WO2003006042A1 - Peptide destine a la regulation de l'activateur tissulaire du plasminogene - Google Patents

Peptide destine a la regulation de l'activateur tissulaire du plasminogene Download PDF

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Publication number
WO2003006042A1
WO2003006042A1 PCT/US2002/020077 US0220077W WO03006042A1 WO 2003006042 A1 WO2003006042 A1 WO 2003006042A1 US 0220077 W US0220077 W US 0220077W WO 03006042 A1 WO03006042 A1 WO 03006042A1
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WO
WIPO (PCT)
Prior art keywords
tpa
upa
polypeptide
pai
fibrinolytic
Prior art date
Application number
PCT/US2002/020077
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English (en)
Inventor
Abd. Al-Roof Higazi
Original Assignee
Thrombotech Ltd.
Karmali, Rashida, A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thrombotech Ltd., Karmali, Rashida, A. filed Critical Thrombotech Ltd.
Priority to EP02752090A priority Critical patent/EP1414479A4/fr
Priority to CA002453309A priority patent/CA2453309A1/fr
Priority to JP2003511848A priority patent/JP2004534842A/ja
Publication of WO2003006042A1 publication Critical patent/WO2003006042A1/fr
Priority to PCT/US2003/007683 priority patent/WO2003095476A2/fr
Priority to US10/386,777 priority patent/US7271143B1/en
Priority to AU2003213856A priority patent/AU2003213856B2/en
Priority to AT03711550T priority patent/ATE525081T1/de
Priority to CA2488968A priority patent/CA2488968C/fr
Priority to JP2004503490A priority patent/JP2006502096A/ja
Priority to ES03711550T priority patent/ES2373713T3/es
Priority to DK03711550.8T priority patent/DK1507547T3/da
Priority to EP03711550A priority patent/EP1507547B1/fr
Priority to IL165066A priority patent/IL165066A/en

