CN1210468A - 含有氧化氮的药物组合物 - Google Patents
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Abstract
本发明涉及含有一氧化氮(NO)的,无菌的,可注射的生理上可接受的溶液的药物组合物,其制备方法,以及检测生理上存在的NO的方法。有关本发明的NO溶液,局部高剂量的NO可引发血管(如冠状血管)中靶向的局部生物学作用,如平滑肌系统的松弛,血小板等的粘附的抑制等等,而不会产生由高剂量引起的全身性的副作用,如血压的临界性降低。有关本发明的检测方法,可在人/哺乳动物的全血中检测到内皮机能失调的存在。
Description
本发明涉及含有氧化氮(NO)的，无菌的，可注射的生理上可接受的溶液的药物组合物，其制备方法和生理上存在的NO的检测方法。
生理上存在的氧化氮(NO)可通过多种生物学功能影响动脉硬化发展中的必要的关键性的过程，例如：使血管平滑肌松弛，抑制血小板、粒细胞和单核细胞与血管壁的粘附，抑制分泌性平滑肌细胞的增殖等，并能直接影响到内皮代谢。
因此，最近几年来已阐明内皮中的氧化氮(NO)可通过很多种机理影响血管壁的代谢以及功能：1．通过刺激可溶性的鸟苷酸环化酶而导致血管平滑肌的松弛，和2．由此参与外周血管阻力和动脉血压的调节，3．另外，可抑制血管平滑肌细胞的有丝分裂发生和增殖，4．抑制血小板、单核细胞和嗜中性粒细胞与血管壁的粘附，和5．通过例如改变表面膜上粘附分子的表达可直接影响到内皮细胞的代谢。其一般性的评论见于：
1．Moncada,S.和Higgs,A.,L-精氨酸-氧化氮途径，新英格兰医学杂志，329:2002-2012,1993。
2．Radomski,M.W.和Moncada,S.，通过氧化氮调节血管的稳态，Thromb.Haemost,70:36-41,1993。
3．Snyder,S.H.和Bredt,D.S.，氧化氮的生物学作用，SciAM266(5):68-77,1992。
4．Gibbons,G.H.和Dzau,V.J.，形成中的血管模型重建概念，新英格兰医学杂志，330:1431-1438,1994。
所有上述方法表示在动脉硬化的病理性血管壁变化进展方面的关键事件。认识到的动脉硬化的危险因素是：动脉高血压，血脂蛋白过高，糖尿病，尼古丁消耗，可能还有年龄和性别，所述危险因素也影响内皮功能(见Moncada,S和Higgs,A,L-精氨酸-氧化氮途径，新英格兰医学杂志，329:2002-2012,1993；Ross,R，粥样硬化的发病机制-最新进展，新英格兰医学杂志，324(No.8):488-500,1986；Safar,M.E和Frohlich,E.D，高血压的动脉系统，未来展望，高血压，26:10-14,1995)。
然而，内皮NO合成的经改变的活性的病理生理学有效的证明仅仅在具有经培养的细胞或分离的器官循环系统(其中NO或其分解代谢产物的定量是可能的)的实验制剂中是成功的。但是，关于这一点，在人体内，迄今为止只有在各种血管区域中与改变的乙酰胆碱诱导的血流反应有关的现象学发现被描述为内皮依赖的血管舒张的间接标记物。在人体内作为内皮机能失调指示剂的内皮组成性NO合成活性的精确量化在以前是不可能的。
最后，在过去的几十年内，很多类型的用于治疗动脉硬化的血管壁改变，如冠心病的NO供体已经被成功地开发和应用(在这方面总的看法参见Feelisch,M，由氮血管舒张药形成氧化氮的生化途径：外源NO供体的适当选择和NO水溶液的制备和运用方面，J.Cardiovasc.Pharmacol,17(suppl.3):S25-S33,1991；Feelisch,M和Noack,E，氮血管舒张药的体外代谢和它们向作用于血管的类型的转化，心脏障碍的机制和处理，由Lewis,B.S和Kimchi,A..编辑，Springer:Berlin,Heidelberg,1991,p.241-255；Harrison,D.G和Bates,J.N，氮血管舒张药，循环，87:1461-1467,1993；DeCaterina,R.Nitrate als Thrombozytenfunctionshemmer[硝酸盐作为血小板功能的抑制剂]，Z.Kardiol,83:463-473,1994)。
NO供体在循环系统的动脉以及静脉部分起作用，也NO-依赖性地影响血管壁与血液的细胞成分(血小板，中性粒细胞和单核细胞)的相互作用。但是，至今还没有使NO以真正的NO溶液的形式直接用于人体循环系统的治疗进展。其根源在于NO在人体循环系统中极其迅速地代谢和失活，一方面，阻止成功和定向的将NO导入人体循环系统，但在另一方面，具有这样的优点，即潜在地可以局部获得很高的NO剂量而不伴随系统副作用。关于上述NO的广泛的抗动脉硬化性质，尤其是最后一点对于外周和冠状动脉中所有的血管内干扰似乎特别有意义。
