CN1452496A - 绵羊副痘病毒毒株抗器官纤维化的用途 - Google Patents
绵羊副痘病毒毒株抗器官纤维化的用途 Download PDFInfo
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Abstract
本发明涉及灭活的副痘病毒在对人预防和治疗与胶原沉积增加相关的疾病的用途，所述疾病影响内脏器官，例如肝脏，还有皮肤及其附加结构。本发明特别涉及病毒性肝炎之后导致的肝脏纤维化或肝硬化，或者乙醇诱发的肝病，例如胆囊纤维化。
Description
本发明涉及灭活的副痘病毒在对人预防和治疗伴随与内脏器官例如肝脏和皮肤及其附加结构受到影响有关的胶原沉积增加的疾病中的用途。本发明特别涉及病毒性肝炎之后的肝脏纤维化和肝硬化，或者乙醇诱发的肝病，还有胆囊纤维化。
本发明特别涉及绵羊副痘病毒(Parapoxvirus ovis)的分离物例如D1701毒株，orf-11毒株，希腊orf毒株176，希腊orf毒株155，新西兰(NZ)分离物，例如NZ2、NZ7和NZ10，还有从D1701得到的Baypamun对人的用途。
除了原始菌株之外，本发明还涉及通过传代和/或适应特定细胞而获得的子代，例如WI38。除了完整病毒之外，本发明还涉及这些病毒的部分或片段。所谓部分理解为利用合适的载体，例如牛痘，在合适的体系，例如成纤维细胞培养物中表达的基因组或亚基因组片段。所谓片段理解为是通过生物化学纯化作用例如色谱法获得的级分，或应用物理方法例如利用超声处理破碎之后获得的颗粒。
已知副痘病毒能刺激脊椎动物非特异性免疫反应。Baypamun是化学灭活的绵羊副痘病毒毒株D1701的制剂，其用于对动物预防，病后调节和治疗传染性疾病，并且防止胁迫诱发的疾病。
专利文献DE 3 504 940 A(Mayr，Ant on)教导了Baypamun对象高能辐射、化学治疗、AIDS、免疫抑制、与年龄相关的损伤和解毒作用诱导的免疫缺陷这样的症状的有益作用，但是该文献没有教导肝脏纤维化的直接减少。DE 3 504 940还教导Baypamun作为辅助手段支持肿瘤治疗的功效，并且其预防新生儿由于母亲不充分免疫防御引起的疾病。
以现有知识作为出发点，令人惊奇地发现，施用灭活的副痘病毒能够减少或防止肝脏纤维化。在动物模型中，在四氯化碳诱导的基于中毒性肝损伤的肝脏纤维化情况下发现了这种作用，在异源血清诱导的并且其中没有肝部感染的肝脏纤维化的情况下也发现了这种作用。这种治疗作用的程度同样令人吃惊：在四氯化碳模型中，与肝脏纤维化相关的胶原的过量产生被抑制60％，而在血清模型中几乎完全被抑制。与这些长期实验的结果相吻合，从急性施用四氯化碳有可能证实，Baypamun和从上述绵羊副痘病毒毒株获得的制剂抑制肝星形细胞转化为产生胶原的肌成纤维细胞类型。
不同病因能够诱导肝脏纤维化和/或肝硬化，例如病毒感染和酗酒，但是不同的病理机理进入一个共同的最终途经，即产生胶原。根据上述非感染性模型得到的动物实验结果证明，施用灭活副痘病毒出人意料地不依赖诱导病因地防止胶原沉积。
因此副痘病毒为对于导致纤维化的所有的疾病来说是共同的最终途经发挥作用提供了新的治疗原理。
这种作用提示，当使用副痘病毒制剂时，会实现特别有效的治疗，即使在病毒诱导的肝脏纤维化的情况下也是如此，因为已知这样的制剂具有另外的免疫刺激作用。
现在发现Baypamun的强有力的抗纤维化作用打开了使用Baypamun或NZ2制剂作为鉴定抗纤维化物质测试中评价抗纤维化作用的参考标准的可能性。
所以，灭活的副痘病毒或它们的子代，和从上述毒株获得的制剂具有广谱的抗纤维化作用，因此不只是适合预防和治疗肝脏纤维化疾病，而且还适合其它器官的纤维化病变，例如肺的，胰脏的，心脏的和皮肤的纤维化疾病。在预防和治疗肝脏纤维化和肝硬化中，特别优选使用副痘病毒的分离物。
根据临床问题，全身施用以副痘病毒为基础的治疗药物，即，例如肌内，皮下，腹膜内，静脉内，口服或者通过吸入，还有局部给药。副痘病毒被纯化和冻干，并且直接在施用之前悬浮于合适的溶剂，或者存在于另一种合适的制剂中，或者以抗胃液口服施用形式或者一些其它口服施用形式存在。
与此相关，多次给药或者根据相应于临床问题的要求的按时间给药的方案长期治疗可能是必需的。