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Classifications

    • H—ELECTRICITY
    • H05—ELECTRIC TECHNIQUES NOT OTHERWISE PROVIDED FOR
    • H05B—ELECTRIC HEATING; ELECTRIC LIGHT SOURCES NOT OTHERWISE PROVIDED FOR; CIRCUIT ARRANGEMENTS FOR ELECTRIC LIGHT SOURCES, IN GENERAL
    • H05B7/00—Heating by electric discharge
    • H05B7/18—Heating by arc discharge
    • H05B7/22—Indirect heating by arc discharge
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/49—Urokinase; Tissue plasminogen activator
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • This invention discloses a peptide comprising of six amino acids (EEIIMD) having the property to bind at the "docking" site in urokinase plasminogen (uPA) activator and in tissue plasminogen activator (tPA) outside the active site.
  • the invention also relates to the regulation of tPA and uPA activity when tPA or uPA is given in treatment of ischemic stroke, in particular to tPA's capacity to induce intracerebral hemorrhage (ICH).
  • Tissue-type plasminogen activator is the only therapy for acute thromboembolic stroke, which is approved by the Food and Drug Administration (FDA).
  • FDA Food and Drug Administration
  • tPA for treatment of ischemic stroke may expose patients to secondary intracerebral hemorrhage. Wardlaw JC et al, Lancet 1997, 350:607-614. This is because there is an approximately six percent incidence of subsequent symptomatic intracerebral hemorrhage and approximately fifty percent of these patients die.
  • the appearance of intracerebral hemorrhage after treatment with tPA is attributed to its capacity to interfere with the normal vasoactivity of the cerebral blood vessels.
  • TPA has been shown to have dose-dependent vasoconstrictory or vasodilatory effects besides promoting the activation of plasminogen.
  • Tissue-type plasminogen activator is a naturally occurring molecule released from vascular endothelial cells, and rapid removal of t-PA from the blood occurs by clearance in the liver.
  • Hepatocytes express the low-density lipoprotein receptor-related protein or d 2 - macroglobulin receptor which bind tPA and complexes of plasminogen activator inhibitor (PAI- 1) with tPA and tcuPA.
  • PAI- 1 plasminogen activator inhibitor
  • endothelial cells express a 170Kda mannose-dependent receptor which is also involved in the rapid clearance of tPA.
  • Plasminogen activator inhibitor type 1 interacts with both tPA and uPA and inhibits the catalytic activity of both proteins.
  • PAI-1 which binds tPA and uPA with high affinity is present at high concentrations in the circulation of patients suffering from hypertension. And, reduction of blood pressure by medical treatment results in a decrease of PAI-1 concentrations.
  • the underlying mechanism of action for the increase of PAI-1 in certain pathological conditions is not understood well. However, the inverse relationship with tPA and/or uPA suggests that PAI-1 serves to neutralize in some way the vasoactive effect of tPA and/or uPA.
  • Simmons M Cardiol.
  • the present invention is directed to gain a better understanding of the control if any, of PAI-1 or tPA or uPA, and to providing a composition or product optimally effective at regulating activity of tPA or uPA, thereby reducing the risk of intracerebral hemorrhage in patients receiving thrombolytic therapy such as tPA and/or uPA.
  • the present invention relates to the composition and use of a polypeptide composed of 6 amino acids () having an inhibitory activity on the vasoactivity of tPA and uPA.
  • polypeptide is useful in the prevention and/or treatment of hemorrhagic disorders associated with tPA treatment administered for treatment of thromboembolic disorders.
  • contemplated by the present invention are methods of reducing the occurrence of intracerebral hemorrhage in patients receiving tPA or uPA as fibromylohytic therapy, by adjunctive therapy with .
  • the present invention is directed to pharmaceutical kits for the treatment of thromboembolic disorders in mammals, the kits comprising a sterile container of tPA in commercially available forms, and a sterile container of each of the agents or a mixture of agents, both in amounts therapeutically effective to treat the thromboembolic disorders, while in the same regimen, preventing the occurrence of side effects of tPA.
  • kits may include, if desired, uPA or tP A in amounts therapeutically effective to treat thromboembolic disorders as well as prevent any side effects.
  • kits of tPA or uPA in combination regimens of other fibrinolytic agents, along with where appropriate. It is further the object of the present invention to provide methods of treating thromboembolic disorders using as conjunctive therapy in combination with one or more of fibrinolytic agents including tPA, uPA, tcuPA, streptokinase, rt-PA or alteplase, rt-PA derivatives (such as reteplase, lanoteplase and TNK-rt-PA), anisoylated plasminogen streptokinase complex (APSC) or anistreplase, or streptokinase derivative.
  • fibrinolytic agents including tPA, uPA, tcuPA, streptokinase, rt-PA or alteplase, rt-PA derivatives (such as reteplase, lanoteplase and TNK-rt-PA), anisoylated plasminogen streptokina
  • Fig. 1 is a graph describing the effect of tPA on phenylephrine-induced contraction of isolated rat aorta rings in vitro.
