Treatment of sepsis by low dose administration of tissue factor pathway inhibitor (TFPI)

Abstract

Methods for prophylactically or therapeutically treating sepsis or septic shock involve administration of tissue factor pathway inhibitor (TFPI) or a TFPI analog to patients suffering from sepsis or other inflammatory conditions. The methods involve the use of continuous intravenous infusion of TFPI or a TFPI analog at low doses to avoid adverse side effects.

What is claimed is:  
     
         1 . A method of treating sepsis comprising: 
 administering TFPI or a TFPI analog to a patient who has sepsis or who is at risk of becoming septic by continuous intravenous infusion at a dose rate equivalent to administration of reference ala-TFPI at a dose rate from about 0.00025 to about 0.050 mg/kg/hr for an administration period at least about 72 hours.    
     
     
         2 . The method of  claim 1  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         3 . The method of  claim 1  wherein said TFPI analog comprises a first Kunitz domain consisting of amino acids 19-89 of SEQ ID NO:1.  
     
     
         4 . The method of  claim 3  wherein said TFPI analog further comprises a second Kunitz domain consisting of amino acids 90-160 of SEQ ID NO:1.  
     
     
         5 . The method of clam 1 wherein said TFPI analog comprises amino acids 1-160 of SEQ ID NO:1.  
     
     
         6 . The method of  claim 1  wherein said TFPI analog comprises a second Kunitz domain consisting of amino acids 90-160 of SEQ ID NO:1.  
     
     
         7 . The method of  claim 1  wherein said dose rate is equivalent to administration of reference ala-TFPI at a dose rate from about 0.010 to about 0.045 mg/kg/hr.  
     
     
         8 . The method of  claim 7  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         9 . The method of  claim 7  wherein said dose rate is equivalent to administration of reference ala-TFPI at a dose rate of about 0.025 mg/kg/hr.  
     
     
         10 . The method of  claim 9  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         11 . The method of  claim 1  wherein said administration period at least about 96 hours.  
     
     
         12 . The method of  claim 11  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         13 . The method of  claim 11  wherein said dose rate is administered to provide a total dose equivalent to administration of reference ala-TFPI at a total dose from about 0.024 to about 4.8 mg/kg.  
     
     
         14 . The method of  claim 13  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         15 . The method of  claim 11  wherein said TFPI or TFPI analog is administered at a dose rate equivalent to administration of reference ala-TFPI at a dose rate of about 0.025 mg/kg/hr.  
     
     
         16 . The method of  claim 15  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         17 . The method of  claim 1  wherein said dose rate is administered to provide a daily dose equivalent to administration of reference ala-TFPI at a daily dose from about 0.006 mg/kg to about 1.2 mg/kg.  
     
     
         18 . The method of  claim 17  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         19 . The method of  claim 1  wherein said TFPI or said TFPI analog is administered to a patient having a baseline International Normalized Ratio (INR) of at least about 1.2.  
     
     
         20 . The method of  claim 19  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         21 . The method of  claim 1  further comprising terminating administering said TFPI or TFPI analog when said patient has an INR either exceeding a baseline INR by at least 20% or having a value of at least about 2.5.  
     
     
         22 . The method of  claim 21  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         23 . The method of  claim 1  wherein said patient has an APACHE II score of at least 20.  
     
     
         24 . The method of  claim 23  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         25 . The method of  claim 1  wherein said patient has a baseline plasma IL-6 concentration of at least about 1000 pg/ml.  
     
     
         26 . The method of  claim 25  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         27 . The method of  claim 1  wherein said patient is suffering from shock.  
     
     
         28 . The method of  claim 27  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         29 . The method of  claim 1  wherein said patient is suffering from ARDS.  
     
     
         30 . The method of  claim 29  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         31 . The method of  claim 1  wherein said patient has a pulmonary score, an ICU score, or a multiple organ dysfunction score that increases during said administration period.  
     
     
         32 . The method of  claim 31  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         33 . The method of  claim 1  wherein said TFPI or TFPI analog is prepared from a lyophilized composition comprising TFPI or a TFPI analog.  
     
     
         34 . The method of  claim 33  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         35 . The method of  claim 1  wherein said TFPI or TFPI analog is administered as a formulation comprising arginine.  
     
     
         36 . The method of  claim 35  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         37 . The method of  claim 1  wherein said TFPI or TFPI analog is administered as a formulation comprising citrate.  
     
