Methods, devices, and compositions for lysis of occlusive blood clots while sparing wound sealing clots

Abstract

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.

1 . A method of treating a patient with symptoms of a heart attack comprising: 
 determining that the patient potentially has had a heart attack based on observing one or more symptoms of a heart attack; and    administering to the patient a composition comprising an amount of a pro-urokinase mutant polypeptide (pro-UK mutant) effective to lyse any potential blood clot causing the symptoms of a heart attack.    
     
     
         2 . The method of  claim 1 , wherein the composition is administered within 24 hours of the onset of symptoms.  
     
     
         3 . The method of  claim 1 , wherein the composition is administered within two hours of the onset of symptoms.  
     
     
         4 . The method of  claim 1 , wherein the composition is administered by intravenous infusion at a pro-UK mutant dosage of 100-200 mg/hour.  
     
     
         5 . The method of  claim 1 , further comprising: 
 obtaining a medical confirmation of acute myocardial infarction; and    administering an infusion of the composition at a pro-UK mutant dosage of 100-120 mg/hour for 60 to 90 minutes.    
     
     
         6 . The method of  claim 1 , wherein the composition is administered prior to angioplasty.  
     
     
         7 . The method of  claim 1 , wherein the composition is administered as a bolus comprising 20-50 mg of the pro-UK mutant.  
     
     
         8 . The method of  claim 1 , wherein the composition is administered as a bolus and an infusion and wherein the total dose of the bolus and infusion together is 20-50 mg.  
     
     
         9 . The method of  claim 1 , wherein the pro-UK mutant is a flexible loop mutant.  
     
     
         10 . The method of  claim 9 , wherein the flexible loop mutant has the amino acid Lysine replaced by the amino acid Histidine at position 300.