  • the contraction of the aorta rings was induced by varying concentrations of phenylephrine in the absence of tPA (filled triangles), in the presence of InM of tPA (filled squares) or in the presence of lOnM tPA (empty squares).
  • the experiments were performed according to procedures described earlier by Haj-Yehia A et al, FASEB J, 2000, 14:1411-1422.
  • Fig. 2 is a bar diagram describing the results of experiments on the vasoactivity of uPA and tPA in the presence or absence of PAI-1, for example, the effect of 2nM uP or InM tPA on phenylephrine induced vasoconstriction was determined in the presence or absence of equimolar concentrations of PAI-1.
  • Fig. 3 is a bar diagram describing the results of studies done on the effect of PAI-1 derived peptide on tPA vasoactivity.
  • the constriction of aorta rings was induced by increasing the concentrations of phenylephrine in the absence or presence of InM tPA, InM tPA and 1 OM , lOmM tPA or lOnM tPA and 1 OM .
  • Fig. 4 is a bar diagram describing the results of experiments on the effect of PAI-1 derived peptide on tPA mediated clot lysis.
  • the capacity of tPA to induce clot lysis was determined in the presence and absence of 1 OM .
  • blood from volunteers was allowed to clot at room temperature for one hour, the blood clot was separated from the plasma, placed on absorbing paper to remove all the serum and cut into several pieces. The pieces were weighed, and placed in PBS buffer alone or containing 100 nM tPA, with or without 1 OM . After incubation for 3 hours at room temperature, the thrombi are separated from the medium, dried and weighed.
  • compositions of the peptide are provided, such compositions having inhibitory effects on tPA and/or uPA related hemorrhagic disorders that result as serious side effects of such fibrinolytic agents.
  • contemplated by the present invention are methods of reducing the occurrence of intra-cerebral hemorrhage in patients receiving tPA or uPA in the treatment of thromboembolic disorders.
  • the present invention also provides pharmaceutical compositions and kits comprising of the polypeptide in combination with one or more of fibrinolytic agents including tPA, uPA, scuPA, tcuPA, streptokinase, rt-PA or alteplase, rt-PA derivatives (such as reteplase, lanoteplase and TNK-rt-PA), anisoylated plasminogen streptokinase complex (APSC) or anistreplase, or streptokinase derivatives.
  • fibrinolytic agents including tPA, uPA, scuPA, tcuPA, streptokinase, rt-PA or alteplase, rt-PA derivatives (such as reteplase, lanoteplase and TNK-rt-PA), anisoylated plasminogen streptokinase complex (APSC) or anistreplase, or streptokinase derivatives.
  • the present invention further provides methods for preventing and/or treating side effects such as intracerebral hemorrhage and related vascular abnormalities associated with fibrinolytic agents such as tPA or uPA, by providing therapeutic regimens - solo or in combination, in combination with an effective amount of to prevent and/or inhibit side effects.
  • side effects such as intracerebral hemorrhage and related vascular abnormalities associated with fibrinolytic agents such as tPA or uPA
  • TPA is a single-chain serine protease composed of 530 amino acids, although originally 527 were identified.
  • the t-PA enzyme is composed of several domains with homologies to other proteins: A finger domain comprising residues 4-50,
  • a growth factor domain comprising residues 50-87, two kringles comprising residues 87-176 and 176-262, and the protease domain constituted by residues 276-527 comprising the catalytic triad.
  • Initial binding of t-PA to fibrin is governed by the finger domain and by kringle 2, which binds to exposed carboxyl-terminal lysine residues.
  • plasminogen binds to fibrin primarily via specific structures called the "lysine-binding site.”
  • one way of regulating fibrinolysis is at the level of plasminogen activation localized at the fibrin surface.
  • Plasminogen activator inhibitors specifically PAI-1 and PAI-2 inhibit the physiological plasminogen activators, for example, PAI-1 is the primary inhibitor of t-PA and u-PA in plasma.
  • PAI-1 a serine protease inhibitor, is a single chain glycoprotein derived from endothelial cells and other cell types. PAI-1 inhibits tPA by the formation of a complex between the active site of tPA and the "bait" residues (Arg 346-Met 347) of PAI-1.
  • the PAI-1 concentration in plasma is increased in several diseases, including venous thromoembolism, obesity, sepsis and coronary artery disease.
  • High PAI-1 activity constitutes an independent risk factor for myocardial infarction in young subjects within three (3) years of the first attack.
  • Plasminogen activator inhibitor type 1 interacts with both tPA and uPA and inhibits the catalytic activity of both proteins.
  • PAI-1 which binds to tPA and uPA with high affinity (Heckman CM, Archires of Biochem Biophysics, 1988, 262:199-210), is also present at high concentrations in the circulation of patients suffering from hypertension. Reduction of blood pressure by medical treatment results in the decrease of PAI-1 concentration. Erden YC et al. AmJ Hypertens, 1999, 12:1071-1076. The underlying mechanism of action to explain the increase of PAI-1 in some pathological conditions is not understood.
