Non-pancreatic proteases for controlling plasma cholecystokinin (cck) concentration and for treating pain

Abstract

This invention relates to methods for maintaining the basal level or reducing the level of cholecystokinin (CCK) in blood plasma of a mammal. Additionally, the invention provides methods for treating pain in a mammal and more particularly, methods for treating abdominal pain in a mammal. The methods include administering to the mammal a non-pancreatic protease or a composition comprising a non-pancreatic protease. The methods of this invention are particularly useful for treating abdominal pain in a mammal suffering from acute or chronic pancreatitis and related conditions.

1 . A method for treating abdominal pain in a mammal comprising administering to said mammal a therapeutically effective amount of a non-pancreatic protease or a composition comprising a therapeutically effective amount of non-pancreatic protease. 
   
   
       2 . A method for reduction of maximum plasma concentration (C max ) of cholecystokinin (CCK) after administration of food in a mammal comprising the step of administering to said mammal with food a therapeutically effective amount of a non-pancreatic protease or a composition comprising a therapeutically effective amount of non-pancreatic protease, wherein said reduction is measured by comparing (a) said C max  in the absence of said protease after food administration to (b) said C max  in the presence of said protease after food administration, and wherein said reduction is selected from the group consisting of:
 (i) at least about 10% to about 25% reduction;   (ii) at least about 25% to about 50% reduction;   (iii) at least about 50% to about 75% reduction; and   (iv) at least about 75% to about 100% reduction.   
   
   
       3 . A method for treating a CCK-related disease in a mammal comprising the step of administering to said mammal a therapeutically effective amount of a non-pancreatic protease or a composition comprising a therapeutically effective amount of a non-pancreatic protease, wherein the plasma cholecystokinin (CCK) level in said mammal after administering said protease is less than or at the same level as the plasma cholecystokinin (CCK) level in said mammal before administering said protease and remains less than or at the same level for a period of time selected from the group consisting of:
 (a) between zero and about 4 hours after administering said protease;   (b) between zero and about 8 hours after administering said protease; and   (c) between zero and about 12 hours after administering said protease.   
   
   
       4 . The method of  claim 1 , wherein the plasma cholecystokinin (CCK) level in said mammal after administering said protease is less than or at the same level as a plasma cholecystokinin (CCK) level in said mammal before administering said protease and remains less than or at the same level for a period of time selected from the group consisting of:
 (a) between zero and about 4 hours after administering said protease;   (b) between zero and about 8 hours after administering said protease; and   (c) between zero and about 12 hours after administering said protease.   
   
   
       5 . The method of  claim 1 , wherein said protease causes a reduction in maximum plasma concentration (C max ) of cholecystokinin (CCK) in said mammal, wherein said reduction is measured by comparing (a) said C max  in the absence of said protease after food administration to (b) said C max  in the presence of said protease after food administration, and wherein said reduction is selected from the group consisting of:
 (i) at least about 10% to about 25% reduction;   (ii) at least about 25% to about 50% reduction;   (iii) at least about 50% to about 75% reduction; and   (iv) at least about 75% to about 100% reduction.   
   
   
       6 - 9 . (canceled) 
   
   
       10 . The method according to any one of  claims 1 - 3 , wherein said non-pancreatic protease is seaprose, serrapeptase, pronase, a pronase component or a mixture thereof. 
   
   
       11 - 13 . (canceled) 
   
   
       14 . The method according to any one of  claims 1 - 3 , wherein said composition further comprises one or more enzymes selected from the group consisting of: lipase and amylase. 
   
   
       15 . (canceled) 
   
   
       16 . The method according to any one of  claims 1 - 3 , wherein said therapeutically effective amount of said non-pancreatic protease is from about 5,000 to about 1,000,000 USP units per dose. 
   
   
       17 - 18 . (canceled) 
   
   
       19 . The method according to  claim 16 , wherein said therapeutically effective amount of said non-pancreatic protease is from about 5,000 to about 250,000 USP units per dose. 
   
   
       20 . The method according to any one of  claims 1 - 3 , wherein said non-pancreatic protease is crosslinked with a crosslinker selected from the group consisting of: multifunctional crosslinkers, homobifunctional crosslinkers, heterobifunctional crosslinkers, zero-order crosslinkers, dialdehyde crosslinkers, halo-triazine crosslinkers, halopyrimidine crosslinkers, anhydride crosslinkers, halide crosslinkers, N-methylol compounds, diisocyanate crosslinkers, diisothiocyanate crosslinkers and aziridine crosslinkers. 
   
   
       21 - 24 . (canceled) 
   
   
       25 . The method according to any one of  claims 1 - 3 , wherein said non-pancreatic protease is administered to said mammal as a non-enterically coated tablet. 
   
   
       26 . The method according to  claim 25 , wherein said non-pancreatic protease is administered to a mammal at a dose of between one and six tablets per meal, wherein said tablet comprises an active protease level selected from the group consisting of: (a) between about 20 mg to about 500 mg; (b) between about 50 mg to about 500 mg; and (c) between about 50 mg to about 250 mg. 
   
   
       27 . The method according to  claim 25 , wherein said non-pancreatic active protease is administered to a mammal as one or more tablets providing an active protease dose per meal selected from the group consisting of: (a) between about 1 mg per kg mammal and 10 mg per kg mammal; (b) between about 1 mg per kg mammal and 3 mg per kg mammal; and (c) between about 1 mg per kg mammal and 2 mg per kg mammal. 
   
   
       28 . The method according to any one of  claims 1 - 3 , wherein said non-pancreatic protease is in the form of crystals. 
   
   
       29 . (canceled) 
   
   
       30 . The method according to  claim 1 , wherein said abdominal pain is associated with pancreatic insufficiency, acute pancreatitis, chronic pancreatitis, cystic fibrosis or post-operative gastrointestinal surgery.