本发明涉及从D1701毒株，orf-11毒株，希腊orf毒株176，希腊orf毒株155，新西兰(NZ)毒株获得的副痘病毒的分离物用于制备对人器官纤维化有预防或治疗作用的药物的用途。优选使用新西兰(NZ)毒株，即NZ2，NZ7和NZ10毒株用于制备对人器官纤维化有预防或治疗作用的药物，其中NZ2毒株是特别优选的。除此之外，通过传代或适应合适的细胞能够修饰上述副痘病毒，并且那些通过传代或适应合适的细胞而获得的副痘病毒能够用于制备对人器官纤维化有预防或治疗作用的药物，与此相关可以使用人细胞，例如WI-38，MRC-5，牛细胞，例如BK-K13A47/Reg或MDBK，和绵羊细胞，例如MDOK，用于传代或适应。也可以使用上述副痘病毒的部分或片段用于制备对人器官纤维化有预防或治疗作用的药物。所谓部分理解为利用合适的载体，例如牛痘病毒，在合适的体系，例如成纤维细胞培养物中表达的基因组或亚基因组片段，所谓片段理解为是表达的病毒颗粒或通过例如超声处理物理破碎的病毒颗粒通过生物化学纯化作用例如色谱法获得的级分。本发明进一步涉及上述绵羊副痘病毒毒株或者如上所述从其获得的修饰物与其它药物结合制备对人器官纤维化有预防或治疗作用的药物和药物制剂的用途，涉及Baypamun本身或者与其它药物结合制备对人器官纤维化有预防或治疗作用的药物和药物制剂的用途。本发明优选涉及上述绵羊副痘病毒毒株或者如上所述从其获得的修饰物与其它药物结合制备用于口服的制剂的用途，例如制备胃液-抗性胶囊。
本发明进一步涉及Baypamun或NZ2制剂作为鉴定抗纤维化物质测试中评价抗纤维化作用的参考标准的用途。
这里举例提到的绵羊副痘病毒NZ-2在2001年7月10日保藏在细胞培养物欧洲中心，应用微生物学和研究中心，Porton Down，Salisbury，Wiltshire，SP4 0JG，United Kingdom。保藏号是。
实施例1
绵羊副痘病毒，毒株D 1701，Bavpamun的效果
方法
将从化学灭活的绵羊副痘病毒，毒株D 1701得到的制剂，Baypamun干燥物质根据说明溶解于水用于注射(根据TCID50(50％组织培养感染剂量)的效价大约是107/毫升)。
以与Baypamun溶液含有相同量的蛋白质的聚明胶肽溶液作为安慰剂溶液，施用给对照组动物。
对每一只动物每次腹膜内施用0.5ml的溶液。每星期给药三次，但是从来不在连续天给药。
在两个动物模型中试验Baypamun，这两种动物中纤维化起源不同，即四氯化碳模型和猪血清模型。
用四氯化碳慢性处理是实验诱导随后发生硬化的肝脏纤维化的标准方法(McLean EK，McLean AEM，Sutton PM.Instant cirrhosis.Br.J Exp.Pathol.1969；50：502-506)。其一般被认为是人肝脏纤维化和肝硬化的模型。使用雌性Sprague-Dawley大鼠。为了保证最大程度诱导四氯化碳的微粒体的新陈代谢，在开始处理之前一周对动物给予1克的异烟肼/升与饮水。每五天，以0.1毫升/100克体重的剂量口服给与四氯化碳(四氯化碳∶矿物油＝1∶1)。处理七星期之后，杀死动物并且检查。与四氯化碳处理平行进行Baypamun处理。
用异源血清处理，例如在大鼠情况下用猪血清处理，同样是文献中常常使用的诱导随后发生硬化的肝脏纤维化的方法，使用该方法，与其它模型相反，只对肝脏实质细胞引起微小的损伤和炎症(Bhunchet，E.和Wake，K.(1992)：间质细胞群在猪血清诱导的大鼠肝脏纤维化中的作用(Role of mesenchymal cell populations inporcine serum-induced rat liver fibrosis)，肝脏学(Hepatology)16：1452-1473)。每周两次腹膜内对每只动物施用0.5毫升的灭菌猪血清(Sigma)处理雌性Sprague Dawley大鼠，给对照动物施用灭菌氯化钠生理溶液(每周两次，0.5毫升/动物，腹膜内)。与猪血清处理平行进行Baypamun处理，但是从不在同一天给药。处理七星期之后，杀死动物并且取出肝脏用于定量测定胶原的量。
对于肝脏组织的组织学检查，从肝脏的右前页穿孔取出标准横列组织圆柱体(大约10×2mm)。用0.1％Picrosirius red溶液将冷冻切片染色，用于检测肝脏纤维化产生的胶原斑。
使用牢固绿作为复染剂用于对比度放大。对每一个切片检测肝脏纤维化的程度，以用Picrosirius red染色面积占总测面积的百分分数表示。将目测显微镜颜色检查参数进行标准化并且在实验自始至终保持不变。在50倍最后放大率下测定在31mm2栅格中标准化过的64个方块。