  • PAI-1 reacts with single chain tPA, two chain tPA and tcuPA.
  • the second-order rate constant for their inhibition of single-chain tPA by PAI-1 is about 10 7 M-' s , while inhibition of two chain tPA and tcuPA is somewhat faster.
  • Positively charged regions in tPA (residues 296- 304) and uPA 9residues 179-184) are involved in this rapid reaction. PAI activity is very rapidly cleared from the circulation by the liver. Except for platelets, which contain both functional and inactive PAI-1, PAI-1 is not stored within cells, but is rapidly and constitutively secreted after synthesis.
  • PAI-1 binds tPA and uPA through two independent epitepes, one of which interacts with the active site.
  • the other epitope is composed of 6 amino acid residues, EEIMD, that correspond to the amino acid residues 350 to 355 of PAI-1.
  • This second epitepe of PAI-1 interacts with a binding "docking" site in uPA and tPA that is outside of the active site. Adams DS et al., J. Biol. Chem, 1999, 266:8476-8482.
  • the present invention describes the effect of the peptide on the vasoactivity of tPA and uPA and indicates that the peptide abolishes the enhancing effect of tPA on phenylephrine- induced vasoconstriction in aorta ring cultures. Similarly, the peptide of the present invention abrogates the enhancing effect of uPA on phenylephrine-induced vasoconstriction.
  • the peptide of the present invention while preventing and/or inhibiting the adverse effects of tPA or uPA on blood vessels has no effect on the fibrinolytic activity of tPA or uPA, so useful in clot lysis during thrombolytic therapy in myocardial infarction, stroke and related complications.
  • tPA The commercially available tPA is produced by recombinant DNA technology (such as recombinant t-PA, rt-PA) in two forms: a single-chain preparation (alteplase) and a double-chain preparation (dute plase).
  • tPA types include reteplase (r-PAO and a mutant of rt-PA, TNK- rt-PA.
  • the preferred dosage regimen of fibrin-selective alteplase consists of a weight-adjusted accelerated (front-loaded) regimen over 90 minutes (15 mg bolus, 0.75 mg/kg over 30 minutes (not to exceed 50 mg] and .05 mg/kg over 60 minutes [not to exceed 35 mg]).
  • the preferred dosage regimen for the peptide consists of an amount effective to prevent the harmful vasoactive effects of tPA on a case by case basis.
  • the peptide may be a component of a sequence of varying numbers of amino acids, or the peptide may have a modification of one or more amino acids in its sequence.
  • the peptide of the present invention is useful in treatment of sepsis, when administered alone in an effective dosage or in combination with traditional anti-coagulant therapy.
  • several antithrombotic mechanisms act in concert to prevent clotting, and to preserve blood fluidity. Any thrombin that escapes the surveillance of this physiological anticoagulant system is available to convert fibrinogen to fibrin. This in turn triggers the fibrinolytic system.
  • Fig. 1 describes a graph describing the effect of tPA on phenylephrine-induced contraction of isolated rat aorta rings in vitro.
  • the contraction of the aorta rings was induced by varying concentrations of phenylephrine in the absence of tPA (filled triangles), in the presence of InM of tPA (filled squares) or in the presence of lOnM tPA (empty squares).
  • the experiments were performed according to procedures described earlier by Haj-Yehia A et al., FASEB J, 2000, 14:1411-1422.
  • tPA has the capacity to induce vasodilatation.
  • Fig. 1 shows that the presence of InM tPA inhibits the vasoconstriction induced by phenylephrine. Increased tPA concentrations induced the opposite effect, i.e., the presence of 1- nM tPA stimulated the vasoconstriction induced by phenylephrine.
  • uPA has the capacity to induce vasoconstriction ⁇ Haj-Yehia A., et al. FASEB J, 2000, 14:1411-1422). Effect of PAI-1 on Vasoactivity of uPA and tPA
  • Fig. 2 describes a bar diagram describing the results of experiments on the vasoactivity of uPA and tPA in the presence of absence of PAI-1, for example, the effect of 2nM utPA or InM tPA on phenylephrine induced vasoconstriction was determined in the presence or absence of equimolar concentrations of PAI-1.
  • Fig. 3 is a bar diagram describing the results of studies done on the effect of PAI-1 derived peptide on tP A vasoactivity.
  • the constriction of aorta rings was induced by increasing the concentrations of phenylephrine in the absence or presence of InM tPA, InM tPA and 1 OM, 10 nM tPA or lOnM tPA and 1 OM .
  • Fig. 4 is a bar diagram describing the results of experiments on the effect of PAI-1 derived peptide on tPA mediated clot lysis.
  • the capacity of tPA to induce clot lysis was determined in the presence and absence of 10M .
  • blood from volunteers was allowed to clot at room temperature for one hour, the blood clot was separated from the plasma, placed on absorbing paper to remove all the serum and cut into several pieces. The pieces were weighed, and placed in PBS buffer alone or containing 100 nM tPA, with or without 10M . After incubation for 3 hours at room temperature, the thrombi are separated from the medium, dried and weighed.

