Urokinase: Difference between revisions

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(Clarified marketed name change. Clarified that both urokinase and TPA breakdown fibrin. There is no supporting literature for pathogenic fibrinogenlysis related to use of either urokinase or TPA when used according to approved product directions, thus...)
 
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{{DrugProjectFormSinglePage
{{Infobox_gene}}
|authorTag={{AL}}
{{Drugbox
|genericName=Urokinase
|aOrAn=a
|drugClass=[[thrombolytic agent]]
|indicationType=treatment
|indication=[[pulmonary embolism]]
|adverseReactions=[[bleeding]] and [[anaphylaxis]]
|blackBoxWarningTitle=Warning Title
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult======Pulmonary Embolism=====
 
* Dosing Information
 
:* Loading dose: '''4,400 IU/kg''' at a rate of '''90 mL/h''' over a period of '''10 minutes.'''
:* Maintenance dose: Continuous infusion of '''4,400 IU/kg/h''' at a rate of '''15 mL''' for '''12 hours'''.
|offLabelAdultGuideSupport=====Coronary artery bypass graft occlusion====
* Dosing Information
:*'''120,000 units/hour'''  (17 - 108 hours)<ref>{{Cite journal
| author = [[K. Mehta]] & [[E. Schechter]]
| title = Long-term angiographic follow-up of occluded saphenous bypass grafts treated with prolonged urokinase infusion
| journal = [[Catheterization and cardiovascular diagnosis]]
| volume = 44
| issue = 3
| pages = 291–296
| year = 1998
| month = July
| pmid = 9676798
}}</ref>
:*Infusion rate was doubled if no clot lysis was evident
:*'''3.70 million units''' (mean duration of infusion was  25.4 h)<ref>{{Cite journal
| author = [[J. R. Hartmann]], [[L. S. McKeever]], [[W. W. O'Neill]], [[C. J. White]], [[P. L. Whitlow]], [[P. S. Gilmore]], [[A. J. Doorey]], [[J. P. Galichia]] & [[E. L. Enger]]
| title = Recanalization of Chronically Occluded Aortocoronary Saphenous Vein Bypass Grafts With Long-Term, Low Dose Direct Infusion of Urokinase (ROBUST): a serial trial
| journal = [[Journal of the American College of Cardiology]]
| volume = 27
| issue = 1
| pages = 60–66
| year = 1996
| month = January
| doi = 10.1016/0735-1097(95)00448-3
| pmid = 8522711
}}</ref>
 
====Coronary artery thrombosis====
* Dosing Information
 
:* 350,000 U/h<ref>{{Cite journal
| author = [[P. S. Teirstein]], [[J. T. 3rd Mann]], [[P. E. Jr Cundey]], [[E. Schechter]], [[W. C. Jacobs]], [[C. L. Grines]], [[D. J. Stagaman]], [[A. J. Lansky]], [[M. A. Hultquist]], [[B. A. Kusnick]], [[R. R. Heuser]], [[H. D. Kleinert]] & [[J. Popma]]
| title = Low- versus high-dose recombinant urokinase for the treatment of chronic saphenous vein graft occlusion
| journal = [[The American journal of cardiology]]
| volume = 83
| issue = 12
| pages = 1623–1628
| year = 1999
| month = June
| pmid = 10392865
}}</ref>
 
====Deep venous thrombosis====
* Intra-arterial Administration
 
:*'''50,000 units twice daily'''<ref>{{Cite journal
| author = [[S. K. Garg]] & [[K. S. Yadav]]
| title = Developing venous gangrene in deep vein thrombosis: intraarterial low-dose burst therapy with urokinase--case reports
| journal = [[Angiology]]
| volume = 50
| issue = 2
| pages = 157–162
| year = 1999
| month = February
| pmid = 10063948
}}</ref>
 
* Intravenous Administration
 
:*'''1500-4000 units/kg/h'''<ref>{{Cite journal
| author = [[A. D'Angelo]] & [[P. M. Mannucci]]
| title = Outcome of treatment of deep-vein thrombosis with urokinase: relationship to dosage, duration of therapy, age of the thrombus and laboratory changes
| journal = [[Thrombosis and haemostasis]]
| volume = 51
| issue = 2
| pages = 236–239
| year = 1984
| month = April
| pmid = 6740556
}}</ref>
   
 
====Empyema====
* Dosing Information
 
:*
 
====Myocardial infarction====
* Dosing Information
 
:*
 
====Pleural effusion====
* Dosing Information
 
:*
 
====Prosthetic cardiac valve thrombosis====
* Dosing Information
 
:*
 
====Venous catheter occlusion====
* Dosing Information
 
:*
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Urokinase in adult patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Urokinase in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Urokinase in pediatric patients.
|contraindications=The use of urokinase is contraindicated in patients with a history of hypersensitivity to the product.
 
