Highly effective fibrinolysis by a sequential synergistic combination of mini-dose tPA plus low-dose mutant proUK.
Highly effective fibrinolysis by a sequential synergistic combination of mini-dose tPA plus low-dose mutant proUK.
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DOI：
10.1371/journal.pone.0122018
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Gurewich V
中科院分区：
文献类型：
--
作者：
Pannell R;Li S;Gurewich V
tPA或proUK单药治疗的溶栓结果未达到预期。由于这些天然活化剂具有内在互补性，因此可以利用这种特性来获得协同优势;然而，这几乎没有进行过评估。ProUK不再可用，因为在药理学浓度下，它在血浆中转化为UK。因此，开发了一种单位点proUK突变体M5来解决这个问题，并用于本研究。在血浆环境中使用预先形成的荧光素化24小时凝块而不是通过标准自动化方法测量纤维蛋白溶解，因为proUK/M5对凝血酶灭活和纤溶酶活化敏感。确定了tPA或M5单独使用可达到的最短50%凝块溶解时间：平均时间分别为55和48分钟。这些基准与6%的tPA单药治疗剂量和40%的M5剂量相匹配：平均溶解时间47分钟，相关纤维蛋白原溶解较少。结果表明，tPA的作用仅限于启动纤溶，这是由M5完成，然后tcM 5。血浆C1-抑制剂通过M5抑制纤维蛋白原溶解，提供保护免受proUK不可用的副作用。总之，通过利用每种激活剂的互补性质和顺序作用模式，可以实现比传统单一疗法更有效的纤维蛋白溶解，同时具有更少的非特异性效应。需要进行体内验证，但在之前的临床试验中，使用tPA和proUK的类似组合（5%和50%单药治疗剂量）已经获得了非常有希望的结果。
Results of thrombolysis by monotherapy with either tPA or proUK have not lived up to expectations. Since these natural activators are inherently complementary, this property can be utilized to a synergistic advantage; and yet, this has undergone little evaluation. ProUK is no longer available because at pharmacological concentrations it converts to UK in plasma. Therefore, a single site proUK mutant, M5, was developed to address this problem and was used in this study. Fibrinolysis was measured using preformed fluoresceinated 24 h old clots in a plasma milieu rather than by the standard automated method, because proUK/M5 is sensitive to inactivation by thrombin and activation by plasmin. The shortest 50% clot lysis time that could be achieved by tPA or M5 alone was determined: mean times were 55 and 48 minutes respectively. These bench marks were matched by 6% of the tPA monotherapy dose combined with 40% that of M5: mean lysis time 47 minutes with less associated fibrinogenolysis. Results showed that the tPA effect was limited to initiating fibrinolysis which was completed by M5 and then tcM5. Plasma C1-inhibitor inhibited fibrinogenolysis by M5, providing protection from side effects not available for proUK. In conclusion, by utilizing the complementary properties and sequential modes of action of each activator, more efficient fibrinolysis with less non-specific effects can be achieved than with traditional monotherapy. In vivo validation is needed, but in a previous clinical trial using a similar combination of tPA and proUK (5% and 50% monotherapy doses) very promising results have already been obtained.
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DOI：
10.1111/j.1432-1033.1997.00316.x
发表时间：
1997-04-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Petersen, LC
通讯作者：
Petersen, LC
影响因子：
15.9
作者：
GUREWICH, V;PANNELL, R;MAO, JI
通讯作者：
MAO, JI
影响因子：
120.7
作者：
HACKE, W;KASTE, M;HENNERICI, M
通讯作者：
HENNERICI, M
影响因子：
10.4
作者：
Gurewich, V.;Pannell, R.;Badylak, S. F.
通讯作者：
Badylak, S. F.
影响因子：
15.9
作者：
PANNELL, R;BLACK, J;GUREWICH, V
通讯作者：
GUREWICH, V