为了定量测定用四氯化碳急性处理大鼠之后肝星形细胞(HSC；也称为Ito细胞或维生素A贮存细胞)转化的程度，免疫组织学检查α-平滑肌肌动蛋白-阳性面积。以200倍最后放大率，每种情况下对每一个切片，在16小叶中心248×180微米领域，确定α-平滑肌肌动蛋白-阳性区。已知HSC向产生胶原并且产生生长因子的肌成纤维细胞样细胞的转化是诱导肝脏纤维化的重要步骤。因此转化的HSC是肝脏纤维原活性的早期指示。
使用Leica Quantimed 500MC(Leica Germany)进行半自动形态测定法。
为了测定OH-脯氨酸，各种情况下干燥50-100mg肝组织并且用6N HCl煮沸大约17小时。在真空烘箱中将酸蒸发掉之后，将残余物溶解于5毫升蒸馏水中并且过滤该溶液。室温下，将200微升这种过滤的溶液与200微升乙醇和200微升氧化溶液(7％氯胺T水合物水溶液，用乙酸盐-柠檬酸盐缓冲液pH6.0以1∶4稀释)一起温育25分钟。之后，加入400微升的Ehrlich′s试剂(20毫升乙醇中12克4-二甲基氨基苯甲醛+20毫升乙醇中2.74毫升的浓硫酸)。35℃下温育3小时之后，在573nm下测定吸收度。OH-脯氨酸水溶液(Sigma)用于标准系列。以每克肝干重的毫克数计算肝脏样品中OH-脯氨酸含量。
为了监测反应性氧自由基的形成，测定肝中还原的α-生育酚(α-TOC)，一种自由基-捕获剂的浓度，同时测定血清中自由基-敏感酶7-乙氧基试卤灵去乙基化酶(EROD)的活性。在四氯化碳中毒情况下这两个参数被特征性地下调，并可估计氧化对组织的损伤的严重性。
通过测定一些标准的血清参数来确定动物的肝脏状态：
丙氨酸氨基转移酶(ALT)，碱性磷酸酶(AP)，天冬氨酸氨基转移酶(AST)，γ-谷氨酰转移酶(GGT)，谷氨酸脱氢酶(GLDH)，和总胆红素(TBIL)。结论：
用Baypamun治疗显著降低四氯化碳处理过的大鼠的肝脏的纤维化退化程度(图1)。另外，可以观察到HSC转化的几乎完全的抑制作用(图2)。Baypamun治疗过的动物的肝脏中增殖的非实质组织细胞数目大大减少(图3)。非实质组织细胞包括HSC和在纤维发生中同样涉及的Kupfer细胞。
肝细胞损伤的血清指征，例如ALT，AP，AST，GGT，GLDH和TBIL(表1)表明正常化趋势。
对照组和Baypamun治疗组中EROD和α-生育酚浓度同样降低提供了两组中四氯化碳中毒产生的毒性反应性氧自由基存在的证据(表1和2)。因此排除了Baypamun″抗纤维化″作用是由于解毒作用的可能性。
在血清模型中，Baypamun表现出几乎完全的纤维化抑制作用(图4)：在Baypamun治疗过的大鼠，肝脏中羟基脯氨酸含量和Siriusred-可染色面积几乎都处于健康对照动物的水平，而在血清处理过的对照大鼠中它们增加了数倍。在Baypamun组，猪血清处理诱导的胶原含量的增加只是对照组相应值的10％。实施例2 绵羊副痘病毒，毒株NZ2 方法：
在叠式罐中复制NZ2病毒。为此，在细胞培养皿中(37℃)在EMEM2gr+10％FCS中将BK克隆3A细胞培养3-5天，直到细胞层达到90-100％汇合。对于各叠式罐使用四个细胞培养皿作为接种物，后者装有培养基(EMEM 2gr+10％FCS)至2.5升容积。37℃下温育3-5天(90-100％汇合细胞层)，用没有加入血清的EMEM 2g置换培养基，并且用NZ2病毒(MOI，0.001-0.01)感染培养基。
达到100％CPE之后(37℃下温育大约7-8天)，收集病毒。为此，将病毒悬浮液装入灭菌培养基小袋并且在-80℃下冷冻。接着在培养室中在37℃下将悬浮液解冻，利用深度床过滤(孔径5微米)使细胞自由化。此后，利用超滤(100kDa截留量)将病毒悬浮液浓缩20-40倍。或者，可以通过超速离心(Ti45，30,000rpm，4℃，60分钟)浓缩病毒。
利用对BK克隆3A细胞的滴定法测定包含在悬浮液中的病毒通过浓缩后达到的效价。使用没有FCS的EMEM培养基将病毒效价调节至6.0之后，在58℃下将病毒热灭活2小时。利用对BK克隆3A细胞进行的灭活对照检查灭活作用。
在实施例1中已经使用过的猪血清诱导大鼠肝脏纤维化的模型中试验绵羊副痘病毒，毒株NZ2：
每周两次对每只动物用0.5毫升的灭菌猪血清(Sigma)腹膜内处理雌性Sprague Dawley大鼠，给对照动物施用灭菌氯化钠生理溶液(每周两次，0.5毫升/动物，腹膜内)。以1.5×105或5.0×105TCID50/动物的剂量每周三次腹膜内施用毒株NZ2(给药体积：0.5毫升/动物)。对于较低剂量，用细胞培养基(Eagle′s最小基本培养基，Sigma)稀释起始材料。用细胞培养基处理对照动物。与用血清处理平行进行用毒株NZ2处理，但是从不在同一天给药。处理七星期之后，杀死动物并且取出肝脏；然后用形态测定法和通过OH-脯氨酸含量定量测定肝脏纤维化。该方法已经在实施例1中描述过。结论：