Because thrombolytic therapy increases the risk of bleeding, urokinase is contraindicated in the situations listed below.
*Active internal bleeding
*Recent (e.g., within two months) cerebrovascular accident
*Recent (e.g., within two months) intracranial or intraspinal surgery
*Recent trauma including cardiopulmonary resuscitation
*Intracranial neoplasm, arteriovenous malformation, or aneurysm
*Known bleeding diatheses
*Severe uncontrolled arterial hypertension
|warnings=====Bleeding====
*The risk of serious bleeding is increased with use of urokinase.
*Fatalities due to hemorrhage, including intracranial and retroperitoneal, have been reported in association with urokinase therapy.
*Concurrent administration of urokinase with other thrombolytic agents, anticoagulants, or agents inhibiting platelet function may further increase the risk of serious bleeding.
*urokinase therapy requires careful attention to all potential bleeding sites (including catheter insertion sites, arterial and venous puncture sites, cutdown sites, and other needle puncture sites).
*Intramuscular injections and nonessential handling of the patient must be avoided during treatment with urokinase.
*Venipunctures should be performed as infrequently as possible and with care to minimize bleeding.
*Should an arterial puncture be necessary, upper extremity vessels are preferable.
*Direct pressure should be applied for at least 30 minutes, a pressure dressing applied, and the puncture site checked frequently for evidence of bleeding.
*In the following conditions, the risk of bleeding may be increased and should be weighed against the anticipated benefits:
:*Recent (within 10 days) major surgery, obstetrical delivery, organ biopsy, previous puncture of non-compressible vessels
:*Recent (within 10 days) serious gastrointestinal bleeding
:*High likelihood of a left heart thrombus, for example, mitral stenosis with atrial fibrillation
:*Subacute bacterial endocarditis
:*Hemostatic defects including those secondary to severe hepatic or renal disease
:*Pregnancy
:*Cerebrovascular disease
:*Diabetic hemorrhagic retinopathy
:*Any other condition in which bleeding might constitute a significant hazard or be particularly difficult to manage because of its location
 
*When internal bleeding occurs, it may be more difficult to manage than that which occurs with conventional anticoagulant therapy.
*Should potentially serious spontaneous bleeding (not controllable by direct pressure) occur, the infusion of urokinase should be terminated immediately, and measures to manage the bleeding implemented.
*Serious blood loss may be managed with volume replacement, including packed red blood cells.
*Dextran should not be used. When appropriate, fresh frozen plasma and/or cryoprecipitate may be considered to reverse the bleeding tendency.
 
====Anaphylaxis and Other Infusion Reactions====
*Post-marketing reports of hypersensitivity reactions have included anaphylaxis (with rare reports of fatal anaphylaxis), bronchospasm, orolingual edema and urticaria
*There have also been reports of other infusion reactions which have included one or more of the following: fever and/or chills/rigors, hypoxia, cyanosis, dyspnea, tachycardia, hypotension, hypertension, acidosis, back pain, vomiting, and nausea.
*Reactions generally occurred within one hour of beginning urokinase infusion.
*Patients who exhibit reactions should be closely monitored and appropriate therapy instituted.
*Infusion reactions generally respond to discontinuation of the infusion and/or administration of intravenous antihistamines, corticosteroids, or adrenergic agents.
*Antipyretics which inhibit platelet function (aspirin and other non-steroidal anti-inflammatory agents) may increase the risk of bleeding and should not be used for treatment of fever.
 
====Cholesterol Embolization====
*Cholesterol embolism has been reported rarely in patients treated with all types of thrombolytic agents; the true incidence is unknown.
*This serious condition, which can be lethal, is also associated with invasive vascular procedures (e.g., cardiac catheterization, angiography, vascular surgery) and/or anticoagulant therapy.
*Clinical features of cholesterol embolism may include livedo reticularis, “purple toe” syndrome, acute renal failure, gangrenous digits, hypertension, pancreatitis, myocardial infarction, cerebral infarction, spinal cord infarction, retinal artery occlusion, bowel infarction and rhabdomyolysis.
 
====Product Source and Formulation with Albumin====
*urokinase is made from human neonatal kidney cells grown in tissue culture.
*Products made from human source material may contain infectious agents, such as viruses, that can cause disease.
*The risk that urokinase will transmit an infectious agent has been reduced by screening donors for prior exposure to certain viruses, by testing donors for the presence of certain current virus infections, by testing for certain viruses during manufacturing, and by inactivating and/or removing certain viruses during manufacturing.
*Despite these measures, urokinase may carry a risk of transmitting infectious agents, including those that cause Creutzfeldt-Jakob disease (CJD) or other diseases not yet known or identified; thus, the risk of transmission of infectious agents cannot be totally eliminated.
*A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is considered extremely remote.
*This product is formulated in 5% albumin, a derivative of human blood.
*Based on effective donor screening and product manufacturing processes, albumin carries an extremely remote risk for transmission of viral diseases.
*A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote.
*No cases of transmission of viral diseases or CJD have ever been identified for albumin.
|clinicalTrials=====Bleeding====
 
Bleeding is the most frequent adverse reaction associated with urokinase and can be fatal.
 
In controlled clinical studies using a 12-hour infusion of urokinase for the treatment of pulmonary embolism (UPET and USPET), bleeding resulting in at least a 5% decrease in hematocrit was reported in 52 of 141 urokinase-treated patients. Significant bleeding events requiring transfusion of greater than 2 units of blood were observed during the 14-day study period in 3 of 141 urokinase-treated patients in these studies. Multiple bleeding events may have occurred in an individual patient. Most bleeding occurred at sites of external incisions and vascular puncture, with lesser frequency in gastrointestinal, genitourinary, intracranial, retroperitoneal, and intramuscular sites.
 
