公开(公告)号：US07074401B2

公开(公告)日：2006-07-11

申请号：US10826826

申请日：2004-04-16

申请人： Victor Gurewich ,  John N. Williams ,  Jian-Ning Liu ,  Paolo Sarmientos ,  Massimiliano Pagani

发明人： Victor Gurewich ,  John N. Williams ,  Jian-Ning Liu ,  Paolo Sarmientos ,  Massimiliano Pagani

IPC分类号： A61K38/49 ,  A61K38/36 ,  C12N9/72 ,  C12N9/64 ,  C07H21/04

CPC分类号： A61L29/16 ,  A61K38/00 ,  A61L31/16 ,  A61L33/0047 ,  A61L2300/254 ,  C12N9/6462 ,  C12Y304/21073

摘要： It has now been discovered that certain mutant forms of pro-urokinase (“pro-UK”), such as so-called pro-UK mutant “M5” (Lys300→His), perform in the manner of pro-UK in lysing “bad” blood clots (those clots that occlude blood vessels), while sparing hemostatic fibrin in the so-called “good” blood clots (those clots that seal wounds, e.g., after surgery or other tissue injury). Thus, these pro-UK mutants are excellent and safe thrombolytic agents. These advantages allow them to be used in a variety of new methods, devices, and compositions useful for thrombolysis and treating various cardiovascular disorders in clinical situations where administration of other known thrombolytic agents has been too risky or even contraindicated.

摘要翻译： 现在已经发现，某些突变形式的前尿激酶（“pro-UK”），例如所谓的pro-UK突变体“M5”（Lys ^{300> His），在 亲英国在裂解“不良”血块（堵塞血管的血块）的方式，同时在所谓的“良好”血块（即手术或其他组织中密封伤口的血栓）节省止血纤维蛋白 伤害）。 因此，这些pro-UK突变体是优秀和安全的溶栓剂。 这些优点使得它们可用于在临床情况下可用于溶栓和治疗各种心血管疾病的各种新方法，装置和组合物中，其中施用其它已知溶栓剂的风险太高或甚至禁忌。}

公开(公告)号：US20050031607A1

公开(公告)日：2005-02-10

申请号：US10826826

申请日：2004-04-16

申请人： Victor Gurewich ,  John Williams ,  Jian-Ning Liu ,  Paolo Sarmientos ,  Massimiliano Pagani

发明人： Victor Gurewich ,  John Williams ,  Jian-Ning Liu ,  Paolo Sarmientos ,  Massimiliano Pagani

IPC分类号： A61K20060101 ,  A61K38/17 ,  A61K38/46 ,  A61K38/48 ,  A61K38/49 ,  A61L29/16 ,  A61P7/02 ,  A61P9/00 ,  C07H21/04 ,  C12N9/64 ,  C12N9/72 ,  C12P21/02

CPC分类号： A61L29/16 ,  A61K38/00 ,  A61L31/16 ,  A61L33/0047 ,  A61L2300/254 ,  C12N9/6462 ,  C12Y304/21073

摘要： It has now been discovered that certain mutant forms of pro-urokinase (“pro-UK”), such as so-called pro-UK mutant “M5” (Lys300→His), perform in the manner of pro-UK in lysing “bad” blood clots (those clots that occlude blood vessels), while sparing hemostatic fibrin in the so-called “good” blood clots (those clots that seal wounds, e.g., after surgery or other tissue injury). Thus, these pro-UK mutants are excellent and safe thrombolytic agents. These advantages allow them to be used in a variety of new methods, devices, and compositions useful for thrombolysis and treating various cardiovascular disorders in clinical situations where administration of other known thrombolytic agents has been too risky or even contraindicated.

