Protamine fragment compositions and methods of use

Abstract

Provided are bioactive, low-toxicity protamine fragments, compositions, combinations, kits and methods of using these components in a variety of embodiments, including neutralizing heparin and reducing post-operative bleeding. Improved protamine fragment-insulin solutions and methods for treating diabetes are also provided.

1 - 47 . (canceled)  
     
     
         48 . The method of  claim 55 , wherein said purified protamine has a molecular weight of between about 400 and about 2000 Daltons.  
     
     
         49 . The method of  claim 48 , wherein said purified protamine has a molecular weight of between about 500 and about 1350 Daltons.  
     
     
         50 . The method of  claim 48 , wherein said purified protamine has a molecular weight of between about 1100 and about 1300 Daltons.  
     
     
         51 - 54 . (canceled)  
     
     
         55 . A method of inactivating heparin or low molecular weight heparin, comprising contacting heparin or low molecular weight heparin with a composition comprising an amount of at least a first purified protamine effective to inactivate heparin or low molecular weight heparin; wherein said purified protamine is bioactive, has a molecular weight of between about 400 and about 2500 Daltons and has reduced immunoresponsiveness or toxicity compared to native protamine.  
     
     
         56 . The method of  claim 55 , wherein said heparin or low molecular weight heparin is located within a mammal and said composition is administered to said mammal.  
     
     
         57 . A method of ameliorating an effect of heparin or low molecular weight heparin in a mammal, comprising administering to said mammal of at least a first pharmaceutical composition comprising an amount of at least a first purified protamine effective to ameliorate an effect of heparin or low molecular weight heparin in said mammal; wherein said purified protamine is bioactive, has a molecular weight of between about 400 and about 2500 Daltons and has reduced immunoresponsiveness or toxicity compared to native protamine.  
     
     
         58 . A method for treating or preventing undue or excessive bleeding in a mammal, comprising administering to a mammal having or at risk for developing excessive bleeding at least a first pharmaceutical composition comprising an amount of at least a first purified protamine effective to treat or prevent undue or excessive bleeding in said mammal, wherein said purified protamine is bioactive has a molecular weight of between about 400 and about 2500 Daltons and has reduced immunoresponsiveness or toxicity compared to native protamine.  
     
     
         59 . The method of  claim 64 , wherein said mammal exhibits excessive bleeding associated with systemic heparinization.  
     
     
         60 . The method of  claim 64 , wherein said mammal exhibits excessive bleeding associated with extracorporeal blood circulation.  
     
     
         61 . The method of  claim 64 , wherein said mammal exhibits excessive bleeding associated with a disease or disorder.  
     
     
         62 . The method of  claim 64 , wherein said mammal exhibits excessive bleeding associated with a trauma or surgery.  
     
     
         63 . The method of  claim 64 , wherein at least a second coagulant is further administered to said mammal.  
     
     
         64 . The method of  claim 56 , wherein said mammal has or is at risk for developing excessive bleeding.  
     
     
         65 . The method  claim 48 , wherein said purified protamine has a molecular weight of about 1300 Daltons.  
     
     
         66 . The method of  claim 48 , wherein said purified protamine has a molecular weight of about 1200 Daltons.  
     
     
         67 . The method of  claim 55 , wherein said composition comprises at least a first and at least a second purified protamine.  
     
     
         68 . The method of  claim 56 , wherein said mammal is a human subject.