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    • 5. 发明申请
    • C-1 INHIBITOR PREVENTS NON-SPECIFIC PLASMINOGEN ACTIVATION BY A PROUROKINASE MUTANT WITHOUT IMPEDING FIBRIN-SPECIFIC FIBRINOLYSIS
    • C-1抑制剂预防非特异性PLASMINOGEN由PROUROKINASE突变体的活化而不影响FIBRIN特异性纤维蛋白溶解
    • WO2010002453A2
    • 2010-01-07
    • PCT/US2009003895
    • 2009-06-30
    • THROMBOLYTIC SCIENCE INTERNATGUREWICH VICTORPANNELL RALPH
    • GUREWICH VICTORPANNELL RALPH
    • A61K38/57A61P7/02
    • A61K38/49A61K38/57C12Y304/21031A61K2300/00
    • A mutant prourokinase plasminogen activator (M5) was developed to make prouPA less subject to spontaneous conversion to tcuPA in blood at therapeutic concentrations. Two-chain M5 was shown to form complexes with C l- inhibitor, which was the principal inhiibitor of tcM5 in plasma. The effect of supplemental additions of Cl- inhibitor on fibrinolysis and fibrinogenolysis by M5 was determined. Supplemental Cl- inhibitor restored the stability of high- dose M5 and prevented fibrinogenolysis but not fibrinolysis, the rate of which was not compromised by the inhibitor.. Due to higher dose tolerance of M5 in the presence of supplemental Cl -inhibitor, the rate of fibrin-specific lysis reached that achievable by nonspecific fibrinolysis, which is the maximum possible for a plasminogen activator.. Plasma Cl-inhibitor stabilized M5 in plasma by inhibiting tcM5 which would otherwise greatly amplify non-specific plasminogen activation causing more tcM5 generation from M5.. This unusual dissociation of inhibitory effects, whereby fibrinogenolysis and not fibrinolysis is inhibited, has significant implications for improving the safety and efficacy of fibrinolysis. Methods of reducing bleeding and non-specific plasminogen activation during fibrinolysis by administering M5 along with exogenous Cl - inhibitor are disclosed.
    • 开发了一种突变型prourokinase纤溶酶原激活物(M5),使得prouPA较少受治疗浓度自发转化为血液中的tcuPA。 显示双链M5与C1-抑制剂形成复合物,其是血浆中tcM5的主要诱导剂。 测定补充添加Cl抑制剂对M5纤维蛋白溶解和纤维蛋白原分解的影响。 补充的Cl-抑制剂恢复了高剂量M5的稳定性,并且防止纤维蛋白溶解而不是纤维蛋白溶解,其速率不受抑制剂的影响。由于在补充的Cl抑制剂存在下M5的较高剂量耐受性, 纤维蛋白特异性裂解达到可通过非特异性纤维蛋白溶解实现,这是血纤维蛋白溶酶原激活剂的最大可能。血浆Cl抑制剂通过抑制tcM5稳定M5,否则会大大扩增非特异性纤溶酶原激活,从M5引起更多的tcM5产生。 这种不寻常的抑制作用的解离,其中纤维蛋白原分解而不是纤维蛋白溶解被抑制,对于提高纤维蛋白溶解的安全性和有效性具有重要的意义。 公开了通过给予M5与外源性Cl-抑制剂在纤维蛋白溶解期间减少出血和非特异性纤溶酶原激活的方法。