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Abstract

La présente invention concerne un polypeptide et son utilisation dans la prévention et/ou le traitement des effets secondaires induits par les activateurs du plasminogène et plus particulièrement tPA ou uPA. L'invention concerne également des compositions combinées et/ou des régimes thérapeutiques faisant intervenir ledit polypeptide et un ou plusieurs activateurs du plasminogène utilisés, ainsi que des méthodes permettant d'obtenir un effet fibrinolytique efficace tout en réduisant les effets secondaires.
PCT/US2002/020077 2001-07-10 2002-06-24 Peptide destine a la regulation de l'activateur tissulaire du plasminogene WO2003006042A1 (fr)

Priority Applications (13)

Application Number Priority Date Filing Date Title
EP02752090A EP1414479A4 (fr) 2001-07-10 2002-06-24 Peptide destine a la regulation de l'activateur tissulaire du plasminogene
CA002453309A CA2453309A1 (fr) 2001-07-10 2002-06-24 Peptide destine a la regulation de l'activateur tissulaire du plasminogene
JP2003511848A JP2004534842A (ja) 2001-07-10 2002-06-24 ヒト組織プラスミノゲン活性化因子の制御ペプチド
EP03711550A EP1507547B1 (fr) 2002-05-08 2003-03-12 Peptides regulant les activateurs du plasminogene de l'urokinase (upa) et du type de tissu (tpa) et procede d'optimisation de l'efficacite therapeutique
US10/386,777 US7271143B1 (en) 2001-07-10 2003-03-12 Peptides for regulation of urokinase (uPA) and tissue type (tPA) plasminogen activator and method of optimizing therapeutic efficacy
PCT/US2003/007683 WO2003095476A2 (fr) 2002-05-08 2003-03-12 Peptides regulant les activateurs du plasminogene de l'urokinase (upa) et du type de tissu (tpa) et procede d'optimisation de l'efficacite therapeutique
AU2003213856A AU2003213856B2 (en) 2002-05-08 2003-03-12 Peptides for regulation of urokinase (uPA) and tissue type (tPA) plasminogen activator and method of optimizing therapeutic efficacy
AT03711550T ATE525081T1 (de) 2002-05-08 2003-03-12 Peptide zur regulierung von urokinase (upa) und gewebe- (tpa) plasminogenaktivator und verfahren zur optimierung der therapeutischen wirksamkeit
CA2488968A CA2488968C (fr) 2002-05-08 2003-03-12 Peptides regulant les activateurs du plasminogene de l'urokinase (upa) et du type de tissu (tpa) et procede d'optimisation de l'efficacite therapeutique
JP2004503490A JP2006502096A (ja) 2002-05-08 2003-03-12 ウロキナーゼ型（ｕＰＡ）および組織型（ｔＰＡ）プラスミノーゲン活性化剤を調節するペプチドおよび治療上の効能を最適化する方法
ES03711550T ES2373713T3 (es) 2002-05-08 2003-03-12 PÉPTIDOS PARA LA REGULACIÓN DE UROQUINASA (uPA) Y ACTIVADOR DE PLASMINÓGENO DE TIPO TEJIDO (tPA) Y MÉTODO PARA OPTIMIZAR LA EFICACIA TERAPÉUTICA.
DK03711550.8T DK1507547T3 (da) 2002-05-08 2003-03-12 Peptider til regulation af urokinaseplasminogenaktivator (UPA) og vævsplasminogenaktivator (TPA) og fremgangsmåde til optimering af terapeutisk effektivitet
IL165066A IL165066A (en) 2002-05-08 2004-11-07 Polypeptide having an inhibitory effect on vasoconstriction induced by plasminogen activators and pharmaceutical compositions containing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US90213501A 2001-07-10 2001-07-10
US09/902,135 2001-07-10

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WO2003006042A1 true WO2003006042A1 (fr) 2003-01-23

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PCT/US2002/020077 WO2003006042A1 (fr) 2001-07-10 2002-06-24 Peptide destine a la regulation de l'activateur tissulaire du plasminogene

