Thrombolytic agents and methods of treatment for thrombosis

Abstract

The foregoing invention relates to a new microbubble preparation and thrombolytic therapy which relies on microbubbles and ultrasound for its lytic activity. The pharmaceutical composition of the invention comprises a liquid solution of microbubbles with an internal atmosphere enhanced with the perfluorocarbon gas which cavitate in the presence of an ultrasound field following intravenous injection or infusion of said composition into said host. For thrombolysis the area of a thrombus is exposed to an ultrasound field in the presence of the microbubbles and significant lysis is experienced. The method and pharmaceutical composition of the invention exhibit thrombolytic properties similar to those of other thrombolytic agents such as urokinase and are less toxic and are clot specific in that they do not introduce a systemic lytic state to a said animal.

1 . A method of relieving trauma associated with obstruction of vessels distal to a thrombus site by increasing blood flow without thrombus dissolution and recanalization in animals comprising: 
 introducing a pharmaceutical composition to an animal with a thrombus by intravenous injection, said pharmaceutical composition comprising a microbubble ultrasound agent, and a pharmaceutically acceptable carrier, wherein said carrier comprises a 5% solution of dextrose and thereafter;    applying ultrasound to the vessels in the area of trauma, distal to the thrombus site.    
     
     
         2 . The method of  claim 2  wherein said microbubble contrast agent comprises: 
 a plurality of gas filled microbubbles with a diameter of from about 0.1 to 10 microns.    
     
     
         3 . The method of  claim 2  wherein said gas is an insoluble gas.  
     
     
         4 . The method of  claim 2  wherein said microbubbles are protein coated.  
     
     
         5 . The method of  claim 3  wherein said protein coated microbubbles are albumin coated microspheres  
     
     
         6 . The method of  claim 2  wherein said insoluble gas is selected from the group consisting perfluoromethane, perfluoroethane, perfluoropropane, perfluorobutane, and perfluoropentane.  
     
     
         7 . The method of  claim 6  wherein said perfluorocarbon gas is perfluorobutane.  
     
     
         8 . The method of  claim 6  wherein said perfluorocarbon gas is perfluoropropane.  
     
     
         9 . The method of  claim 2  further comprising the following steps: 
 mixing an aqueous solution comprising 2% to about 10 T by weight of human serum albumin diluted about 2-fold to about 8-fold with 5% to 50% by weight dextrose; and    exposing said solution to a sonication horn to generate stable microbubbles from about 0.1 to 10 microns in diameter to create said pharmaceutical composition.    
     
     
         10 . The method of  claim 9  wherein said dilution of albumin with dextrose is a 3-fold dilution.  
     
     
         11 . The method of  claim 9  wherein said human serum albumin is a 5% by weight solution.  
     
     
         12 . The method of  claim 9  wherein said dextrose is a 5% by weight solution.  
     
     
         13 . A method of relieving trauma associated with obstruction of vessels to a thrombus site by increasing blood flow with thrombus dissolution and recanalization in animals comprising: 
 introducing a pharmaceutical composition to an animal with a thrombus by intravenous injection, said pharmaceutical composition comprising a microbubble ultrasound agent, and a pharmaceutically acceptable carrier, wherein said carrier comprises a 5% solution of dextrose and thereafter;    applying ultrasound to the pharmaceutical composition following intravenous injection and during transit to the thrombus.    
     
     
         14 . The method of  claim 13  wherein said microbubble contrast agent comprises: 
 a plurality of gas filled microbubbles with a diameter of from about 0.1 to 10 microns.    
     
     
         15 . The method of  claim 14  further comprising the following steps: 
 mixing an aqueous solution comprising 2% to about 10% by weight of human serum albumin diluted about 2-fold to about 8-fold with 5% to 50% by weight dextrose; and    exposing said solution to a sonication horn to generate stable microbubbles from about 0.1 to 10 microns in diameter to create said pharmaceutical composition.    
     
     
         16 . A method of relieving trauma associated with obstruction of vessels close to a thrombus site by increasing blood flow with thrombus dissolution and recanalization in animals comprising: 
 introducing a pharmaceutical composition to an animal with a thrombus by intravenous injection, said pharmaceutical composition comprising a microbubble ultrasound agent, and a pharmaceutically acceptable carrier, wherein said carrier comprises a 5% solution of dextrose and thereafter;    applying ultrasound to the vessels in the area of trauma, close to and not on the thrombus site.