,对6~8周的雌性BALB/C小鼠,在开始日和第一天皮下注射0.1ml,第6、8、14天皮下注射0.2ml,使之引起过敏反应。第20天把稀释1000倍的0.2ml的豚草抗原给小鼠腹腔内注射,诱发反应后,回收腹腔浸润细胞,进行吉姆萨染色,测定嗜酸性白细胞数量,结果,嗜酸性白细胞数量在诱发后第24小时达到峰值。
用上述嗜酸性白细胞增多模型,每周2次持续3周皮下给以本发明活化小鼠免疫球蛋白(150mg/kg/日)直至产生反应,观察嗜酸性白细胞增多作用。同样给以天然型小鼠免疫球蛋白进行比较试验。
如果如表1所示。以下实验结果用Student′st-test法,求和对照例平均值的显著差,用*表示。〔*:p<0.05,**:p<0.01,***:p<0.001〕
〔表1〕
被检药品 | 腹腔内浸润嗜酸性白细胞数量 |
不致敏 | 0.19±0.06 |
对照 | 5.56±0.58 |
免疫球蛋白 | 5.63±0.87 |
本发明活化免疫球蛋白 | 1.06±0.25*** |
2.免疫调整作用
免疫调整作用是把三硝基苯(TNP)特异抗体产生和TNP特异延迟型(DTH)反应作为指标进行测定。
(1)三硝基苯结合羊红血球(TNP-SRBC)的调制
把三硝基苯磺酸(TNBS)溶解在磷酸缓冲生理盐水(40mg/7.0ml,PH7.2)中,把1ml羊红血球颗粒边搅拌边滴加到该溶液中。在遮光条件下,在室温搅拌数次放置20分钟后,用生理食盐水洗涤3次。3000rpm离心分离5分钟后,用生理食盐水调至5×109/ml。
(2)TNP特异抗体的产生
把109个TNP-SRBC腹腔内给以6~8周的雌性BALB/C小鼠,通过使用二硝基苯-牛血清白蛋白的酶免疫测定法测定血清中抗TNP抗体。结果确认产生了抗TNP-IgM、抗TNP-IgG的强抗体,分别在第4~6天和6~8天达到峰值。
(3)TNP特异DTH反应
继续用产生上述抗体的小鼠,在TNP-SRBC致敏反应后的第14天,把TNBS(4.7mg/ml,0.025ml)注射到后肢右脚脚掌上,使之诱发TNP特异DTH反应。诱发24小时后,用千分尺测定两脚脚掌的厚度,用左右肿胀差表示DTH反应强度。结果表明在诱发24小时后,可明确地观察到DTH反应。
(4)被检药物作用的测定
用上述实验系统,把本发明活化小鼠免疫球蛋白(150mg/kg/日)和天然型小鼠免疫球蛋白(150mg/kg/日)和环孢菌素A(100mg/kg/日),从TNP-SRBC致敏反应发生日开始,在4天内皮下注射给药,然后观察对产生抗TNP抗体和TNP特异DTH反应的作用。
产生抗TNP抗体的结果如图1所示,TNP特异DTH反应结果如表2所示。〔表2〕
被检药品 | 脚掌的肿胀(×10-2mm ) |
不致敏 | 30.0±3.4 |
对照 | 63.3±4.0 |
免疫球蛋白 | 53.9±5.0 |
本发明活化免疫球蛋白环孢菌素A | 35.8±3.0***35.8±3.3** |
3.自身免疫疾病改善作用
实验过敏反应性脑脊髓炎(EAE)是自身免疫疾病,特别是用作多发性硬化症、疫苗接种后脑炎等脱髓性疾病的最好的实验模型。被动的EAE是根据常法(M.Naiki等、Int.J.Immunopharmac.,13卷、2/3号、235~243页、1991年版上记载的)如下诱导的。把相当于豚鼠髓磷脂碱性蛋白质引起炎症部位的第68到第84氨基酸序列的合成肽(MBP68-84)的磷酸缓冲食盐水溶液(0.2mg/ml)和含有加热结核死菌2.5mg/ml的完全佐剂疫菌(H37Ra)等量混合,给雌路易斯系大白鼠(160~170g)左后肢脚掌皮下注射0.1ml。12天后取出免疫的大白鼠脾脏细胞,用含有2μg/ml刀豆球蛋白A的培养液体外培养72小时。洗涤后,把2×107个的培养细胞从尾静脉注射到另外的未处理过的大白鼠中,使之诱发被动EAE。
从注射入培养脾脏细胞之日起,把溶解在生理盐水中的被检药物皮下注射,每隔一天进行一次,共进行4次,连日观察临床症状,进行评价。临床判定标准共分六段:0是正常、1是尾下垂、2是轻度步行困难或对侧麻痹、3是中度运动失调或下肢麻痹、4是重度两下肢林痹、5是重度四肢麻痹和濒临死亡状态。本发明活化免疫球蛋白对EAE的改善效果的临床评价如图2所示。
如表1所示,本发明的活化免疫球蛋白在豚草花粉抗原诱导的嗜酸性白细胞增多模型中,明显地抑制了向腹腔内的嗜酸性白细胞浸润。如图1所示,本发明的活化免疫球蛋白对产生IgM和IgG抗体有显著的增强作用。免疫抑制剂环孢菌素A显著地抑制了两抗体的产生。如表2所示,对延迟型过敏反应(DTH),本发明的活化免疫球蛋白和环孢菌素A一样显示了优良的抑制作用。
