Methods and compositions for activated protein c with reduced anticoagulant properties

Abstract

This invention relates to a novel form of protein C or activated protein C. More specifically, the invention is directed to a variant of protein C that is activated at a higher rate than wild-type or other variants and produces an activated protein C with reduced anticoagulant properties while retaining the protective anti-inflammatory and anti-apoptotic properties of wild-type activated protein C. This novel APC variant will be beneficial for treating inflammatory and apoptotic disorders with a reduced risk for bleeding.

1 . A method for treating inflammation or apoptosis in a human patient comprised of administrated cross-linked protein C in an injectable physiological solution parenterally. 
     
     
         2 . The method of  claim 1  whereby the cross-linked protein C is administered by intravenous injection. 
     
     
         3 . The method of  claim 1  whereby the cross-linked protein C is administered by continuous infusion from about 0.01 μg/kg/hr to about 500 μg/kg/hr for about 1 to about 240 hours. 
     
     
         4 . The method of  claim 1  whereby the cross-linked protein C is administered such that plasma ranges are from about 2 ng/ml to about 1000 ng/ml. 
     
     
         5 . The method of  claim 1  whereby the inflammation is associated with disease selected from the group consisting of sepsis, severe sepsis, and septic shock. 
     
     
         6 . The method of  claim 1  whereby the inflammation is associated with disease selected from the group consisting of inflammatory bowel disease, vasculitis, renal ischemia, and pancreatitis. 
     
     
         7 . The method of  claim 1  whereby inflammation or apoptosis is associated with a neurological disease selected from the group consisting of ischemic stroke, Alzheimer's disease, Huntington disease, multiple sclerosis, ischemia, epilepsy, amyotrophic and lateral sclerosis. 
     
     
         8 . A method for treating inflammation or apoptosis in a human patient comprised of administrated cross-linked activated protein C in an injectable physiological solution parenterally. 
     
     
         9 . The method of  claim 8  whereby the cross-linked activated protein C is administered by continuous infusion may be from about 0.01 μg/kg/hr to about 50 μg/kg/hr for about 1 to about 240 hours. 
     
     
         10 . The method of  claim 8  whereby the cross-linked activated protein C is administered such that plasma ranges are from about 2 ng/ml to about 100 ng/ml. 
     
     
         11 . The method of  claim 8  whereby the inflammation is associated with disease selected from the group consisting of sepsis, severe sepsis, and septic shock. 
     
     
         12 . The method of  claim 8  whereby the inflammation is associated with disease selected from the group consisting of inflammatory bowel disease, vasculitis, renal ischemia, and pancreatitis. 
     
     
         13 . The method of  claim 8  whereby inflammation or apoptosis is associated with a neurological disease selected from the group consisting of ischemic stroke, Alzheimer's disease, Huntington disease, multiple sclerosis, ischemia, epilepsy, amyotrophic and lateral sclerosis. 
     
     
         14 . A method for treating ischemic stroke in a human comprised of administering cross-linked activated protein C in an injectable physiological solution parenterally. 
     
     
         15 . The method of  claim 14  whereby the cross-linked activated protein C is administered by continuous infusion may be from about 0.01 μg/kg/hr to about 50 μg/kg/hr for about 1 to about 240 hours. 
     
     
         16 . The method of  claim 14  whereby the cross-linked activated protein C is administered such that plasma ranges are from about 2 ng/ml to about 100 ng/ml. 
     
     
         17 . The method of  claim 14  whereby the cross-linked activated protein C is administered at about 2 milligrams per kilogram intravenously. 
     
     
         18 . The method of  claim 14  whereby the cross-linked activated protein C is administered after a stroke.