     
         38 . The method of  claim 37  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         39 . The method of  claim 1  wherein said TFPI or TFPI analog has a concentration of about 0.15 mg/ml in a formulation comprising about 300 mM arginine hydrochloride and about 20 mM sodium citrate and having a pH of about 5.5.  
     
     
         40 . The method of  claim 39  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         41 . The method of  claim 1  further comprising administering, during or within 24 hours of said administration period, an additional agent selected from the group consisting of an antibiotic, an antibody, an endotoxin antagonist, a tissue factor analog having anticoagulant activity, an immunostimulant, a cell adhesion blocker, heparin, BPI protein, an IL-1 antagonist, pafase (PAF enzyme inhibitor), a TNF inhibitor, an IL-6 inhibitor, and an inhibitor of complement.  
     
     
         42 . The method of  claim 41  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         43 . The method of  claim 41  wherein said additional agent is an antibody, wherein said antibody binds specifically to an antigen selected from the group consisting of TNF, IL-6, and M-CSF.  
     
     
         44 . The method of  claim 43  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         45 . A prophylactic method for decreasing the risk and severity of sepsis, said method comprising administering TFPI or a TFPI analog to a patient susceptible to sepsis or suspected of being septic by continuous intravenous infusion at a dose rate equivalent to administration of reference ala-TFPI at a dose rate from about 0.00025 to about 0.050 mg/kg/hr for an administration period of at least about 72 hours.  
     
     
         46 . The method of  claim 45  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         47 . The method of  claim 45  wherein said TFPI analog comprises a first Kunitz domain consisting of amino acids 19-89 of SEQ ID NO:1.  
     
     
         48 . The method of  claim 47  wherein said TFPI analog further comprises a second Kunitz domain consisting of amino acids 90-160 of SEQ ID NO:1.  
     
     
         49 . The method of  claim 45  wherein said TFPI analog comprises amino acids 1-160 of SEQ ID NO:1.  
     
     
         49 . The method of  claim 45  wherein said TFPI analog comprises a second Kunitz domain consisting of amino acids 90-160 of SEQ ID NO:1.  
     
     
         50 . The method of  claim 45  wherein said dose rate is equivalent to administration of reference ala-TFPI at a dose rate from about 0.010 to about 0.045 mg/kg/hr.  
     
     
         51 . The method of  claim 50  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         52 . The method of  claim 50  wherein said dose rate is equivalent to administration of reference ala-TFPI at a dose rate of about 0.025 mg/kg/hr.  
     
     
         53 . The method of  claim 52  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         54 . The method of  claim 45  wherein said administration period is at least about 96 hours.  
     
     
         55 . The method of  claim 54  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         56 . The method of  claim 54  wherein said dose rate equivalent to administration of reference ala-TFPI at a dose rate of about 0.025 mg/kg/hr.  
     
     
         57 . The method of  claim 56  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         58 . A method for prophylactically and therapeutically treating acute inflammation, including sepsis and septic shock, said method comprising administering to a patient (i) a continuous intravenous infusion of TFPI or a TFPI analog at a dose rate equivalent to administration of reference ala-TFPI at a dose rate from about 0.00025 to about 0.050 mg/kg/hr and (ii) an additional agent selected from the group consisting of an antibiotic, a monoclonal antibody, a cytokine inhibitor, and a complement inhibitor.  
     
     
         59 . The method of  claim 58  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         60 . A method for treating a disease state not associated with DIC and in which TNF, IL-1, or another cytokine up-regulates tissue factor, said method comprising administering to a patient a continuous intravenous infusion of an agent selected from the group consisting of TFPI or a TFPI analog at a dose rate equivalent to administration of reference ala-TFPI at a dose rate from about 0.00025 to about 0.050 mg/kg/hr for an administration period of at least about 72 hours.  
     
     
         61 . The method of  claim 60  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         62 . The method of  claim 60  wherein said disease state is chronic or acute inflammation.  
     
     
         63 . The method of  claim 62  wherein said TFPI analog is non-glycosylated ala-TFPI.  
     
     
         64 . The method of  claim 60  wherein said patient has a plasma concentration of IL-6 that is reduced during said administration period.  
     
     
         65 . The method of  claim 64  wherein said TFPI analog is non-glycosylated ala-TFPI.