先有的免疫抑制剂环孢菌素A对IgM和IgG抗体产生及DTH反应都显示了显著的抑制作用,但本发明的活化免疫球蛋白对抗体产生显示了增强作用,对DTH反应显示了抑制作用。这明确地表明本发明的活化免疫球蛋白和先有的免疫抑制剂具有明显不同的免疫调整作用。
从图2的结果可以看出,本发明的活化免疫球蛋白对自身免疫疾病模型实验用过敏反应性脑脊髓炎(EAE),明显地抑制了EAE引发的临床症状。而给以天然型小鼠免疫球蛋白的组和对照组一样,没有EAE抑制作用。
对于调制本发明的活化免疫球蛋白时免疫球蛋白和组胺成份的混合比进行研究,在实施例1中,组胺成份是免疫球蛋白的1/10时,调制出的本发明活化免疫球蛋白和实施例1一样具有显著的嗜酸性白细胞增多抑制作用和EAE抑制作用,但组胺成份是免疫球蛋白的1/100时,也未见比1/10时有更强的抑制作用。另外,口服和皮下给药显示了几乎相同的嗜酸性白细胞增多抑制作用和抗体产生增强作用等药理活性。
在上述任何一个药理实验中,没进行过本发明活化处理的通常的免疫球蛋白是没有作用的,很明显这些药理作用是通过本发明活化处理后,特异地赋与给免疫球蛋白的。
以上药理实验结果表明,由免疫球蛋白和组胺成份混合处理后,再除去组胺成份,得到的本发明活化免疫球蛋白是免疫球蛋白单独成份而且具有天然型免疫球蛋白所不具有的有用的药理作用。这种优良的药理作用是和环孢菌素等先有免疫抑制剂明显不同的特异免疫调整作用。本发明活化免疫球蛋白不仅有嗜酸性白细胞增多抑制作用而且显示了对自身免疫疾病模型EAE也有显著的改善效果,所以它是治疗全身性红斑狼疮、慢性关节风湿病等胶原病、多发性硬化症、疫苗接种后脑炎等脱髓性疾病、自身免疫性溶血性贫血、慢性甲状腺炎、桥本病等自身免疫疾病和各种免疫不全症有用的药物。基于它对嗜酸性白细胞增多的抑制作用,本发明活化免疫球蛋白可用作引发感染症、寄生虫疾病、呼吸道疾病、自身免疫疾病、恶性肿瘤等嗜酸性白细胞增多症的治疗药。
嗜酸性白细胞都集中在接受刺激产生炎症的部位,是引起炎症症状的效应细胞。抑制嗜酸性白细胞增多的药物也可作为抑制炎症的药物。本发明活化免疫球蛋白不仅能抑制上述嗜酸性白细胞增多,而且能抑制DTH反应引起的肿胀,改善炎症性自身免疫疾病(被动EAE),作为优良的抗炎药是非常有用的。另外嗜酸性白细胞和过敏反应症状有很深的关系,本发明活化免疫球蛋白可作为支气管哮喘、过敏性鼻炎、血管运动性鼻炎、荨麻疹、慢性湿疹、特应性皮炎等各种过敏性疾病的治疗及预防药。
本发明活化球蛋白可和适当的医药用载体或稀释剂组合以后作为医药使用,也可做成口服或非口服的固体、半固体、液体或气体剂型,根据该领域的常用方法,做成制剂使用。在制剂中,作为有效成份的本发明活化球蛋白可单独使用或和其它医药活性成份配合使用。
作为注射剂,最好做成注射用蒸馏水或生理盐水等张溶液制剂。另外,在制剂时,除本发明活化免疫球蛋白成份以外,也可适当加入溶解辅助剂、等张剂、稳定剂、缓冲剂、保存剂等添加剂,例如可利用柠檬酸、苯甲酸钠、甘氨酸、亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代硫酸钠、盐酸半胱氨酸、磷酸盐、抗坏血酸钠、氯化钠、碳酸氢钠等。另外,本发明医药组合物也可做成用时溶解的注射剂,可把干燥的粉末充填到管形瓶中,或把药剂溶液注入管形瓶中以后,冷冻干燥,做成冷冻干燥制剂。此时,除上述的添加剂以外,必要时也可添加葡萄糖、甘露糖醇、山梨糖醇等赋形剂。
本发明活化球蛋白在做成口服制剂时,可直接使用或适当地加入适量的添加剂,例如有乳糖、甘露糖醇、玉米淀粉、土豆淀粉等常用的赋形剂;结晶纤维素、纤维素衍生物、阿拉伯树胶、玉米淀粉、明胶等粘合剂;玉米淀粉、土豆淀粉、羧甲基纤维素钾盐等崩解剂;滑石粉、硬脂酸镁等润滑剂;其它还有增量剂、润湿剂、缓冲剂、保存剂、香料等,可做成片剂、散剂、颗粒剂或胶囊剂。另外,根据患者状况和疾病种类,在治疗时,可做成上述以外的剂型,例如有吸入剂、气雾剂、软膏、滴眼剂、栓剂等。
本发明活化球蛋白的最佳给药量要根据疾病种类、病症程度、患者年龄、性别、剂形、给药方法、给药时间等设定。例如使用注射剂的情况下,为了得到所期望的效果,一般成人可一周皮下注射一次至数次1至300mg,优选5至150mg,但本发明对此并没有特殊的限制。
〔附图的简单说明〕
〔图1〕
表示本发明活化免疫球蛋白对抗TNP抗体产生的增强作用。
〔图2〕
表示本发明活化免疫球蛋白对实验用过敏性脑脊髓炎症的抑制作用。
Claims (10)
1.活化免疫球蛋白,是将1g的免疫球蛋白与换算成组胺为0.015μg-150μg的组胺成分混合处理后,从混合物中除去组胺成分后得到的,具有嗜酸性白细胞增多抑制作用、免疫调整作用、自身免疫疾病改善作用、抗炎症作用和抗过敏作用。
2.含有权利要求1记载的活化免疫球蛋白的医药品。