图5给出了胶原测定的结果。出人意料地，用毒株NZ2处理能抑制肝脏纤维化的发展：与健康动物相比，血清处理的对照动物表现出OH-脯氨酸含量和Sirius red-染色胶原的显著增加。NZ2以剂量依赖方式减少了这种增加。这种作用的程度也是出人意料的：5×105TCID50剂量将肝脏中胶原含量的增加减少至比对照值少10％。组织学制品的定性分析表明具有胶原中隔的动物的比例在1.5×105TCID50组从93％(14/15)减少到33％(5/15)，在5.0×105TCID50组减少到0％。实施例3 口服施用PPVO之后的抗纤维化作用
将PPVO配制成胃液-抗性胶囊中的干燥冻干物(Elanco，Indianapolis，USA)。
如下对各六只实验动物的四组动物进行处理：对一个对照组(第1组)只口服给与胃液-抗性胶囊(没有PPVO)，另外腹膜内注射无菌氯化钠溶液(0.5毫升/动物)。第2组中，和0.5毫升四氯化碳/动物一起口服给与胃液-抗性胶囊(没有PPVO)，另外腹膜内注射0.5毫升生理氯化钠溶液。对第3组的动物，和0.5毫升四氯化碳/动物一起口服给与胃液-抗性胶囊(没有PPVO)。另外，对第3组的动物腹膜内注射给与0.5毫升注射用水中PPVO D1701(剂量：5×106TCID50/动物)。对第4组的动物，口服给与PPVO D1701(剂量：5×106TCID50/动物，配制成胃液-抗性胶囊)和0.5ml四氯化碳。还对第4组的动物腹膜内注射施用了0.5毫升无菌氯化钠溶液。
48小时之后，取出肝脏，并且用代表性组织切片对每一只动物免疫组织化学测定α-平滑肌肌动蛋白(α-SMA)阳性小叶中心面积，以总测面积的百分比来表示(Johnson S J，Hines J E，Burt A D.，急性肝损伤之后窦周细胞表型调控：定量分析(Phenotypic modulationof perisinusoidal cells following acute liver injury：aquantitative analysis)，Int.J Exp.Path.1992；73：765-772)。这个值是肝星形细胞转化的一个量度。
根据上文所述进行两个实验系列。表3给出了第一个实验系列的实验结果，表4给出了第二个实验系列的实验结果。
在第一个实验系列中，腹膜内施用PPVO D1701的动物(第3组)的肝组织中α-SMA-阳性小叶中心区面积的比例比没有接受PPVO的动物说不清地高(与其它实验结果相反)。因为这个原因，进行第二个实验系列作为重复实验。
在这两个实验系列中，与对照组相比较(各种情况下第2组)，发现在口服施用PPVO D1701(各种情况下第4组)之后，相符并且出人意料地发现，转化作用被抑制大约50％。在第二个实验系列中，口服施用PPVO D1701(第4组)之后转化作用的抑制与腹膜内施用PPVOD1701(第3组)观察到相似的效果。
从这些结果可以推出，在口服施用之后，PPVO也起着抗纤维化作用。
表1
| Baypamun对肝状态的血清参数和中毒指征的影响 | |
| ALT AST AP GGT GLDH TBIL ERODU/l U/l U/l U/l U/l μmol/l nmolgx分钟 | |
| 对照SEM四氯化碳SEMCt+BaypamunSEM | 49.1 45.7 162.8 0.8 12.5 1.6 0.303.7 8.7 14.76 0.2 7.9 0.2 0.0295.6 92.4 392.7 6.1 37.1 2.9 0.1514.7 14.1 43.0 1.3 14.8 0.3 0.0172.0 65.9 329.5 4.5 18.2 1.9 0.179.9 9.1 26.9 0.8 4.0 0.2 0.03 |
ALT：丙氨酸氨基转移酶；GLDH：谷氨酸脱氢酶；
AST：天冬氨酸氨基转移酶；TBIL：总胆红素；
AP：碱性磷酸酶；EROD：7-乙氧基试卤灵去乙基化酶；
GGT：γ-谷氨酰转移酶
表2
| Baypamun的影响 | |
| 对肝α-生育酚 | |
| α-生育酚nmol/克组织 | |
| 对照SEM | 73.12.2 |
| 四氯化碳SEM | 35.72.3 |
| T.+BaypamunSEM | 38.56.1 |
