Method of Treating Ascites

Abstract

The invention relates to the treatment of ascites, and especially refractory ascites, with an orally bioavailable prodrug of dopamine. A preferred prodrug of dopamine is docarpamine. In one embodiment treated patients are, prior to treatment, on doses of furosemide >80 mg/day and/or spironolactone >100 mg/day or equivalent doses of an alternative loop-acting and/or distal-acting diuretic. The ascites treated by the invention are typically caused by liver cirrhosis due to alcohol or non-alcoholic fatty liver disease and generally not due to viral hepatitis or primary biliary cholangitis. Typical patients have an activated renin-angiotensin-aldosterone levels as may be indicated by elevated levels of renin and/or aldosterone. Refractory ascites treatable according to the invention are such that patients beginning treatment require large volume paracentesis at a minimum of: (a) 3 times in 60 days, (b) 4 times in 90 days or (c) at least once every 30 days over a 90-day period. The invention also contemplates treating diuretic intractable ascites. Target plasma dopamine levels are disclosed by with dosing with the contemplated dopamine prodrugs may be guided. Preferred dosing is greater that 2250 mg per day, with more preferred doses exceeding 3500 mg per day.

What is claimed is: 
     
         1 . A method of treating a patient with ascites, comprising administering to said patient a therapeutically effective amount of docarpamine. 
     
     
         2 . A method according to  claim 1 , wherein said therapeutically effective amount of docarpamine is greater than 2,250 per day. 
     
     
         3 . A method according to  claim 2 , wherein said therapeutically effective amount of docarpamine is greater than 3,500 mg/day 
     
     
         4 . A method according to  claim 1 , wherein, prior to said administering docarpamine, the patient is treated for more than 1 week with doses of furosemide >80 mg/day and/or spironolactone >100 mg/day or equivalent doses of an alternative loop-acting and/or distal-acting diuretic. 
     
     
         5 . A method according to  claim 1  wherein the dose of diuretic agents is not limited by diuretic-induced renal impairment. 
     
     
         6 . The method according to  claim 1 , further comprising at least one second administration of docarpamine during which said patient is also being treated with furosemide >80 mg/day and/or spironolactone >100 mg/day. 
     
     
         7 . The method according to  claim 1 , wherein said ascites is caused by liver cirrhosis due to alcohol or non-alcoholic fatty liver disease. 
     
     
         8 . The method according to  claim 1 , wherein said ascites is not caused by cirrhosis due to viral hepatitis or primary biliary cholangitis. 
     
     
         9 . The method according to  claim 1 , wherein said patient has a serum aldosterone level exceeding 21 ng/dL (582.5 pmol/L) and or a serum renin concentration exceeding 40 pg/mL (1.0 pmol/L). 
     
     
         10 . The method according to  claim 1 , wherein, prior to treatment, said patient required large volume paracentesis at a minimum of: (a) 3 times in 60 days, (b) 4 times in 90 days or (c) at least once every 30 days over a 90-day period. 
     
     
         11 . The method according to  claim 1 , wherein said patient is unresponsive to sodium-restricted diet and intensive diuretic therapy. 
     
     
         12 . The method according to  claim 1 , wherein prior to treatment said patient has a 24-hour urinary sodium excretion of less than 40 mEq during treatment with one or more diuretic agents. 
     
     
         13 . A method of treating a patient with diuretic intractable ascites, comprising administering to said patient a therapeutically effective amount of docarpamine, wherein said a patient experienced one or more diuretic-induced complications selected from the group consisting of: diuretic-induced hepatic encephalopathy; diuretic-induced renal impairment; diuretic-induced hyponatremia; and diuretic-induced hypokalemia. 
     
     
         14 . A method of treating a patient with ascites, comprising: administering to said patient a first amount of docarpamine; obtaining the concentration of dopamine in the blood, serum or plasma of said patient; and administering a second amount of docarpamine to said patient, wherein said second amount is selected based on the concentration of dopamine obtained.