摘要翻译： 现在已经发现，某些突变形式的前尿激酶（“pro-UK”），例如所谓的pro-UK突变体“M5”（Lys3-3> His），以pro- 英国在裂解“不良”血块（那些堵塞血管的血块），同时将所谓的“良好”血块（那些密封伤口例如手术或其他组织损伤后的血栓）节省止血纤维蛋白。 因此，这些pro-UK突变体是优秀和安全的溶栓剂。 这些优点使得它们可用于在临床情况下可用于溶栓和治疗各种心血管疾病的各种新方法，装置和组合物中，其中施用其它已知溶栓剂的风险太高或甚至禁忌。

公开(公告)号：US20090136557A1

公开(公告)日：2009-05-28

申请号：US12187807

申请日：2008-08-07

申请人： Victor Gurewich ,  Jian-Ning Liu ,  Paolo Sarmientos

发明人： Victor Gurewich ,  Jian-Ning Liu ,  Paolo Sarmientos

IPC分类号： A61F2/02 ,  A61K38/48

CPC分类号： A61L29/16 ,  A61K38/00 ,  A61L31/16 ,  A61L33/0047 ,  A61L2300/254 ,  C12N9/6462 ,  C12Y304/21073

摘要： It has now been discovered that certain mutant forms of pro-urokinase (“pro-UK”), such as so-called pro-UK mutant “M5” (Lys.sup.300.fwdarw.His)-, perform in the manner of pro-UK in lysing “bad” blood clots (those clots that occlude blood vessels), while sparing hemostatic fibrin in the so-called “good” blood clots (those clots that seal wounds, e.g., after surgery or other tissue injury). Thus, these pro-UK mutants are excellent and safe thrombolytic agents. These advantages allow them to be used in a variety of new methods, devices, and compositions useful for thrombolysis and treating various cardiovascular disorders in clinical situations where administration of other known thrombolytic agents has been too risky or even contraindicated.

公开(公告)号：US20090226410A1

公开(公告)日：2009-09-10

申请号：US12165082

申请日：2008-06-30

申请人： Victor Gurewich ,  Jian-Ning Liu ,  Paolo Sarmientos

发明人： Victor Gurewich ,  Jian-Ning Liu ,  Paolo Sarmientos

IPC分类号： A61K38/45 ,  A61P9/00

CPC分类号： A61L29/16 ,  A61K38/00 ,  A61L31/16 ,  A61L33/0047 ,  A61L2300/254 ,  C12N9/6462 ,  C12Y304/21073

摘要： It has now been discovered that certain mutant forms of pro-urokinase (“pro-UK”), such as so-called pro-UK mutant “M5” (Lys.sup.300.fwdarw.His)-, perform in the manner of pro-UK in lysing “bad” blood clots (those clots that occlude blood vessels), while sparing hemostatic fibrin in the so-called “good” blood clots (those clots that seal wounds, e.g., after surgery or other tissue injury). Thus, these pro-UK mutants are excellent and safe thrombolytic agents. These advantages allow them to be used in a variety of new methods, devices, and compositions useful for thrombolysis and treating various cardiovascular disorders in clinical situations where administration of other known thrombolytic agents has been too risky or even contraindicated.

摘要翻译： 现在已经发现，某些突变形式的前尿激酶（“pro-UK”），例如所谓的pro-UK突变体“M5”（Lys.sup.300.fwdarw.His））以这种方式 亲英国在裂解“不良”血块（堵塞血管的血块），同时将所谓“良好”血块中的止血纤维蛋白（例如手术或其他组织损伤后的血栓密封） 。 因此，这些pro-UK突变体是优秀和安全的溶栓剂。 这些优点使得它们可用于在临床情况下可用于溶栓和治疗各种心血管疾病的各种新方法，装置和组合物中，其中施用其它已知溶栓剂的风险太高或甚至禁忌。