现在，在高度发达的工业国如美国和德国，每年进行超过370000例冠状动脉干扰(PTCA，等等)(参见Gleichmann,U.,Mannebach,H和Lichtlen,P.10.Bericht über Struktur und Leistungszahlen derHerzkatheterlabors in der Bundesrepublik Deutschland[德国心导管实验室结构和工作报告]，Z.Kardiol,84:327-333,1995)。
最初的成功率达到90％，但10％的PTCA导致早期闭塞或血栓形成。另外，根据引用的文献，在25-50％的病例中，手术之后的头六个月会形成再狭窄。世界范围内实施的血管成形术的总数估计到2000年会超过一百万，也就是说每年预计会发生高达400000例再狭窄。这些数字强调迫切需要治疗以降低PTCA后的急性或慢性再狭窄率。用钙拮抗剂，有机硝酸酯和ACE抑制剂干扰的系统药理研究已经显示对于再狭窄率没有效果。甚至大量其它机械方法(directional atherectomy，激光血管成形术，斯坦特移植，rotablation)也未能导致再狭窄率的全面降低，这些方法限于某些龛指示。最近，这导致了新LDD(局部药物输送)系统，如被包被的斯坦特修复术，Kaplan-simpson灌注导管(斯坦福大学)，微灌注导管(Cordis)或多孔PTCA气球导管(ACS)的发展。使用这些系统似乎第一次可以将高局部剂量的药物输送到冠状动脉的血管壁。由于NO在人体血液中被迅速代谢，现在，在冠状动脉干扰期间将NO以高剂量局部导入冠状动脉，并因此以引言中所述的方式在局部点应用上述NO的所有生物学作用，如血管平滑肌松弛，抑制血小板和嗜中性单核细胞的粘附，而不伴随系统作用，例如，由于高剂量而产生的临界性血压下降，看来是极其需要和有用的。
如在开始时提到的，动脉高血压，血脂蛋白过高和糖尿病是主要的致动脉粥样硬化的危险因素。流行病数据指示仅仅动脉高血压及其引发的心血管疾病的总死亡率即达25％；(参见Strauer,B.E.DasHochdruckherz[The hypertensive heart],Berlin,Heidelberg,NewYork:Springer Verlag,1991,pp.1-241)。
至今还不能通过任何常规的临床参数检测被定义为动脉硬化的主要起搏点的内皮机能失调。所以，从早期诊断，以及对这类内皮机能失调的鉴别治疗影响的一般性观点出发，用于心血管医药领域的可靠的检测方法是需要的。
因此，本发明的目的是提供含有NO的，无菌的，可注射的生理上可接受的溶液的药物组合物，其制备方法和检测生理上存在的NO的方法。
此目的已按下文解释和权利要求所公开的内容完成。
根据本发明的实施方案，药物组合物由用NO饱和的0.9％生理氯化钠溶液组成。
在本发明的药物组合物中，在0.9％生理氯化钠溶液中的NO饱和浓度随温度的增加而有区别地降低。
根据本发明特别有利的实施方案，在0℃下，0.9％生理氯化钠溶液中NO饱和浓度的值是3.26 NO[μmo1/L]，在25℃是1.85NO[μmol/L]，在37℃是1.52 NO[μmol/L]，而在50℃是1.26NO[μmol/L]。
根据本发明，药物组合物这样制备：为了排除氧气，将氩气通入无菌的，可注射的0.9％氯化钠溶液直至任何残留的氧气含量都被除去，然后通入NO直到NO在0.9％氯化钠溶液中达到饱和浓度。
根据本发明的另一实施方案，本发明的NO溶液可以用于制备治疗哺乳动物内皮机能失调的药物组合物。
下列实施例1阐述了用于制备无菌的，可注射的NO溶液及其制剂的装置的结构。
实施例1
a)．设备的构造
设备的构造在图1中示出，其中
1．NO 3.0储罐(AGA)；
2．氩气5.0储罐(Linde)；
3．装有在饱和KOH(w∶v)中的5％pyrogallol(pyrogallolz.A.612,Merck)的洗气瓶；
4．装有20％KOH z.A.5033(Merck)的洗气瓶；
5．洗气瓶，干的；
6．三颈圆底烧瓶(250ml)，装有0.9％NaCl溶液，带有3个接地插入物，在每个中掺入：
a)活塞
b)Luer-锁三通活塞
c)三通活塞
7．洗气瓶，空的，作为水阱
8．装有KOH z.A.5033(Merck)的洗气瓶，作为水阱；
A．各个气密接地接头；
B．气密三通活塞；
C．气密接地接头；
D．气密三通活塞；
E．用于连接各个洗气瓶的气密接地接头。所有设备的部件都通过气密管(Tygon R 3603型)连接。TeflonPlastibrand(Brand)密封圈被用于密封，0.2μm(微孔)的Millex型GS滤膜被用作滤膜。b)无菌NO溶液的制备
用浓苛性苏打溶液(NaOH)清洗所有玻璃容器，并且在每种情况下用aquabidestillata和HPLC水再洗涤10次。然后依次连接洗气瓶(3),(4),(5)，其中在(3)中放入在饱和KOH(w∶v)中的pyrogallol(5％)用于除去痕量的氧气，在(4)中放入20％KOH用于除去较高含量的氧化氮，而(5)是干燥的，与其连接的是三颈圆底烧瓶，其中放入NaCl溶液(0.9％)，通入氩气45分钟。将在上升管中发现的NaCl溶液部分丢弃，利用氩气从无菌的气密封的注射器和相关的传导系统以及0.2μm滤膜的无菌过滤器中除去氧气，并且往无氧的，气密封的注射器中注入用于稀释NO溶液需要的NaCl体积。最后，将氧化氮(NO)通入系统45分钟。