表3
腹膜内或口服给药PPVO之后，PPVO对施用纤维发生剂量的四氯化碳之后的肝星形细胞转化的影响(第一个实验系列)
| 纤维化 | 施药 | 剂量 | α-SMA(％) |
| 第1组完整 | 口服空胶囊+腹膜内施用注射用水 | --- | 0.28±0.04 |
| 第2组四氯化碳 | 口服空胶囊+腹膜内施用注射用水 | --- | 2.76±0.79 |
| 第3组四氯化碳 | 腹膜内施用注射用水中的PPVO+口服空胶囊 | 5×106TCID50/动物 | 5.05±2.00 |
| 第4组四氯化碳 | 口服施用胶囊内的PPVO+腹膜内施用注射用水 | 5×106TCID50/动物 | 1.46±0.34 |
表4
腹膜内或口服给药PPVO之后，PPVO对施用纤维发生剂量的四氯化碳之后的肝星形细胞转化的影响(第二个实验系列)
| 纤维化 | 施药 | 剂量 | α-SMA(％) |
| 完整第1组 | 口服空胶囊+腹膜内施用注射用水 | --- | 0.20±0.04 |
| 四氯化碳第2组 | 口服空胶囊+腹膜内施用注射用水 | --- | 3.18±0.56 |
| 四氯化碳第3组 | 腹膜内施用注射用水中的PPVO+口服空胶囊 | 5×106TCID50/动物 | 1.22±0.35 |
| 四氯化碳第4组 | 口服施用胶囊内的PPVO+腹膜内施用注射用水 | 5×106TCID50/动物 | 1.55±0.34 |
Claims (10)
1.副痘病毒的分离物用于制备对人器官纤维化有预防或治疗作用的药物的用途。
2.副痘病毒，例如D1701毒株，orf-11毒株，希腊orf毒株176，希腊orf毒株155以及新西兰(NZ)毒株的分离物用于制备对人器官纤维化有预防或治疗作用的药物的用途。
3.根据权利要求1-2的副痘病毒的分离物的用途，其特征在于用于制备对人器官纤维化有预防或治疗作用的药物的新西兰(NZ)毒株是NZ2、NZ7和NZ10毒株。
4.通过传代或适应合适的细胞而修饰的权利要求1-3的副痘病毒用于制备对人器官纤维化有预防或治疗作用的药物的用途。
5.通过传代或适应合适的细胞而修饰的权利要求1-3的副痘病毒用于制备对人器官纤维化有预防或治疗作用的药物的用途，其特征在于使用人细胞，例如WI-38或MRC-5，牛细胞，例如BK-K13A47/Reg或MDBK，和绵羊细胞，例如MDOK，用于传代或适应。
6.根据权利要求1-5的病毒的部分或片段用于制备对人器官纤维化有预防或治疗作用的药物的用途，其特征在于所述部分理解为利用合适的载体，例如牛痘病毒，在合适的体系，例如成纤维细胞培养物中表达的基因组或亚基因组片段，所谓片段理解为是表达的或物理破碎的病毒颗粒通过生物化学纯化作用例如色谱法而获得的级分。
7.根据权利要求1-6的一种分离物与其它药物一起用于制备对人器官纤维化有预防或治疗作用的药物和药物制剂的用途。
8.绵羊副痘病毒D1701本身或者与其它药物一起用于制备对人器官纤维化有预防或治疗作用的药物和药物制剂的用途。
9.绵羊副痘病毒D1701或NZ2的制剂作为鉴定抗纤维化物质测试中评价抗纤维化作用的参考标准的用途。
10.根据权利要求8的绵羊副痘病毒D1701的用途，其特征在于所述药物制剂和药物适合口服给药。
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| DE10122233A DE10122233A1 (de) | 2000-07-11 | 2001-05-08 | Verwendung von Stämmen des Parapoxvirus ovis gegen Organfibrosen |
| DE10122233.5 | 2001-05-08 | ||
| PCT/EP2001/007978 WO2002004019A2 (de) | 2000-07-11 | 2001-07-11 | Verwendung von stämmen des parapoxvirus ovis gegen organfibrosen |
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| AU2002353031A1 (en) | 2001-12-07 | 2003-06-23 | Bayer Corporation | Use of parapox b2l protein to treat cancer and modify immune responses |