公开(公告)号：US20070148160A1

公开(公告)日：2007-06-28

申请号：US11447455

申请日：2006-06-06

申请人： Victor Gurewich ,  Jian-Ning Liu ,  Paolo Sarmientos

发明人： Victor Gurewich ,  Jian-Ning Liu ,  Paolo Sarmientos

IPC分类号： A61K38/48

CPC分类号： A61L29/16 ,  A61K38/00 ,  A61L31/16 ,  A61L33/0047 ,  A61L2300/254 ,  C12N9/6462 ,  C12Y304/21073

摘要： It has now been discovered that certain mutant forms of pro-urokinase (“pro-UK”), such as so-called pro-UK mutant “M5” (Lys.sup.300.fwdarw.His)-, perform in the manner of pro-UK in lysing “bad” blood clots (those clots that occlude blood vessels), while sparing hemostatic fibrin in the so-called “good” blood clots (those clots that seal wounds, e.g., after surgery or other tissue injury). Thus, these pro-UK mutants are excellent and safe thrombolytic agents. These advantages allow them to be used in a variety of new methods, devices, and compositions useful for thrombolysis and treating various cardiovascular disorders in clinical situations where administration of other known thrombolytic agents has been too risky or even contraindicated.

摘要翻译： 现在已经发现，某些突变形式的前尿激酶（“pro-UK”），例如所谓的pro-UK突变体“M5”（Lys.sup.300.fwdarw.His））以这种方式 亲英国在裂解“不良”血块（堵塞血管的血块），同时将所谓“良好”血块中的止血纤维蛋白（例如手术或其他组织损伤后的血栓密封） 。 因此，这些pro-UK突变体是优秀和安全的溶栓剂。 这些优点使得它们可用于在临床情况下可用于溶栓和治疗各种心血管疾病的各种新方法，装置和组合物中，其中施用其它已知溶栓剂的风险太高或甚至禁忌。

公开(公告)号：US5472692A

公开(公告)日：1995-12-05

申请号：US087163

申请日：1993-07-02

申请人： Jian-Ning Liu ,  Victor Gurewich

发明人： Jian-Ning Liu ,  Victor Gurewich

IPC分类号： C12N15/09 ,  A61K38/00 ,  A61K38/46 ,  A61P7/02 ,  C07K14/745 ,  C12N1/15 ,  C12N1/19 ,  C12N1/21 ,  C12N5/10 ,  C12N9/72 ,  C12N15/57 ,  C12R1/91 ,  A61K38/49 ,  C12N9/48

CPC分类号： C12Y304/21073 ,  C12N9/6459 ,  C12N9/6462 ,  C12Y304/21069 ,  A61K38/00

摘要： The invention relates to thrombolytically active pro-urokinase (pro-UK) mutants comprising the amino acid sequence of native pro-UK, but including a mutation which causes the pro-UK mutants to induce less fibrinogenolysis and non-specific plasminogen activation than native pro-UK, to have at least a 10-fold lower intrinsic activity than native pro-UK, and to have substantially the same fibrin promotion and thrombolytic activity after plasmin activation compared to native pro-UK when administered to a patient.

摘要翻译： 本发明涉及包含天然亲UK的氨基酸序列的溶栓活性的原尿激酶（pro-UK）突变体，但是包括引起前UK突变体诱导的纤维蛋白原分解和非特异性纤溶酶原激活的突变比天然pro -UK与天然亲UK相比具有至少10倍的内在活性，并且当给予患者时，与原始亲UK相比，在纤溶酶活化后具有基本上相同的纤维蛋白促进和血栓溶解活性。

公开(公告)号：US20090010916A1

公开(公告)日：2009-01-08

申请号：US12215966

申请日：2008-07-01

申请人： Victor Gurewich ,  Ralph Pannell

发明人： Victor Gurewich ,  Ralph Pannell

IPC分类号： A61K38/49 ,  A61P7/00

CPC分类号： A61K38/49 ,  A61K38/57 ,  C12Y304/21031 ,  Y02A50/473 ,  A61K2300/00

摘要： 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 C1-inhibitor, which was the principal inhibitor of tcM5 in plasma. The effect of supplemental additions of C1-inhibitor on fibrinolysis and fibrinogenolysis by M5 was determined. Supplemental C1-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 C1-inhibitor, the rate of fibrin-specific lysis reached that achievable by nonspecific fibrinolysis, which is the maximum possible for a plasminogen activator. Plasma C1-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 C1-inhibitor are disclosed.