====Sources of Information on Adverse Reactions====
 
There are limited well-controlled clinical studies performed using urokinase. The adverse reactions described in the following sections reflect both the clinical use of urokinase in the general population and limited controlled study data. Because post-marketing reports of adverse reactions are voluntary and the population is of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to drug exposure.
 
====Allergic Reactions====
 
Rare cases of fatal anaphylaxis have been reported. In controlled clinical trials, allergic reaction was reported in 1 of 141 patients (<1%).
 
The following allergic-type reactions have been observed in clinical trials and/or post-marketing experience: bronchospasm, orolingual edema, urticaria, skin rash, and pruritus.
 
Infusion reaction symptoms include hypoxia, cyanosis, dyspnea, tachycardia, hypotension, hypertension, acidosis, fever and/or chills/rigors, back pain, vomiting, and nausea.
 
====Other Adverse Reactions====
 
Other adverse events occurring in patients receiving urokinase therapy in clinical studies, regardless of causality, include myocardial infarction, recurrent pulmonary embolism, hemiplegia, stroke, decreased hematocrit, substernal pain, thrombocytopenia, and diaphoresis.
 
====Immunogenicity====
 
The immunogenicity of urokinase has not been studied.
|postmarketing=Adverse reactions reported from post-marketing experience include cardiac arrest, vascular embolization (cerebral and distal) including cholesterol emboli, cerebral vascular accident, pulmonary edema, reperfusion ventricular arrhythmias and chest pain. A cause and effect relationship has not been established.
|drugInteractions=*Anticoagulants and agents that alter platelet function (such as aspirin, other non-steroidal anti-inflammatory agents, dipyridamole, and GP IIb/IIIa inhibitors) may increase the risk of serious bleeding.
*Administration of urokinase prior to, during, or after thrombolytic agents may increase the risk of serious bleeding.
*Because concomitant use of urokinase with agents that alter coagulation, inhibit platelet function, or are thrombolytic may further increase the potential for bleeding complications, careful monitoring for bleeding is recommended.
*The interaction of urokinase with other drugs has not been studied and is not known.
|FDAPregCat=B
|useInPregnancyFDA=Reproduction studies have been performed in mice and rats at doses up to 1,000 times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to urokinase. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
|AUSPregCat=B1
|useInPregnancyAUS=Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.
|useInNursing=It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when urokinase is administered to a nursing woman.
|useInPed=Safety and effectiveness in pediatric patients have not been established.
|useInGeri=Clinical studies of urokinase did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. urokinase should be used with caution in elderly patients.
|administration=*urokinase is administered using a constant infusion pump that is capable of delivering a total volume of 195 mL.
*The loading dose of urokinase admixture (4,400 international units per kilogram) should be delivered at a rate of 90 mL per hour over a period of 10 minutes.
*This is followed by a continuous infusion of 4,400 international units per kilogram per hour of urokinase at a rate of 15 mL per hour for 12 hours.
*Since some of the urokinase admixture will remain in the tubing at the end of an infusion pump delivery cycle, the following flush procedure should be performed to insure that the total dose of urokinase is administered. A solution of 0.9% Sodium *Chloride Injection, USP, or 5% Dextrose Injection, USP, approximately equal in amount to the volume of the tubing in the infusion set should be administered via the pump to flush the urokinase admixture from the entire length of the infusion set. The pump should be set to administer the flush solution at the continuous rate of 15 mL per hour.
*No other drug products/solutions may be administered in the same line with Kinlytic
 
====Preparation====
*The Dose Preparation-Pulmonary Embolism chart is a guidance tool/aid provided for the convenience of the practitioner and may not be complete for every patient.
*urokinase contains no preservatives. Do not reconstitute until immediately before use. *Any unused portion of the reconstituted material should be discarded.
*Reconstitute urokinase by aseptically adding 5 mL of Sterile Water for Injection, USP, without preservatives, to the vial. DO NOT USE Bacteriostatic Water for Injection, USP.
*After reconstitution, the drug product will contain 50,000 international units per milliliter.
*After reconstituting, visually inspect each vial of urokinase for discoloration and for the presence of particulate material. The solution should be pale and straw-colored; highly colored solutions should not be used. Thin translucent filaments may occasionally occur in reconstituted urokinase vials, but do not indicate any decrease in potency of this product. To minimize formation of filaments, avoid shaking the vial during reconstitution. Roll and tilt the vial to enhance reconstitution. The solution may be terminally filtered, for example, through a 0.45 micron or smaller cellulose membrane filter.
*No other medication should be added to this solution.
*Prior to infusing, dilute the reconstituted urokinase with 0.9% Sodium Chloride *Injection, USP or 5% Dextrose Injection, USP.
 
The following Dose Preparation-Pulmonary Embolism chart may be used as an aid in the preparation of urokinase for administration. For administration directions, see next section.
 
