Method for using lipoprotein associated coagulation inhibitor to treat sepsis

Abstract

A method for prophylactically or therapeutically treating sepsis or septic shock is described, wherein an inhibitor to tissue factor is administered to septic patients. Additionally, a method for treating inflammation is described wherein the inhibitor is administered to pateints. This inhibitor is termed lipoprotein associated coagulation inhibitor, or commonly LACI. It is 38 kD and has 276 amino acids. LACI has now been shown to be useful for the treatment of sepsis, septic shock and inflammation.

We claim:  
     
         1 . A method of treating sepsis-associated DIC comprising: 
 administering to a patient who has sepsis-associated DIC a therapeutically effective amount of LACI in the absence of heparin.    
     
     
         2 . The method of  claim 1  wherein said LACI comprises a first Kunitz-domain consisting of amino acids 47-117.  
     
     
         3 . The method of  claim 1  wherein said LACI comprises a second Kunitz domain consisting of amino acids 118-188.  
     
     
         4 . The method of  claim 1  wherein said LACI comprises a first and a second Kunitz domain consisting of amino acids 47-188.  
     
     
         5 . The method of  claim 2  wherein said LACI lacks a third domain.  
     
     
         6 . The method of  claim 1  wherein said LACI is administered in a total daily dose of 4-20 mg/kg.  
     
     
         7 . The method of  claim 1  wherein said LACI is administered in a total daily dose of 6-10 mg/kg.  
     
     
         8 . The method of  claim 1  wherein said LACI is administered in a total daily-dose of 2-50 mg/kg.  
     
     
         9 . A method for treating septic patients who do not have DIC, comprising: 
 administering to a septic patient who does not have DIC a therapeutically effective amount of LACI.    
     
     
         10 . The method of  claim 9  wherein said LACI is administered at a dose of 1 ug to 20 ug per kg.  
     
     
         11 . The method of  claim 9  wherein said LACI is administered at a dose of 20 ug to 10 mg per kg.  
     
     
         12 . The method of  claim 9  wherein said LACI is administered at a dose of 1 mg to 7 mg per kg.  
     
     
         13 . The method of  claim 9  wherein said LACI comprises a first Kunitz-domain consisting of amino acids 47-117.  
     
     
         14 . The method of  claim 9  wherein said LACI comprises a second Kunitz domain consisting of amino acids 118-188.  
     
     
         15 . The method of  claim 9  wherein said LACI comprises a first and a second Kunitz domain consisting of amino acids 47-188.  
     
     
         16 . The method of  claim 13  wherein said LACI lacks a third domain.  
     
     
         17 . A prophylactic method for decreasing the risk and severity of sepsis comprising: 
 administering to a patient susceptible to sepsis a prophylactically effective amount of LACI.    
     
     
         18 . The method of  claim 17  wherein said LACI comprises a first Kunitz-domain consisting of amino acids 47-117.  
     
     
         19 . The method of  claim 17  wherein said LACI comprises a second Kunitz domain consisting of amino acids 118-188.  
     
     
         20 . The method of  claim 17  wherein said LACI comprises a first and a second Kunitz domain consisting of amino acids 47-188.  
     
     
         21 . The method of  claim 18  wherein said LACI lacks a third domain.  
     
     
         22 . The method of  claim 17  wherein said LACI is administered at a dose of 1 ug to 20 ug per kg.  
     
     
         23 . The method of  claim 17  wherein said LACI is administered at a dose of 20 ug to 10 mg per kg.  
     
     
         24 . The method of  claim 17  wherein said LACI is administered at a dose of 1 mg to 7 mg per kg.  
     
     
         25 . A method for prophylactically and therapeutically treating acute inflammation, including sepsis and septic shock, comprising administering to a patient a therapeutically effective amount of LACI.  
     
     
         26 . A method in accordance with  claim 25 , wherein LACI is administered at a dose between 1 μg/kg to 20 mg/kg.  
     
     
         27 . A method in accordance with  claim 25 , wherein LACI is administered at a dose between 20 μg/kg to 10 mg/kg.  
     
     
         28 . A method in accordance with  claim 25 , wherein LACI is administered at a dose between 1 to 7 mg/kg.  
     
     
         29 . A method in accordance with  claim 25  further comprising adding an additional agent to treat sepsis.  
     
     
         30 . A method in accordance with  claim 29 , wherein the additional agents are selected from the group consisting of antibiotics, monoclonal antibodies, and cytokine and complement inhibitors.  
     
     
         31 . A method in accordance with  claim 25 , wherein LACI is chemically conjugated to a polymer consisting essentially of PEG or POG.  
     
     
         32 . A method in accordance with  claim 25 , wherein LACI includes a fragment or a hybrid molecule thereof.  
     
     
         33 . A method in accordance with  claim 25 , wherein sepsis is treated by inducing native LACI.  
     
     
         34 . A method for treating a disease state in which TNF, IL-1 and other cytokines up-regulate tissue factor comprising administering LACI.  
     
     
         35 . A method in accordance with  claim 34 , wherein the disease state is chronic or acute inflammation.  
     
     
         36 . A method in accordance with  claim 34 , wherein the in vivo circulating concentration of IL-6 is reduced.  
     
     
         37 . A method for treating inflammation comprising administering to a patient a therapeutically effective amount of LACI or a fragment thereof.  
     
     
         38 . A method in accordance with  claim 37 , wherein LACI is administered at a dose between 1 μg/kg to 20 mg/kg.  
     
     
         39 . A method in accordance with  claim 37 , wherein LACI is administered at a dose between 20 μg/kg to 10 mg/kg.  
     
     
         40 . A method in accordance with  claim 37 , wherein LACI is administered at a dose between 1 to 7 mg/kg.