3.权利要求2记载的医药品,是嗜酸性白细胞增多抑制剂。
4.权利要求2记载的医药品,是免疫调整剂。
5.权利要求2记载的医药品,是自身免疫疾病治疗剂。
6.权利要求2记载的医药品,是抗炎剂。
7.权利要求2记载的医药品,是抗过敏剂。
8.权利要求2记载的医药品,是注射剂。
9.权利要求2记载的医药品,是口服制剂。
10.免疫球蛋白的活化方法,是将1g的免疫球蛋白与换算成组胺为0.015μg-150μg的组胺成分混合处理后,从混合物中除去组胺成分。
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JP7227045A JPH0959180A (ja) | 1995-08-11 | 1995-08-11 | 活性化免疫グロブリン |
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JP227045/95 | 1995-08-11 |
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EP (1) | EP0758656B1 (zh) |
JP (1) | JPH0959180A (zh) |
KR (1) | KR100436811B1 (zh) |
CN (1) | CN1108818C (zh) |
AT (1) | ATE252603T1 (zh) |
AU (1) | AU713296B2 (zh) |
CA (1) | CA2183020A1 (zh) |
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JPH10212246A (ja) * | 1997-01-30 | 1998-08-11 | Nippon Zoki Pharmaceut Co Ltd | 経口投与用製剤 |
US6124437A (en) * | 1997-03-19 | 2000-09-26 | Welfide Corporation | Immunoglobulin preparation and preparation process thereof |
JP2000143536A (ja) | 1998-11-13 | 2000-05-23 | Nippon Zoki Pharmaceut Co Ltd | 抗浮腫剤 |
DE19944122A1 (de) * | 1999-09-15 | 2001-03-29 | Wolfgang Loh | Histamin-Immunglobulin-Komplexe zur Behandlung von entzündlichen Erkrankungen bei Säugetieren |
KR20070108320A (ko) * | 2006-03-20 | 2007-11-09 | 전숙영 | 알레르기질환 및 자가면역질환의 치료를 위한 약학적조성물, 그의 용도 및 알레르기질환 및 자가면역질환의치료방법 |
RU2505312C2 (ru) * | 2010-08-06 | 2014-01-27 | Олег Ильич Эпштейн | Комплексное лекарственное средство для лечения гриппа различных типов |
RU2502521C2 (ru) * | 2010-08-06 | 2013-12-27 | Олег Ильич Эпштейн | Комплексное лекарственное средство для лечения бактериальных инфекций и способ лечения бактериальных инфекций |
CN110801013B (zh) * | 2019-11-19 | 2023-03-31 | 西北农林科技大学 | 一种生物化学法制备非过敏生漆或漆酚的方法及其产品 |
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US3873697A (en) | 1972-11-11 | 1975-03-25 | Mack Chem Pharm | Histamine antigen |
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US4705685A (en) * | 1982-05-17 | 1987-11-10 | Mcmichael John | Methods and materials for treatment of disease states involving immunological factors |