摘要翻译： 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的主要抑制剂。 确定补充添加C1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C1抑制剂恢复了高剂量M5的稳定性，并且预防了纤维蛋白原分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C1抑制剂存在下M5的较高的剂量耐受性，纤维蛋白特异性裂解的速率达到通过非特异性纤维蛋白溶解可达到的速率，这是纤溶酶原激活剂的最大可能性。 血浆C1抑制剂通过抑制tcM5在血浆中稳定M5，否则会大大扩增非特异性纤溶酶原激活，导致M5产生更多的tcM5。 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功效具有重要的意义。 公开了通过与外源性C1抑制剂一起施用M5来减少纤维蛋白溶解期间出血和非特异性纤溶酶原激活的方法。

公开(公告)号：US4381346A

公开(公告)日：1983-04-26

申请号：US182976

申请日：1980-09-02

申请人： Syed S. Huasin ,  Boguslaw Lipinski ,  Victor Gurewich

发明人： Syed S. Huasin ,  Boguslaw Lipinski ,  Victor Gurewich

IPC分类号： A61K38/00 ,  C12N9/72 ,  C12N9/48

CPC分类号： C12N9/6456 ,  A61K38/00

摘要： The existence of high fibrin-affinity urokinase is discovered by an isolation procedure using fibrin precipitated on an adsorptive-solid matrix. By the method described, the high affinity form of plasminogen activator can be isolated directly from urine or from kidney tissue culture medium. The method is economical and provides a relatively high yield of the activator. The high affinity that this plasminogen activator has for fibrin is a property that makes it an improved thrombolytic agent and when radiolabelled provides a new diagnostic agent for the specific detection of fibrin thrombi through nuclear scanning. The newly-isolated plasminogen activator has the following characteristics: a molecular weight of about 56,000 Daltons, a specific activity of about 40,000-50,000 CTA units/mg, the appearance of a single chain structure and a high affinity for fibrin.

摘要翻译： 高纤维蛋白亲和性尿激酶的存在是通过使用沉淀在吸附固体基质上的纤维蛋白的分离方法发现的。 通过所述方法，纤溶酶原激活物的高亲和力形式可直接从尿或肾组织培养基中分离。 该方法是经济的并且提供了相对高的活化剂产率。 这种纤溶酶原激活剂对纤维蛋白的高亲和力是使其成为改进的溶栓剂的特性，当放射性标记为核扫描的纤维蛋白血栓特异性检测提供了新的诊断剂。 新分离的纤溶酶原激活物具有以下特征：约56,000道尔顿的分子量，约40,000-50,000 CTA单位/ mg的比活性，单链结构的外观和对纤维蛋白的高亲和力。

公开(公告)号：US08187592B2

公开(公告)日：2012-05-29

申请号：US12947573

申请日：2010-11-16

申请人： Victor Gurewich ,  Ralph Pannell

发明人： Victor Gurewich ,  Ralph Pannell

IPC分类号： C12N9/72 ,  C12N9/68 ,  A61K38/48

CPC分类号： A61K38/57 ,  A61K38/49 ,  C12Y304/21073 ,  A61K2300/00

摘要： A mutant prourokinase plasminogen activator (M5) was developed to make prouPA less subject to spontaneous activation during fibrinolysis. C1-inhibitor complexes with tcM5. The effect of C1-inhibitor on fibrinolysis and fibrinogenolysis by M5 was determined. Supplemental C1-inhibitor restores the stability of M5 but not that of prouPA. Clot lysis by M5 with supplemental C1-inhibitor showed no attenuation of the rate of fibrinolysis, whereas fibrinogenolysis was prevented by C1-inhibitor. Due to higher dose tolerance of M5 with C1-inhibitor, the rate of fibrin-specific lysis reached that achievable by nonspecific fibrinolysis without inhibitor. Plasma C1-inhibitor stabilized M5 in plasma by inhibiting tcM5 and thereby non-specific plasminogen activation. At the same time, fibrin-specific plasminogen activation remained unimpaired. This unusual dissociation of effects 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 C1-inhibitor are disclosed.

