Methods 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. Preferred dosing is greater that 2250 mg per day, with more preferred doses exceeding 3500 mg per day.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority from U.S. provisional Ser. No. 62 / 936,270, filed 15 Nov. 2019, U.S. provisional Ser. No. 62 / 943,605, filed 4 Dec. 2019 and U.S. provisional Ser. No. 63 / 067,411, filed 19 Aug. 2020.BACKGROUND OF THE INVENTION[0002]Ascites is a pathologic accumulation of fluid within the peritoneal cavity. It is most commonly associated with cirrhosis of the liver (84% of cases), but is also seen with some forms of cancer (6% of cases, most frequently associated with breast, bronchus, ovary, stomach, pancreas and colon cancer), heart failure (3%), tuberculosis (1%), dialysis, pancreatic disease and other conditions (Runyon 1992).[0003]Refractory Ascites (RA) is a serious medical complication of liver cirrhosis that occurs when ascites can no longer be treated with diuretics and salt restriction, and requires additional and repeated clinical intervention, including large volume paracentesis. It is associated with a significan...

AI Technical Summary

Benefits of technology

The invention is about a method of treating patients with ascites, which involves administering a therapeutic amount of the drug docarpamine. The method can be used in patients who have been treated with diuretic agents for more than a week and who are not limited by diuretic-induced renal impairment. The method can also be used in patients with ascites caused by liver cirrhosis due to alcohol or non-alcoholic fatty liver disease, as well as patients who have not been diagnosed with a specific cause of ascites. The method can also be used in patients who have a high serum aldosterone level or a high serum renin concentration. The invention also includes a method of treating patients who require large volume paracentesis at least once every three days or who have experienced diuretic-induced complications. The method involves administering a daily dose of 4500 mg of docarpamine, preferably divided into two or three doses per day.

Problems solved by technology

It is associated with a significant shortening of life expectancy, increased use of medical resources, and ultimately is only curable by liver transplantation.

However, as cirrhosis progresses, the escape of fluids overcomes the lymphatic return, leading to progressive accumulation of fluid directly into the peritoneal cavity.

Thus, renal sodium retention mainly occurs proximally to the site of action of both anti-mineralocorticoid and loop diuretics (e.g. spironolactone and furosemide), and this can explain why diuretic treatment becomes unsuccessful in some patients.

At present, the only curative intervention for RA is liver transplantation, but this option is not available for many patients for a variety of reasons including general medical condition and absence of suitable donor organs.

Dopamine produces natriuretic and positive inotropic effects when administered intravenously, but it is not bioavailable when administered orally due to high rates of metabolism in the gut and the liver.

None of the vasoconstrictor drugs have been approved for the treatment of ascites or RA in the U.S. and many studies on the renal effects of dopamine and related drugs suggest it would not be effective in treating ascites or RA.

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