重新用氩气将氧气从过滤器和将存在的稀溶液导入注射器的传导系统中完全除去。在上升管中发现的NO溶液部分被丢弃，之后将整个传导系统和无菌过滤器用NO溶液充分洗涤。所需体积的NO溶液立即转入预先用给出的NaCl溶液经三通活塞(B)通过无菌过滤器(在各种情况下可以是安培，小瓶，注射器，等等)制备的气密的首次包装。
本发明的另一方案是定量检测哺乳动物内皮机能失调的检测方法。
以前，动脉高血压，糖尿病和/或血脂蛋白过高的患者的内皮机能失调只能通过高花费的诊断方法来确定，如动脉穿刺，随后局部施用乙酰胆碱，与标准的适当年龄的小组相比使被检查的循环区域中产生的血流反应的血液动力学量化(参见Calver,A.,Collier,J和Vallance,P，抑制和刺激胰岛素依赖型糖尿病患者的前臂动脉床中氧化氮的合成，临床研究杂志，90:2548-2554,1992；Creager,M.A.,Cooke,J.P.,Mendelsohn,M.E.,Gallagher,S.J.,Coleman,S.M.,Loscalzo,J和Dzau,V.J，血胆甾醇过多患者的前臂阻力血管的受损害的血管舒张，临床研究杂志，86:228-234,1990；Kelm,M.,Preik,M.,Motz,W和Strauer,B.E,Endotheliale Funktionbei Patienten mitarteriellerHypertonie[动脉高血压患者的内皮功能]，见于ZellulareMechanismen der Herz-Kreislaufregulation[心血管调节的细胞机制]，由Gante,D.编辑，Stuttgart:Schattauer,1993,p.139-150；Linder,L.,Kiowski,W.,Bühler,F.R和Luscher,T.F，人前臂体内循环中衍生自内皮的松弛因子释放的的间接证据，循环，81:1762-1767,1990;Panza,J.A.,Epstein,S.E和QuyyumiA.A.，血管紧张的生理节奏变化及其与交感神经血管收缩活性的关系，新英格兰杂志，325:986-990,1990)。
另外，在对此纯现象学方法的纵向研究中，我们试图用文献证明通过ACE抑制剂的降压疗法对例如动脉高血压患者的内皮机能失调的可能的治疗效果，然而，我们未能成功，因为研究探讨的方法变化很大(见Creager,M.A和Roddy,M.-A,Captopril和enalapril对高血压患者内皮功能的影响，高血压，24:499-505,1994)。
另外，通过依赖于变化的乙酰胆碱的血流反应的纯现象学方法不能区分动脉硬化诱导的内皮机能失调的程度是基于降低的NO合成和/或增加的NO分解代谢(见Kelm,M.,Preik,M.,Koster,A.,Heinzelmann,A.,Motz,W.，和Strauer,B.E，给原发性高血压患者施用有机硝酸酯后氧化氮依赖型血管舒张的减弱，见：氧化氮生物学，由Moncada,S编辑，伦敦：Portland出版公司，1994,p509-513；Kelm,M.,FeelischM.,Krebber,T.,Deussen,A.,Motz,W和Strauer,B.E，氧化氮(NO)在调节高血压大鼠心脏的冠状血管紧张中的作用；维持NO的形成能力并增加NO的基本生成，高血压，25:186-193,1995；Kelm,M.,Preik,M.,Hafner,D.,Strauer,B.E，内皮机能失调的高血压患者中涉及对氧化氮的受损的血流反应的多因子过程的证据，高血压，出版中，1996)。
本发明的检测方法允许测量哺乳动物全血、尤其是人的全血中的亚硝酸盐含量，在人的循环系统中，亚硝酸盐是内皮组成型NO合成之活性的特异性的标记物。
下列实施例2解释了检测方法。实施例2人全血中亚硝酸盐的检测方法
将1ml血置于含有1ml的1mol/L浓NaOH终止溶液的注射器中，随后立即加入50μl的1mol/L浓磷酸(H3PO4)以中和所得的血/NaOH混合物，以10,000g的转速将所述混合物置于离心机(Universal30RF,hettichfirm)中离心5分钟，将所得的上清液轻轻倾入超滤管(Sartorius截留10,000)中，在2,000g的转速下重新离心15分钟(Eppendorf离心管5402C,Eppendorffirm)。将所得的水-白色超滤物转移到能承受1.5ml体积的反应容器中，并用HPLC水按1∶10的比率稀释。
接着可以立即进行分析，或者将所得样品储存于-80℃下放置1个月。药理学研究1．亚硝酸盐作为cNOS的特异性诊断试剂
以我们自己的有关人心血管系统中NO代谢的知识作为基础，准确地测定作为内皮组成型NO合成之活性的特异性标记物的亚硝酸盐。