摘要翻译： 开发了突变型prourokinase纤溶酶原激活物（M5），使prouPA在纤维蛋白溶解过程中较少受到自发激活。 C1抑制剂与tcM5复合物。 测定了C1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C1抑制剂恢复M5的稳定性，而不是prouPA的稳定性。 M5与补体C1抑制剂的凝血酶裂解显示纤维蛋白溶解速率没有减弱，而C1抑制剂阻止了纤维蛋白原分解。 由于M5与C1抑制剂的较高剂量耐受性，纤维蛋白特异性裂解的速率达到通过非特异性纤维蛋白溶解而无抑制剂可达到的速率。 血浆C1抑制剂通过抑制tcM5稳定M5，从而抑制非特异性纤溶酶原激活。 同时，纤维蛋白特异性纤溶酶原激活仍然没有受到损害。 这种不寻常的效应解离对于提高纤维蛋白溶解的安全性和有效性具有重要意义。 公开了通过与外源性C1抑制剂一起施用M5来减少纤维蛋白溶解期间出血和非特异性纤溶酶原激活的方法。

公开(公告)号：US20070298023A1

公开(公告)日：2007-12-27

申请号：US11732620

申请日：2007-04-04

申请人： Victor Gurewich ,  Ralph Pannell

发明人： Victor Gurewich ,  Ralph Pannell

IPC分类号： A61K38/48

CPC分类号： A61K38/57 ,  A61K38/49 ,  C12Y304/21073 ,  A61K2300/00

摘要： A mutant prourokinase plasminogen activator (M5) was developed to make prouPA less subject to spontaneous activation during fibrinolysis. C1-inhibitor complexes with tcM5. The effect of C1-inhibitor on fibrinolysis and fibrinogenolysis by M5 was determined. Supplemental C1-inhibitor restores the stability of M5 but not that of prouPA. Clot lysis by M5 with supplemental C1-inhibitor showed no attenuation of the rate of fibrinolysis, whereas fibrinogenolysis was prevented by C1-inhibitor. Due to higher dose tolerance of M5 with C1-inhibitor, the rate of fibrin-specific lysis reached that achievable by nonspecific fibrinolysis without inhibitor. Plasma C1-inhibitor stabilized M5 in plasma by inhibiting tcM5 and thereby non-specific plasminogen activation. At the same time, fibrin-specific plasminogen activation remained unimpaired. This unusual dissociation of effects 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 C1-inhibitor are disclosed.

摘要翻译： 开发了突变型prourokinase纤溶酶原激活物（M5），使prouPA在纤维蛋白溶解过程中较少受到自发激活。 C1抑制剂与tcM5复合物。 测定了C1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C1抑制剂恢复M5的稳定性，而不是prouPA的稳定性。 M5与补体C1抑制剂的凝血酶裂解显示纤维蛋白溶解速率没有减弱，而C1抑制剂阻止了纤维蛋白原分解。 由于M5与C1抑制剂的较高剂量耐受性，纤维蛋白特异性裂解的速率达到通过非特异性纤维蛋白溶解而无抑制剂可达到的速率。 血浆C1抑制剂通过抑制tcM 5稳定M5，从而使非特异性纤溶酶原激活。 同时，纤维蛋白特异性纤溶酶原激活仍然没有受到损害。 这种不寻常的效应解离对于提高纤维蛋白溶解的安全性和有效性具有重要意义。 公开了通过与外源性C1抑制剂一起施用M5来减少纤维蛋白溶解期间出血和非特异性纤溶酶原激活的方法。