[[Image:Urokinase Dose-preparation.png|thumb|650px|left]]
{{clr}}
 
====Anticoagulation After Terminating Urokinase Treatment====
After infusing urokinase, anticoagulation treatment is recommended to prevent recurrent thrombosis. Do not begin anticoagulation until the aPTT has decreased to less than twice the normal control value. If heparin is used, do not administer a loading dose of heparin. Treatment should be followed by oral anticoagulants.
|monitoring======General=====
 
urokinase should be used in hospitals where the recommended diagnostic and monitoring techniques are available.
 
The clinical response and vital signs should be observed frequently during and following urokinase infusion. Blood pressure should not be taken in the lower extremities to avoid dislodgement of possible deep vein thrombi.
 
=====Laboratory Tests=====
 
Before beginning thrombolytic therapy, obtain a hematocrit, platelet count, and an activated partial thromboplastin time (aPTT). If heparin has been given, it should be discontinued and the aPTT should be less than twice the normal control value before thrombolytic therapy is started.
 
Following intravenous infusion of urokinase, before (re)instituting anticoagulants, the aPTT should be less than twice the normal control value.
 
Results of coagulation tests and measures of fibrinolytic activity do not reliably predict either efficacy or risk of bleeding for patients receiving urokinase.
|drugBox={{Drugbox2
| Verifiedfields = changed
| Verifiedfields = changed
| verifiedrevid = 409091966
| verifiedrevid = 409091966
| IUPAC_name =
| IUPAC_name =
 
<!-- Clinical data -->
<!--Clinical data-->
| tradename =   
| tradename =   
| Drugs.com = {{drugs.com|monograph|urokinase}}
| Drugs.com = {{drugs.com|monograph|urokinase}}
Line 255: Line 10:
| legal_status =   
| legal_status =   
| routes_of_administration =
| routes_of_administration =
 
<!-- Pharmacokinetic data -->
<!--Pharmacokinetic data-->
| bioavailability =   
| bioavailability =   
| protein_bound =   
| protein_bound =   
| metabolism =   
| metabolism =   
| elimination_half-life =
| elimination_half-life =
 
<!-- Identifiers -->
<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 9039-53-6
| CAS_number = 9039-53-6
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| ChEMBL = 1201420
| ChEMBL = 1201420
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = NA
| ChemSpiderID = none
 
<!-- Chemical data -->
<!--Chemical data-->
| C=1376 | H=2145 | N=383 | O=406 | S=18
| C=1376 | H=2145 | N=383 | O=406 | S=18  
| molecular_weight = 31126.5 g/mol
| molecular_weight = 31126.5 g/mol
}}
}}
{{infobox protein
'''Urokinase''', also known as '''urokinase-type plasminogen activator''' ('''uPA'''), is a [[serine protease]] present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947.<ref>{{cite journal|last1=Degryse|first1=Bernard|title=The urokinase receptor system as strategic therapeutic target: challenges for the 21st century|journal=Current Pharmaceutical Design|date=1 June 2011|volume=17|issue=19|pages=1872–1873|doi=10.2174/138161211796718161}}</ref> Urokinase was originally isolated from human [[urine]], and it is also present in the [[blood]] and in the [[extracellular matrix]] of many tissues. The primary physiological substrate of this enzyme is [[plasminogen]], which is an inactive form ([[zymogen]]) of the serine protease [[plasmin]]. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in [[thrombolysis]] or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression.<ref>{{cite journal|last1=Tang|first1=Linlin|last2=Han|first2=Xiuzhen|title=The urokinase plasminogen activator system in breast cancer invasion and metastasis|journal=Biomedicine & Pharmacotherapy|date=March 2013|volume=67|issue=2|pages=179–182|doi=10.1016/j.biopha.2012.10.003}}</ref>
| Name = plasminogen activator, urokinase
 
| caption = PLAU
Urokinase is encoded in humans by the ''PLAU'' gene, which stands for "plasminogen activator, urokinase".<ref name="pmid2415429">{{cite journal | vauthors = Nagai M, Hiramatsu R, Kanéda T, Hayasuke N, Arimura H, Nishida M, Suyama T | title = Molecular cloning of cDNA coding for human preprourokinase | journal = Gene | volume = 36 | issue = 1-2 | pages = 183–8 | date = Dec 1985 | pmid = 2415429 | pmc = | doi = 10.1016/0378-1119(85)90084-8 }}</ref> The same symbol represents the gene in other animal species.
| image =  
 
| width =  
== Function ==
| HGNCid = 9052
The ''PLAU'' gene encodes a serine protease ({{EC number|3.4.21.73}}) involved in degradation of the extracellular matrix and possibly tumor cell migration and proliferation. A specific polymorphism in this gene may be associated with late-onset Alzheimer disease and also with decreased affinity for fibrin-binding. The protein encoded by this gene converts plasminogen to plasmin by specific cleavage of an Arg-Val bond in plasminogen. This gene's proprotein is cleaved at a Lys-Ile bond by plasmin to form a two-chain derivative in which a single disulfide bond connects the amino-terminal A-chain to the catalytically active, carboxy-terminal B-chain. This two-chain derivative is also called HMW-uPA (high molecular weight uPA). HMW-uPA can be further processed into LMW-uPA (low molecular weight uPA) by cleavage of chain A into a short chain A (A1) and an amino-terminal fragment. LMW-uPA is proteolytically active but does not bind to the uPA receptor.<ref>{{cite web | title = Entrez Gene: PLAU plasminogen activator, urokinase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5328| accessdate = }}</ref>
| Symbol = [[PLAU]]
 