使用实施例2中所述的特异性的终止溶液，它可以防止人血中的亚硝酸盐快速地转变成硝酸盐，从而在制备样品的过程中不会导致亚硝酸盐的任何可估计到的损失，而且在样品的制备和随后的测定之后能够回收亚硝酸盐。另外，还发展了高度敏感的测定方法，该方法联合使用整合到2-通道HPLC系统中的紫外光和电化学检测，使得能够同时和高度敏感地定量测定人或哺乳动物全血样品中的亚硝酸盐和硝酸盐，用试验受试者取得了下列结果：
根据实验性的研究，已显示出在基础条件下，动脉和静脉内皮细胞中NO的产生有所不同，已发现人动脉血样品中所含的亚硝酸盐浓度(1310±50nmol/L)比静脉血管区域的样品中的(1100±40nmol/L)高。如上所述，与之形成对比的是硝酸盐的血清值并未显示出特别的差异，人心血管系统的动脉和静脉部分的样品中测得的平均值皆为42±6μmol/L(n=5)。另外，通过人前臂循环系统模型表明：在静止时，将内皮-依赖性扩张剂乙酰胆碱和缓激肽局部灌注到A.Brachialis会剂量依赖性地导致血流量4倍以上的增加(n=7)。在血流量增加的过程中，有文献证明来自Vena cubitalis的样品中亚硝酸盐血清浓度呈剂量-依赖性地增加，尤其是对两个中介体而言。因此，尽管前臂血流区的血流量增加4倍以上，但在灌注了两种组成型内皮NO合成刺激剂后，亚硝酸盐的血清浓度呈特异性地增加。这意味着亚硝酸盐特异性地和剂量依赖性地反映了此血流区中增加的内皮NO产生。另外，针对两种物质，发现了血流量增加和血清中亚硝酸盐浓度的增加以及通过前臂血流区释放的速率之间的高度重要的关系(见图2和3)。另外，在对照研究中，显示出不依赖于内皮的血管舒张药罂粟碱导致血流量类似地增加4倍，但未论证亚硝酸盐血清浓度的增加。另外，同时灌注L-NMMA作为组成型内皮NO合成的立体特异性抑制剂(6μmol/min)显示出与对照条件(n=3)相比，血流反应和亚硝酸盐的血清浓度降低了40％。概括地说，这些研究证实了通过先进的方法学，第一次可以局部地和特异性地定量检测血管系统中内皮组成型NO合成的活性，因此可诊断其与内皮机能失调有关的功能性状态。2．左哺乳动物的循环系统，特别是人循环系统中使用本发明的可靠的NO溶液的疗法
由于NO在人循环系统中的快速代谢，本发明的可靠的NO溶液可被用作治疗剂以得到局部非常高效的NO浓度，而不会同时引发有害的全身性副作用。选择前臂循环的模型，以逐渐增加的剂量局部使用含水的NO标准以检测受试者。由于NO在人血中的代谢，连续的灌注不适于此疗法，而大丸剂技术实际上更有效。所选择的储存液的浓度和应用的动力学必需选择得使对应于环形的循环体积和从应用点到阻力动脉的转运时间的含水NO溶液的清楚限定的大丸剂能可再生地到达靶向的血流区。从图4和5可看出，利用此大丸剂技术，在顶点以及血流反应曲线下表面以上，NO可再生地导致血流量呈剂量依赖性地增加，而不会导致全身性的可测的血压降低。另外，其它的毒理学研究表明在研究过程中使用NO，在相关剂量下，试验受试者血液中的正铁血红蛋白含量没有变化。另外，使用上述终止溶液显示出：在此血流区域使用NO的过程中，Vena cubitalis中的血清亚硝酸盐浓度增加了111±12％，而亚硝酸盐的血清浓度(45±8μmol/L)在干扰过程中没有显著的变化。对通过大丸剂技术使用的此含水NO标准的局部血流反应与各个试验受试者的体表区域高显著地相关，并且不依赖于心率或全身性动脉血压的水平。3．图2-5的解释图2
局部动脉内灌注剂量逐渐增加的乙酰胆碱后(数据见图6)，前臂血流量变化(FBF)和亚硝酸盐的血清浓度(A)以及前臂循环中NO或亚硝酸盐的释放速率之间的关系。线性回归分析显示r=0.997和p=0.003。图3
局部动脉内灌注剂量逐渐增加的缓激肽后(数据见图7)，前臂血流量变化(FBF)和亚硝酸盐的血清浓度(A)以及前臂循环中NO或亚硝酸盐的释放速率之间的关系。线性回归分析显示r=0.985和p=0.001。图4
前臂循环中NO诱导的血管舒张的剂量反应曲线。体积描记法测定的前臂血流量(FBF)增加对NO剂量作图，所述NO以大丸剂技术在NO溶液的盐水标准液中被使用(n=6，平均值±SEM)。图5
前臂循环中NO诱导的血管舒张的剂量反应曲线。曲线以下区域作图的是FBF变化，试验受试者与图4/5中相同(n=6，平均值±SEM)。
Claims (6)
1．无菌的，可注射的，生理上可接受溶液的药物组合物，其特征在于该组合物具有随温度增加而降低的氧化氮(NO)含量，并且不含氧，由用NO饱和的0.9％氯化钠溶液组成。
2．根据权利要求1的药物组合物，其特征在于0.9％氯化钠溶液中的NO和浓度随温度的增加而有区别地降低。
3．根据权利要求1和2的药物组合物，其特征在于0.9％氯化钠溶液中的NO饱和浓度在0℃下是3.26 NO[μmol/L]，在25℃是1.85NO[μmol/L]，在37℃是1.52 NO[μmol/L]，而在50℃是1.26NO[μmol/L]。
4．制备根据权利要求1-3的药物组合物的方法，其特征在于为了排除氧气，将氩气通入无菌的，可注射的0.9％氯化钠溶液直至任何残留的氧气含量都被除去，然后通入NO直到NO在0.9％氯化钠溶液中达到饱和浓度。
5．不含氧的，由NO饱和的0.9％氯化钠溶液组成的无菌的，可注射的生理上可接受的溶液在制备治疗哺乳动物内皮机能失调的权利要求1-3的药物组合物中的用途。
