Administration of serine protease inhibitors to the stomach

Abstract

The inventors have unexpectedly discovered that shock and/or potential multi-organ failure due to shock can be effectively treated by administration of liquid high-dose protease inhibitor formulations to a location upstream of where pancreatic proteases are introduced into the gastrointestinal tract. Most preferably, administration is directly to the stomach, for example, via nasogastric tube under a protocol effective to treat shock by such administration without the need of providing significant quantities of the protease inhibitor to the jejunum and/or ileum.

What is claimed is: 
     
         1 . A method of treating at least one of shock and potential multi-organ failure due to shock in a mammal, comprising:
 diagnosing the mammal with a shock condition;   administering a therapeutically effective amount of a protease inhibitor in a liquid formulation at a dosage of at least 20 mg/kg;   wherein the liquid formulation is administered to a location in a gastrointestinal tract, wherein the location is upstream of another location at which pancreatic proteases are released into the gastrointestinal tract; and   wherein the liquid formulation is administered under a protocol effective to treat the shock and potential multi-organ failure from the location.   
     
     
         2 . The method of  claim 1  wherein the location is the stomach and wherein the step of administering is performed via administration via a nasogastric tube or a catheter. 
     
     
         3 . The method of  claim 1  wherein the location is the stomach and wherein the step of administering is performed via administration via an oral solution or direct injection. 
     
     
         4 . The method of  claim 1  wherein the step of administering is performed by administration of a single undivided dose per day. 
     
     
         5 . The method of  claim 1  wherein the step of administering is performed, optionally using divided daily doses, over at least two days. 
     
     
         6 . The method of  claim 1  wherein the dosage is at least 50 mg/kg. 
     
     
         7 . The method of  claim 1  wherein the dosage is at least 100 mg/kg. 
     
     
         8 . The method of  claim 1  wherein the liquid formulation comprises the protease inhibitor at a concentration of between 0.5 mM and 50 mM. 
     
     
         9 . The method of claim I wherein administration is performed at a daily dosage of between 2 g to 20 g. 
     
     
         10 . The method of  claim 1  wherein the protease inhibitor in the liquid formulation is a serine protease inhibitor. 
     
     
         11 . The method of  claim 1  wherein the protease inhibitor in the liquid formulation is selected from the group consisting of tranexamic acid, FOY, ANGD, camostate, an alpha-1 anti-trypsin, a serpine, and an MMP protease inhibitor. 
     
     
         12 . The method of  claim 1  further comprising administering a second protease inhibitor formulation to the mammal. 
     
     
         13 . The method of  claim 1  wherein the second protease, inhibitor formulation comprises a protease inhibitor that is the same as the protease inhibitor in the liquid formulation. 
     
     
         14 . The method of  claim 1  further comprising administering an oxygen carrier to the mammal in an amount effective to reduce organ damage due to shock. 
     
     
         15 . The method of  claim 1  wherein the shock condition is a traumatic shock, a septic shock, a cardiogenic shock, a hypovolemic shock, a shock from surgical intervention, or a shock from exposure to radiation. 
     
     
         16 . The method of  claim 1  wherein the step of diagnosing the shock condition comprises measurement of a blood amylase or a blood protease activity, 
     
     
         17 . The method of  claim 1  wherein the mammal is a human. 
     
     
         18 . The method of  claim 17  wherein the dosage is at least 25 mg kg, and wherein the protease inhibitor in the liquid formulation is FOY. 
     
     
         19 . The method of  claim 18  wherein the administration comprises daily administration of the liquid formulation for at least seven days. 
     
     
         20 . The method of  claim 19  wherein the administration comprises administration of the liquid formulation via nasogastric