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EP (1) EP1414479A4 (fr)
JP (1) JP2004534842A (fr)
KR (1) KR20040018442A (fr)
BR (1) BRPI0211234B1 (fr)
CA (1) CA2453309A1 (fr)
WO (1) WO2003006042A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1496936A1 (fr) * 2002-03-29 2005-01-19 The Johns Hopkins University Thrombolyse hemorragique intraventriculaire
EP1507547A2 (fr) * 2002-05-08 2005-02-23 Thrombotech Ltd Peptides regulant les activateurs du plasminogene de l'urokinase (upa) et du type de tissu (tpa) et procede d'optimisation de l'efficacite therapeutique
EP2468289A1 (fr) 2007-07-24 2012-06-27 Thrombotech Ltd. Peptides dérivés d'un inhibiteur-1 d'activateur de plasminigène et utilisations correspondantes
US9115279B2 (en) 2013-03-15 2015-08-25 Asahi Kasei Plastics North America, Inc. Polypropylene compounds with high impact performance and improved stress whitening resistance
EP3535390A4 (fr) * 2016-11-02 2020-11-25 Inc. Aronora Combinaison d'analogue de thrombine e-we et d'un fibrinolytique

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100958999B1 (ko) * 2007-12-07 2010-05-20 주식회사 포스코 전기로
KR101782406B1 (ko) 2015-06-11 2017-09-27 김철민 기능성 마네킹

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ADAMS ET AL.: "A synthetic DNA encoding a modified human urokinase resistant to inhibition by serum plasminogen activator inhibitor", J. BIOL. CHEM., vol. 266, no. 13, May 1991 (1991-05-01), pages 8476 - 8482, XP002955289 *
CIPOLLA ET AL.: "Postischemic attenuation of cerebral artery reactivity is increased in the presence of tissue plasminogen activator", STROKE, vol. 31, no. 4, April 2000 (2000-04-01), pages 940 - 945, XP002955291 *
HALEY E.C.: "Editorial comment: postischemic attenuation of cerebral artery reactivity is increased in the presence of tissue plasminogen activator", STROKE, vol. 31, no. 4, April 2000 (2000-04-01), pages 945, XP002955288 *
See also references of EP1414479A4 *
XUE ET AL.: "Interfering with the inhibitory mechanism of serpins: crystal structure of a complex formed between cleaved plasminogen activator inhibitor type 1 and a reactive-centre loop peptide", STRUCTURE, vol. 6, no. 5, 1998, pages 627 - 636, XP002955290 *
ZHANG ET AL.: "Regulation of single chain urokinase binding internalization and degradation by a plasminogen activator inhibitor 1-derived peptide", J. BIOL. CHEM., vol. 272, no. 43, October 1997 (1997-10-01), pages 27053 - 27057, XP002916340 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1496936A1 (fr) * 2002-03-29 2005-01-19 The Johns Hopkins University Thrombolyse hemorragique intraventriculaire
EP1496936A4 (fr) * 2002-03-29 2008-05-21 Univ Johns Hopkins Thrombolyse hemorragique intraventriculaire
EP1507547A2 (fr) * 2002-05-08 2005-02-23 Thrombotech Ltd Peptides regulant les activateurs du plasminogene de l'urokinase (upa) et du type de tissu (tpa) et procede d'optimisation de l'efficacite therapeutique
EP1507547A4 (fr) * 2002-05-08 2007-03-14 Thrombotech Ltd Peptides regulant les activateurs du plasminogene de l'urokinase (upa) et du type de tissu (tpa) et procede d'optimisation de l'efficacite therapeutique
EP2468289A1 (fr) 2007-07-24 2012-06-27 Thrombotech Ltd. Peptides dérivés d'un inhibiteur-1 d'activateur de plasminigène et utilisations correspondantes
US8507436B2 (en) 2007-07-24 2013-08-13 D-Pharm Ltd. Peptides derived from plasminogen activator inhibitor-1 and uses thereof
US9115279B2 (en) 2013-03-15 2015-08-25 Asahi Kasei Plastics North America, Inc. Polypropylene compounds with high impact performance and improved stress whitening resistance
EP3535390A4 (fr) * 2016-11-02 2020-11-25 Inc. Aronora Combinaison d'analogue de thrombine e-we et d'un fibrinolytique

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EP1414479A1 (fr) 2004-05-06
KR20040018442A (ko) 2004-03-03
EP1414479A4 (fr) 2005-07-13
BRPI0211234B1 (pt) 2018-04-03
CA2453309A1 (fr) 2003-01-23
JP2004534842A (ja) 2004-11-18

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