6．定量测定哺乳动物内皮机能失调的检测方法，其特征在于将充分排除氧的已测量体积的全血置于类似体积的浓NaOH终止溶液(1mol/L)中，加入50μl浓磷酸(1mol/L)，以10,000g的转速离心5分钟，将所得的上清液轻轻倾入超滤管中，在2,000g的转速下重新离心15分钟，然后用HPLC水按1∶10的比率稀释所得的超滤物，按已知的方式测定亚硝酸盐的含量。
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| Application Number | Priority Date | Filing Date | Title |
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| DE1996104361 DE19604361C2 (de) | 1996-02-07 | 1996-02-07 | Verwendung gasdichter Primärpackmittel für pharmazeutische Zusammensetzungen |
| DE19604361.1 | 1996-02-07 |
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| CN1210468A true CN1210468A (zh) | 1999-03-10 |
| CN1126549C CN1126549C (zh) | 2003-11-05 |
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| US (1) | US6103769A (zh) |
| EP (2) | EP1121934A1 (zh) |
| JP (1) | JPH11507948A (zh) |
| KR (1) | KR100298228B1 (zh) |
| CN (1) | CN1126549C (zh) |
| CA (1) | CA2244454C (zh) |
| DE (1) | DE19654895C2 (zh) |
| HK (1) | HK1045640A1 (zh) |
| NO (1) | NO983135L (zh) |
| WO (1) | WO1997028810A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1308438C (zh) * | 2002-01-11 | 2007-04-04 | 大卫·R·怀特洛克 | 含有氨氧化细菌的化合物以及使用的方法 |
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| DE19854808C2 (de) * | 1998-11-27 | 2001-03-01 | Sanol Arznei Schwarz Gmbh | Detektionsverfahren |
| CA2383974A1 (en) * | 1999-09-08 | 2001-03-15 | Nitromed Inc. | Methods of treating and preventing congestive heart failure with hydralazine compounds and isosorbide dinitrate or isosorbide mononitrate |
| US7537785B2 (en) * | 1999-10-29 | 2009-05-26 | Nitromed, Inc. | Composition for treating vascular diseases characterized by nitric oxide insufficiency |
| EP1244455B1 (en) | 1999-10-29 | 2009-07-22 | Nitromed, Inc. | Methods of treating vascular diseases characterized by nitric oxide insufficiency |
| US7235237B2 (en) * | 1999-10-29 | 2007-06-26 | Nitromed, Inc. | Methods of treating vascular diseases characterized by nitric oxide insufficiency |
| US7708989B2 (en) * | 1999-10-29 | 2010-05-04 | Nitromed, Inc. | Methods of treating vascular diseases characterized by nitric oxide insufficiency |