| AltSymbols =  
== Structure ==
| EntrezGene = 5328
Urokinase is a 411-[[residue (chemistry)|residue]] [[protein]], consisting of three [[Domain (biology)|domains]]: the serine protease domain, the [[kringle domain]], and the [[growth factor domain]]. Urokinase is synthesized as a zymogen form (prourokinase or single-chain urokinase), and is activated by proteolytic cleavage between Lys158 and Ile159. The two resulting chains are kept together by a [[disulfide]] bond.
| OMIM = 191840
 
| RefSeq = NM_002658
== Interaction partners ==
| UniProt = P00749
The most important inhibitors of urokinase are the [[serpin]]s [[plasminogen activator inhibitor-1]] (PAI-1) and [[plasminogen activator inhibitor-2]] (PAI-2), which inhibit the protease activity irreversibly. In the extracellular matrix, urokinase is tethered to the [[cell membrane]] by its interaction to the [[urokinase receptor]].
| PDB =  
 
| ECnumber = 3.4.21.31
[[Image:Fibrinolysis.png|center|framed|Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.]]
| Chromosome = 10
 
| Arm = q
uPa also interacts with [[protein C inhibitor]].<ref name=pmid2752144>{{cite journal | vauthors = Geiger M, Huber K, Wojta J, Stingl L, Espana F, Griffin JH, Binder BR | title = Complex formation between urokinase and plasma protein C inhibitor in vitro and in vivo | journal = Blood | volume = 74 | issue = 2 | pages = 722–8 | date = Aug 1989 | pmid = 2752144 }}</ref><ref name=pmid2551064>{{cite journal | vauthors = España F, Berrettini M, Griffin JH | title = Purification and characterization of plasma protein C inhibitor | journal = Thromb. Res. | volume = 55 | issue = 3 | pages = 369–84 | date = Aug 1989 | pmid = 2551064 | doi = 10.1016/0049-3848(89)90069-8 }}</ref>
| Band = 24
 
| LocusSupplementaryData =  
== Urokinase and cancer ==
}}
Elevated [[gene expression|expression]] levels of urokinase and several other components of the [[plasminogen activation system]] are found to be correlated with [[tumor]] [[malignancy]]. It is believed that the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to [[metastasis]]. This makes urokinase an attractive [[drug target]], and, so, [[Enzyme inhibitor|inhibitor]]s have been sought to be used as anticancer agents.<ref name="pmid10738907">{{cite journal |vauthors=Jankun J, Skrzypczak-Jankun E | title = Molecular basis of specific inhibition of urokinase plasminogen activator by amiloride | journal = Cancer Biochem. Biophys. | volume = 17 | issue = 1-2 | pages = 109–23 |date=July 1999 | pmid = 10738907 | doi = }}</ref><ref name="pmid21544803">{{cite journal |vauthors=Matthews H, Ranson M, Kelso MJ | title = Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty? | journal = Int. J. Cancer | volume = 129 | issue = 9 | pages = 2051–61 |date=November 2011 | pmid = 21544803 | doi = 10.1002/ijc.26156 }}</ref> However, incompatibilities between the human and [[murine]] systems hamper clinical evaluation of these agents. Through its interaction with the [[urokinase receptor]], urokinase affects several other aspects of cancer biology such as cell adhesion, migration, and cellular [[mitotic]] pathways.
|mechAction=Urokinase is an enzyme (protein) produced by the kidney, and found in the urine. There are two forms of urokinase which differ in molecular weight but have similar clinical effects. urokinase is the low molecular weight form. urokinase acts on the endogenous fibrinolytic system. It converts plasminogen to the enzyme plasmin. Plasmin degrades fibrin clots as well as fibrinogen and some other plasma proteins.
 
|structure=The principal active ingredient of urokinase is the low molecular weight form of urokinase, and consists of an A chain of 2,000 daltons linked by a sulfhydryl bond to a B chain of 30,400 daltons.
As of December 7, 2012, Mesupron, a small molecule serine protease inhibitor developed by the WILEX pharmaceutical company, has completed phase II trials.<ref name="urlGemcitabine With or Without WX-671 in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed By Surgery - Full Text View - ClinicalTrials.gov">{{cite web | url = http://www.clinicaltrials.gov/ct2/show/NCT00499265 | title = Gemcitabine With or Without WX-671 in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed By Surgery  | work = | publisher = ClinicalTrials.gov }}</ref>  Mesupron appears to be safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival in human breast cancer.<ref name="urlFox Chase Cancer Center : New Small Molecule Inhibitor Could be a Safe and First-Line Treatment for Metastatic Breast Cancer">{{cite web | url = http://www.fccc.edu/information/news/press-releases/2012/2012-12-07-SABC-Goldstein-WILEX.html | title = Fox Chase Cancer Center : New Small Molecule Inhibitor Could be a Safe and First-Line Treatment for Metastatic Breast Cancer | work = Press Release | publisher =Temple University Health System }}</ref>
|PD=Intravenous infusion of urokinase in doses recommended for lysis of pulmonary embolism is followed by increased fibrinolytic activity in the circulation. This effect disappears within a few hours after discontinuation, but a decrease in plasma levels of fibrinogen and plasminogen and an increase in the amount of circulating fibrin and fibrinogen degradation products may persist for 12-24 hours.2 There is a lack of correlation between embolus resolution and changes in coagulation and fibrinolytic assay results.
 