| US6752995B2 (en) * | 2002-04-15 | 2004-06-22 | Board Of Regents, The University Of Texas System | Nucleic acid and polypeptide sequences useful as adjuvants |
| EP1574211A1 (en) * | 2004-03-09 | 2005-09-14 | Inserm | Use of antagonists of the CB1 receptor for the manufacture of a composition useful for the treatment of hepatic diseases |
| WO2012045473A1 (en) * | 2010-10-07 | 2012-04-12 | Technische Universität München | Viruses for the treatment of fibrosis |
| EA201891848A1 (ru) * | 2016-02-16 | 2019-02-28 | Осака Юниверсити | Фармацевтическая композиция для применения в лечении фиброза |
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| DE2714665A1 (de) * | 1977-04-01 | 1978-10-05 | Mayr Anton | Praeparat zur behandlung von herpes zoster und anderen herpes-infektionen, sowie verfahren zu seiner herstellung |
| US4360510A (en) * | 1979-11-30 | 1982-11-23 | Proctor Julian W | Method for screening anti-tumor agents of the reticulo-endothelial stimulant class |
| US4663306A (en) * | 1983-09-23 | 1987-05-05 | Ribi Immunochem Research, Inc. | Pyridine-soluble extract-refined detoxified endotoxin composition and use |
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| PT885013E (pt) * | 1996-04-15 | 2002-01-30 | Anton Mayr Prof Dr Med Vet Dr | Utilizacao de indutores de para-imunidade multipotentes baseados em poxvirus ou parapoxvirus atenuados e nao imunogenicos para a fabricacao de medicamentos |
| DE19922407A1 (de) * | 1999-05-14 | 2000-11-16 | Bayer Ag | Organ-, gewebs- und zellspezifisches Immuntherapeutikum für chronische virale Infektionen, sowie entzündliche, degenerative und proliferative Erkrankungen insbesondere der Leber sowie Krebs auf der Basis von rekombinantem Parapoxvirus |
| IL139593A (en) * | 2000-11-09 | 2010-12-30 | Biogem Optical Ltd | Method for the detection of viable microorganisms |
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