US4704273A (en) | 1982-05-17 | 1987-11-03 | Mcmichael John | Methods and materials for treatment of rheumatoid arthritis |
JPS58225027A (ja) * | 1982-06-23 | 1983-12-27 | Fujirebio Inc | ヒスタミン加グロブリン製剤 |
US4705687A (en) | 1985-06-17 | 1987-11-10 | Ortho Pharmaceutical (Canada) Ltd. | Treatment of autoimmune diseases such as rheumatoid arthritis with suppressor factor |
US5112738A (en) | 1985-07-03 | 1992-05-12 | Miles Inc. | Histamine derivatives, immunogen conjugates and antibodies raised thereto |
US5244902A (en) | 1989-08-21 | 1993-09-14 | Beth Israel Hospital Association | Topical application of spiperone or derivatives thereof for treatment of pathological conditions associated with immune responses |
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US5192773A (en) | 1990-07-02 | 1993-03-09 | Vertex Pharmaceuticals, Inc. | Immunosuppressive compounds |
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CHEMICAL ABSTRACTS,VOL.115,NO3 1991-07-22 VOLOKHOVSKAYA et al."histaglobulin and changes in conjunctival structure in vernal conjunctivities * |
CHEMICAL ABSTRACTS,VOL.115,NO3 1991-07-22 VOLOKHOVSKAYA et al."histaglobulin and changes in conjunctival structure in vernal conjunctivities;CHEMICAL ABSTRACTS,VOL.67,NO.5 1967-07-31 A.GETLIK et al."Long_term sesitivity threshold limit to acetylcholine during the treatment of pneumg * |
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EP0758656A2 (en) | 1997-02-19 |
DE69630423T2 (de) | 2004-06-17 |
TW442495B (en) | 2001-06-23 |
CA2183020A1 (en) | 1997-02-12 |
US6627194B1 (en) | 2003-09-30 |
AU6203396A (en) | 1997-02-13 |
KR100436811B1 (ko) | 2004-08-25 |
CN1148505A (zh) | 1997-04-30 |
EP0758656A3 (en) | 1997-08-06 |
JPH0959180A (ja) | 1997-03-04 |
DE69630423D1 (de) | 2003-11-27 |
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ATE252603T1 (de) | 2003-11-15 |
KR970009812A (ko) | 1997-03-27 |
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