|PK=Information about the pharmacokinetic properties in man is limited. Urokinase administered by intravenous infusion is rapidly cleared by the liver with an elimination half-life for biologic activity of 12.6 ± 6.2 minutes and a distribution volume of 11.5 L. Small fractions of the administered dose are excreted in bile and urine. Although the pharmacokinetics of exogenously administered urokinase have not been characterized in patients with hepatic impairment, endogenous urokinase-type plasminogen activator plasma levels are elevated 2- to 4-fold in patients with moderate to severe cirrhosis.1 Thus, reduced urokinase clearance in patients with hepatic impairment might be expected.
== Clinical applications ==
|nonClinToxic=Adequate data are not available on the long-term potential for carcinogenicity in animals or humans.
Urokinase is effective for the restoration of flow to intravenous catheters blocked by clotted blood or fibrin (catheter clearance).  Catheters are used extensively to administer treatments to patients for such purposes as dialysis, nutrition, antibiotic treatment and cancer treatment.  Approximately 25% of catheters become blocked, meaning that affected patients cannot receive treatment until the catheter has been cleared or replaced. Urokinase is also used clinically as a [[thrombolysis|thrombolytic]] agent in the treatment of severe or massive [[deep venous thrombosis]], peripheral arterial occlusive disease, [[pulmonary embolism]], acute [[myocardial infarction]] (AMI, heart attack), and occluded [[dialysis]] cannulas (catheter clearance). It is also administered intrapleurally to improve the drainage of complicated pleural effusions and empyemas. Urokinase is marketed as Kinlytic (formerly Abbokinase) and competes with [[tissue plasminogen activator|recombinant tissue plasminogen activator]] (e.g., alteplase) as a thrombolytic drug.
|howSupplied=urokinase is supplied as a sterile lyophilized preparation (NDC 24430-1003-1).
 
Each vial contains 250,000 international units urokinase activity, 25 mg mannitol, 250 mg Albumin (Human), and 50 mg sodium chloride.
All plasminogen activators (urokinase, TPA) catalyze the production of plasmin, which in turn leads to the breakdown of the fibrin lattice structure in blood clots.  While there are commonalities in the mode of action for urokinase and TPA, urokinase has some advantages for treatment of peripheral clots (Pulmonary Embolism, Deep Vein Thrombosis, Peripheral arterial occlusive disease).
|storage=Refrigerate urokinase powder at 2° to 8°C (36° to 46°F)
 
|alcohol=Alcohol-Urokinase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Unlike TPA, which is activated by binding to the fibrin within clots, urokinase is not sequestered by fibrin and therefore does not specifically attack hemostatic clots.  This makes urokinase less likely to break down such hemostatic clots that are essential for ongoing blood vessel repair throughout the body.  Dissolution of these “good” clots can lead to serious adverse events through hemorrhagic bleeding.  Years of clinical study have confirmed the safety advantage of using urokinase.<ref>{{Cite journal|last=Ouriel, K. et al.|first=|date=2000|title=Complications Associated with the Use of Urokinase and Recombinant Tissue Plasminogen Activator for Catheter-directed Peripheral Arterial and Venous Thrombolysis|url=|journal=JVIR|volume=11|pages=295-298|via=}}</ref> <ref>{{Cite journal|last=Cina, C. et al.|first=|date=1999|title=Intraarterial Catheter-Directed Thrombolysis: Urokinase versus Tissue Plasminogen Activator|url=|journal=Ann Vasc Surg|volume=13|pages=571-575|via=}}</ref> Consequently, urokinase has been preferentially used in [[deep venous thrombosis]] and peripheral arterial occlusive disease where it is administered directly to the site of the clot while TPA is preferred in AMI where peripheral bleeding is a secondary consideration.  
|brandNames=*Abbokinase
 
*Kinlytic
==References==
|nlmPatientInfo=(Link to patient information page)
{{Reflist|2}}
|drugShortage=Drug Shortage
 
}}
== Further reading ==
{{LabelImage
{{refbegin}}
|fileName=Urokinase FDA panel.png
* {{cite journal | vauthors = Ploug M, Gårdsvoll H, Jørgensen TJ, Lønborg Hansen L, Danø K | title = Structural analysis of the interaction between urokinase-type plasminogen activator and its receptor: a potential target for anti-invasive cancer therapy. | journal = Biochem. Soc. Trans. | volume = 30 | issue = 2 | pages = 177–83 | year = 2002 | pmid = 12023847 | doi = 10.1042/BST0300177 }}
}}
* {{cite journal | vauthors = Alfano M, Sidenius N, Blasi F, Poli G | title = The role of urokinase-type plasminogen activator (uPA)/uPA receptor in HIV-1 infection. | journal = J. Leukoc. Biol. | volume = 74 | issue = 5 | pages = 750–6 | year = 2004 | pmid = 12960238 | doi = 10.1189/jlb.0403176 }}
* {{cite journal | vauthors = Harbeck N, Kates RE, Gauger K, Willems A, Kiechle M, Magdolen V, Schmitt M | title = Urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I: novel tumor-derived factors with a high prognostic and predictive impact in breast cancer. | journal = Thromb. Haemost. | volume = 91 | issue = 3 | pages = 450–6 | year = 2004 | pmid = 14983219 | doi = 10.1160/TH03-12-0798 }}
* {{cite journal | vauthors = Gilabert-Estelles J, Ramon LA, España F, Gilabert J, Castello R, Estelles A | title = Expression of the fibrinolytic components in endometriosis. | journal = Pathophysiol. Haemost. Thromb. | volume = 35 | issue = 1-2 | pages = 136–40 | year = 2006 | pmid = 16855359 | doi = 10.1159/000093556 }}
{{refend}}
 