| US20030120256A1 (en) * | 2001-07-03 | 2003-06-26 | Syntheon, Llc | Methods and apparatus for sclerosing the wall of a varicose vein |
| US7077836B2 (en) * | 2000-07-21 | 2006-07-18 | Vein Rx, Inc. | Methods and apparatus for sclerosing the wall of a varicose vein |
| US20050113798A1 (en) * | 2000-07-21 | 2005-05-26 | Slater Charles R. | Methods and apparatus for treating the interior of a blood vessel |
| US20050107738A1 (en) * | 2000-07-21 | 2005-05-19 | Slater Charles R. | Occludable intravascular catheter for drug delivery and method of using the same |
| US6432077B1 (en) | 2000-12-26 | 2002-08-13 | Sensormedics Corporation | Device and method for treatment of surface infections with nitric oxide |
| US20030134332A1 (en) * | 2001-11-28 | 2003-07-17 | Boykin Joseph V. | Diagnosis of endothelial dysfunction by nitric oxide bioactivity index |
| EP1701747B1 (en) * | 2004-01-07 | 2014-03-12 | Noxilizer, Inc. | Sterilisation method |
| US8017074B2 (en) | 2004-01-07 | 2011-09-13 | Noxilizer, Inc. | Sterilization system and device |
| CA2573562A1 (en) * | 2004-07-16 | 2006-02-23 | Nitromed, Inc. | Compositions and methods related to heart failure |
| JP2008509781A (ja) * | 2004-08-19 | 2008-04-03 | ベインアールエックス，インコーポレイティド | 薬物送達用の閉塞可能な血管内カテーテル及びこれを使用する方法 |
| SE0402221D0 (sv) | 2004-09-14 | 2004-09-14 | Aerocrine Ab | Treatment of insufficient perfusion |
| KR20060072734A (ko) * | 2004-12-23 | 2006-06-28 | 두산인프라코어 주식회사 | 건설중장비의 압축공기 공급장치 |
| PL1879599T3 (pl) * | 2005-04-20 | 2014-03-31 | Hutchinson Fred Cancer Res | Sposoby, kompozycje i wyroby do zwiększania przeżywalności komórek, tkanek, narządów i organizmów |
| EP1984010A4 (en) * | 2006-02-17 | 2010-09-08 | Nitromed Inc | METHOD FOR USE OF HYDRALAZIN COMPOUNDS AND ISOSORBIDE DINITRATE OR ISOSORBIDE MONONITRATE |
| US20080200873A1 (en) * | 2007-02-16 | 2008-08-21 | Alejandro Espinosa | Methods and Apparatus for Infusing the Interior of a Blood Vessel |
| US8157747B2 (en) | 2008-02-15 | 2012-04-17 | Lary Research & Development, Llc | Single-use indicator for a surgical instrument and a surgical instrument incorporating same |
| US8425837B2 (en) | 2009-02-23 | 2013-04-23 | Noxilizer, Inc. | Device and method for gas sterilization |