{{Coagulation}}
{{Antithrombotics}}
{{Serine endopeptidases}}
{{Enzymes}}
{{PDB Gallery|geneid=5328}}
{{Portal bar|Molecular and Cellular Biology|border=no}}
 
[[Category:Antithrombotic enzymes]]
[[Category:EC 3.4.21]]

Latest revision as of 15:40, 10 October 2018

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SpeciesHumanMouse
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Urokinase
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Chemical and physical data
FormulaC1376H2145N383O406S18
Molar mass31126.5 g/mol
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Urokinase, also known as urokinase-type plasminogen activator (uPA), is a serine protease present in humans and other animals. The human urokinase protein was discovered, but not named, by McFarlane and Pilling in 1947.[1] Urokinase was originally isolated from human urine, and it is also present in the blood and in the extracellular matrix of many tissues. The primary physiological substrate of this enzyme is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin. Activation of plasmin triggers a proteolytic cascade that, depending on the physiological environment, participates in thrombolysis or extracellular matrix degradation. This cascade had been involved in vascular diseases and cancer progression.[2]

Urokinase is encoded in humans by the PLAU gene, which stands for "plasminogen activator, urokinase".[3] The same symbol represents the gene in other animal species.

Function

The PLAU gene encodes a serine protease (EC 3.4.21.73) involved in degradation of the extracellular matrix and possibly tumor cell migration and proliferation. A specific polymorphism in this gene may be associated with late-onset Alzheimer disease and also with decreased affinity for fibrin-binding. The protein encoded by this gene converts plasminogen to plasmin by specific cleavage of an Arg-Val bond in plasminogen. This gene's proprotein is cleaved at a Lys-Ile bond by plasmin to form a two-chain derivative in which a single disulfide bond connects the amino-terminal A-chain to the catalytically active, carboxy-terminal B-chain. This two-chain derivative is also called HMW-uPA (high molecular weight uPA). HMW-uPA can be further processed into LMW-uPA (low molecular weight uPA) by cleavage of chain A into a short chain A (A1) and an amino-terminal fragment. LMW-uPA is proteolytically active but does not bind to the uPA receptor.[4]

Structure

Urokinase is a 411-residue protein, consisting of three domains: the serine protease domain, the kringle domain, and the growth factor domain. Urokinase is synthesized as a zymogen form (prourokinase or single-chain urokinase), and is activated by proteolytic cleavage between Lys158 and Ile159. The two resulting chains are kept together by a disulfide bond.

Interaction partners

The most important inhibitors of urokinase are the serpins plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2), which inhibit the protease activity irreversibly. In the extracellular matrix, urokinase is tethered to the cell membrane by its interaction to the urokinase receptor.

Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.

uPa also interacts with protein C inhibitor.[5][6]

Urokinase and cancer

Elevated expression levels of urokinase and several other components of the plasminogen activation system are found to be correlated with tumor malignancy. It is believed that the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to metastasis. This makes urokinase an attractive drug target, and, so, inhibitors have been sought to be used as anticancer agents.[7][8] However, incompatibilities between the human and murine systems hamper clinical evaluation of these agents. Through its interaction with the urokinase receptor, urokinase affects several other aspects of cancer biology such as cell adhesion, migration, and cellular mitotic pathways.

As of December 7, 2012, Mesupron, a small molecule serine protease inhibitor developed by the WILEX pharmaceutical company, has completed phase II trials.[9] Mesupron appears to be safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival in human breast cancer.[10]

Clinical applications

Urokinase is effective for the restoration of flow to intravenous catheters blocked by clotted blood or fibrin (catheter clearance). Catheters are used extensively to administer treatments to patients for such purposes as dialysis, nutrition, antibiotic treatment and cancer treatment. Approximately 25% of catheters become blocked, meaning that affected patients cannot receive treatment until the catheter has been cleared or replaced. Urokinase is also used clinically as a thrombolytic agent in the treatment of severe or massive deep venous thrombosis, peripheral arterial occlusive disease, pulmonary embolism, acute myocardial infarction (AMI, heart attack), and occluded dialysis cannulas (catheter clearance). It is also administered intrapleurally to improve the drainage of complicated pleural effusions and empyemas. Urokinase is marketed as Kinlytic (formerly Abbokinase) and competes with recombinant tissue plasminogen activator (e.g., alteplase) as a thrombolytic drug.

All plasminogen activators (urokinase, TPA) catalyze the production of plasmin, which in turn leads to the breakdown of the fibrin lattice structure in blood clots.  While there are commonalities in the mode of action for urokinase and TPA, urokinase has some advantages for treatment of peripheral clots (Pulmonary Embolism, Deep Vein Thrombosis, Peripheral arterial occlusive disease).

Unlike TPA, which is activated by binding to the fibrin within clots, urokinase is not sequestered by fibrin and therefore does not specifically attack hemostatic clots.  This makes urokinase less likely to break down such hemostatic clots that are essential for ongoing blood vessel repair throughout the body.  Dissolution of these “good” clots can lead to serious adverse events through hemorrhagic bleeding.  Years of clinical study have confirmed the safety advantage of using urokinase.[11] [12] Consequently, urokinase has been preferentially used in deep venous thrombosis and peripheral arterial occlusive disease where it is administered directly to the site of the clot while TPA is preferred in AMI where peripheral bleeding is a secondary consideration.  

References

  1. ↑ Degryse, Bernard (1 June 2011). "The urokinase receptor system as strategic therapeutic target: challenges for the 21st century". Current Pharmaceutical Design. 17 (19): 1872–1873. doi:10.2174/138161211796718161.
  2. ↑ Tang, Linlin; Han, Xiuzhen (March 2013). "The urokinase plasminogen activator system in breast cancer invasion and metastasis". Biomedicine & Pharmacotherapy. 67 (2): 179–182. doi:10.1016/j.biopha.2012.10.003.
  3. ↑ Nagai M, Hiramatsu R, Kanéda T, Hayasuke N, Arimura H, Nishida M, Suyama T (Dec 1985). "Molecular cloning of cDNA coding for human preprourokinase". Gene. 36 (1–2): 183–8. doi:10.1016/0378-1119(85)90084-8. PMID 2415429.
  4. ↑ "Entrez Gene: PLAU plasminogen activator, urokinase".
  5. ↑ Geiger M, Huber K, Wojta J, Stingl L, Espana F, Griffin JH, Binder BR (Aug 1989). "Complex formation between urokinase and plasma protein C inhibitor in vitro and in vivo". Blood. 74 (2): 722–8. PMID 2752144.
  6. ↑ España F, Berrettini M, Griffin JH (Aug 1989). "Purification and characterization of plasma protein C inhibitor". Thromb. Res. 55 (3): 369–84. doi:10.1016/0049-3848(89)90069-8. PMID 2551064.
  7. ↑ Jankun J, Skrzypczak-Jankun E (July 1999). "Molecular basis of specific inhibition of urokinase plasminogen activator by amiloride". Cancer Biochem. Biophys. 17 (1–2): 109–23. PMID 10738907.
  8. ↑ Matthews H, Ranson M, Kelso MJ (November 2011). "Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty?". Int. J. Cancer. 129 (9): 2051–61. doi:10.1002/ijc.26156. PMID 21544803.
  9. ↑ "Gemcitabine With or Without WX-671 in Treating Patients With Locally Advanced Pancreatic Cancer That Cannot Be Removed By Surgery". ClinicalTrials.gov.
  10. ↑ "Fox Chase Cancer Center : New Small Molecule Inhibitor Could be a Safe and First-Line Treatment for Metastatic Breast Cancer". Press Release. Temple University Health System.
  11. ↑ Ouriel, K.; et al. (2000). "Complications Associated with the Use of Urokinase and Recombinant Tissue Plasminogen Activator for Catheter-directed Peripheral Arterial and Venous Thrombolysis". JVIR. 11: 295–298.
  12. ↑ Cina, C.; et al. (1999). "Intraarterial Catheter-Directed Thrombolysis: Urokinase versus Tissue Plasminogen Activator". Ann Vasc Surg. 13: 571–575.

Further reading

  • Ploug M, Gårdsvoll H, Jørgensen TJ, Lønborg Hansen L, Danø K (2002). "Structural analysis of the interaction between urokinase-type plasminogen activator and its receptor: a potential target for anti-invasive cancer therapy". Biochem. Soc. Trans. 30 (2): 177–83. doi:10.1042/BST0300177. PMID 12023847.
  • Alfano M, Sidenius N, Blasi F, Poli G (2004). "The role of urokinase-type plasminogen activator (uPA)/uPA receptor in HIV-1 infection". J. Leukoc. Biol. 74 (5): 750–6. doi:10.1189/jlb.0403176. PMID 12960238.
  • Harbeck N, Kates RE, Gauger K, Willems A, Kiechle M, Magdolen V, Schmitt M (2004). "Urokinase-type plasminogen activator (uPA) and its inhibitor PAI-I: novel tumor-derived factors with a high prognostic and predictive impact in breast cancer". Thromb. Haemost. 91 (3): 450–6. doi:10.1160/TH03-12-0798. PMID 14983219.
  • Gilabert-Estelles J, Ramon LA, España F, Gilabert J, Castello R, Estelles A (2006). "Expression of the fibrinolytic components in endometriosis". Pathophysiol. Haemost. Thromb. 35 (1–2): 136–40. doi:10.1159/000093556. PMID 16855359.
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