| GB2579240B (en) | 2018-11-27 | 2020-12-16 | Attgeno Ab | New processes, compositions and medical uses |
| CN112107595A (zh) * | 2019-06-19 | 2020-12-22 | 华南理工大学 | 一种芳基硫酸酯酶和葡萄糖苷醛酸酶抑制剂及其制备方法和应用 |
| GB202007929D0 (en) | 2020-05-27 | 2020-07-08 | Attgeno Ab | New medical uses |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH05507226A (ja) * | 1990-06-15 | 1993-10-21 | コートラック・メディカル・インコーポレーテッド | 薬物投与装置および方法 |
| US5536241A (en) * | 1990-12-05 | 1996-07-16 | The General Hospital Corporation | Methods and devices for relaxing smooth muscle contractions |
| US5428070A (en) * | 1993-06-11 | 1995-06-27 | The Board Of Trustees Of The Leland Stanford Junior University | Treatment of vascular degenerative diseases by modulation of endogenous nitric oxide production of activity |
| JPH07165610A (ja) * | 1993-12-15 | 1995-06-27 | Hiroshi Maeda | 血圧制御剤 |
| DE4410997A1 (de) * | 1994-03-30 | 1995-10-26 | Isis Pharma Gmbh | Pharmazeutische Zubereitungen und Arzneistoffe zur Prävention und Behandlung endothelialer Dysfunktionen |
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- 1997-02-03 JP JP9528127A patent/JPH11507948A/ja active Pending
- 1997-02-03 KR KR1019980706102A patent/KR100298228B1/ko not_active IP Right Cessation
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- 1997-02-03 US US09/125,085 patent/US6103769A/en not_active Expired - Fee Related
- 1997-02-03 CN CN97192105A patent/CN1126549C/zh not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1308438C (zh) * | 2002-01-11 | 2007-04-04 | 大卫·R·怀特洛克 | 含有氨氧化细菌的化合物以及使用的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR19990082372A (ko) | 1999-11-25 |
| JPH11507948A (ja) | 1999-07-13 |
| EP0938324A1 (de) | 1999-09-01 |
| US6103769A (en) | 2000-08-15 |
| NO983135L (no) | 1998-07-07 |
| KR100298228B1 (ko) | 2001-10-26 |
| CA2244454A1 (en) | 1997-08-14 |
| CN1126549C (zh) | 2003-11-05 |
| EP1121934A1 (de) | 2001-08-08 |
| CA2244454C (en) | 2002-12-10 |
| WO1997028810A1 (de) | 1997-08-14 |
| HK1045640A1 (zh) | 2002-12-06 |
| DE19654895C2 (de) | 2000-07-27 |
| DE19654895A1 (de) | 1997-10-02 |
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