Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-17
2003-07-22
Pryor, Alton N. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S725000, C424S702000
Reexamination Certificate
active
06596762
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides formulations and methods for preventing and treating liver injury that occurs in hepatic steatosis and steatohepatitis, as well as diseases associated with these conditions, including, but not limited to, nonalcoholic steatohepatitis. The method includes the administration of a composition that includes selected antioxidant compounds.
BACKGROUND OF THE INVENTION
Hepatic steatosis (fatty liver) and steatohepatitis (fatty liver with inflammation or scarring) are two forms of the fatty liver disease that develops in children and adults, frequently associated with being overweight or obese. This disease develops in at least 10-20% of adolescents and adults that are obese and in 5-10% of those that are overweight. This type of liver disease is often referred to as non-alcoholic steatohepatitis (NASH), because it occurs in the absence of a significant amount of alcohol intake. Currently, over 35% of the US population of adults and adolescents are overweight or obese, so this liver disease is probably the most common liver disease in the US and other developed countries. NASH has now been shown to lead to fibrosis (scarring) in at least 20-30% of patients who have undergone liver biopsies and is an increasing reason for patients to be evaluated for liver transplantation because of liver failure. Since obesity is now developing in childhood at an alarmingly increasing rate, NASH will probably be even more common in adults in the next decade, and will most likely become a more frequent cause of cirrhosis in adults and as an indication for liver transplantation.
The cause of NASH is not clearly understood, however, the combination of obesity, which causes the build-up of fat in the liver, and a second insult are proposed to lead to NASH from a benign form of fatty liver (
Gastroenterology
1998; 114:842-45). This secondary insult is now felt by many researchers in the field (see Detailed Description below) to be caused by an additional oxidant stress (free radical damage) to the liver caused by abnormal metabolism of the cell containing fat, small increases of iron deposited in the liver in certain individuals, blood-born chemicals (cytokines) released from other tissues that contain fat, or increased production of free radicals by mitochondria (the energy producing part of each cell) in liver cells that contain fat. Whatever the cause of the oxidant stress, it appears to accelerate damage to the liver cells and stimulate the production of scar tissue (fibrosis) by certain cells in the liver (hepatic stellate cells) that leads to the fibrosis and eventual cirrhosis of the liver.
Dr. Joel Lavine of San Diego has published a pilot trial using only vitamin E in children with NASH and showed that serum AST and ALT were reduced during therapy. There were no liver biopsies performed after treatment to determine if there was an effect on hepatic fibrosis or the extent of steatosis during or after therapy (Lavine, June 2000,
J. Pediatr.
136:711-713). This treatment used oral Vitamin E at a dose between 400 and 1200 IU per day. Lavine et al. did not use compounds other than Vitamin E.
U.S. Pat. No. 6,136,859, issued Oct. 24, 2000, to Henriksen describes the a pharmaceutical composition comprising organic or inorganic selenium, &bgr;-carotene or vitamin A, ascorbic acid, &agr;-tocopherol, methionine and coenzyme Q10 with a pharmaceutically acceptable carrier for treating liver diseases including steatohepatitis. The selenium is provided in a range of from 0.01-0.1% by weight of the composition or 0.05 mg-0.15 mg selenium per dose. The &bgr;-carotene is provided in a range of from 0.65-0.85% by weight of the composition or 3 mg-5 mg &bgr;-carotene per dose. The &agr;-tocopherol is provided in a range of from 8.55-9.55% by weight of the composition or 40 mg-87 mg &agr;-tocopherol per dose.
U.S. Pat. No. 6,180,139, issued Jan. 30, 2001 to Hsia et al. describes a method to treat NASH comprising administering compositions composed of lechithin, antioxidants (at least vitamin C or vitamin E, and may also include vitamin A and/or selenium) and vitamin B complex. In this composition, the antioxidants and vitamin B complex is provided at a total dosage of 675 to 4050 mg per daily dose. In the only example, vitamin E is provided at about 71.4 units (mg) per dose, &bgr;-carotene is provided at about 5 units (mg) per dose, and selenium is provided at about 15.6 units (mg) of selenium yeast at 1600 &mgr;g/g. The example composition also included vitamin C, vitamin B complex, and other components.
PCT Publication No. WO 00/62774, published Oct. 26, 2000 describes a method to treat various disorders, including hepatic steatosis, with compositions comprising isoflavonoids.
PCT Publication No. WO 98/41216, published Sep. 24, 1998 describes a method to treat hepatic steatosis using a bile acid sequestrant (e.g., cholestyramine), optionally in combination with omega-3 polyunsaturated fatty acids, short-chain fatty acids, glutamine, arginine, an antioxidant, ribonucleic acids or nucleotides. Antioxidants include vitamins A, C, E and &bgr;-carotene but dosage is not specified.
U.S. Pat. No. 6,218,437, issued Apr. 17, 2001 to Chojkier describes methods for treatment of viral hepatitis C by administering vitamin E and other compounds with antioxidant properties. The vitamin E is administered at a dose of from 800 units daily to 1600 units daily. This patent does not teach a method to treat hepatic steatosis.
U.S. Pat. No. 6,069,167, issued May 30, 2000 to Sokol describes the use of a combination of selected antioxidants to treat a different condition of the liver known as cholestasis. Cholestasis is characterized as a group of disorders in which bile flow in the liver is impaired or blocked. U.S. Pat. No. 6,069,167 describes the use of Vitamin E in an amount between 25 and 100 IU/kg/day, &bgr;-carotene in an amount between 0.5 and 5 mg/kg/day, and selenium in an amount between 1 and 5 &mgr;g/kg/day to treat cholestasis. Cholestasis is a completely different liver condition than hepatic steatosis which affects a completely different patient population than hepatic steatosis. Therefore, there is no expected correlation between a composition useful for the treatment of cholestasis and a composition useful for treatment of hepatic steatosis. U.S. Pat. No. 6,069,167 does not teach or suggest any composition useful for the treatment of hepatic steatosis.
U.S. Pat. No. 5,763,435, issued Jun. 9, 1998 to Setchell describes the use of ursodeoxycholic acid to treat a disorder, including cancers and liver disorders.
U.S. Pat. No. 6,075,132, issued Jun. 13, 2000 to Mandai et al. describes ursodeoxycholic acid derivatives, which is described as being useful for the preparation of medicines.
U.S. Pat. No. 5,955,456, issued Sep. 21, 1999 to Prato et al. describes injectable compositions comprising urosdeoxycholic acid or tauroursodeoxycholic acid, which is described as being useful for the treatment of various pathological conditions of the liver.
There are currently no effective treatments for NASH, except for the recommendation that patients lose weight. With weight loss, abnormal elevations of liver enzymes released into the blood by the liver in NASH are reduced, however, the effect of weight loss on scarring and the amount of fat in the liver have not been well studied. Unfortunately, it is a fact that it is very difficult for obese and overweight people to lose and keep off this extra weight. Therefore, new, effective, non-toxic therapies that are designed to reduce liver injury and prevent or reduce scarring in the liver in patients with NASH are certainly needed.
SUMMARY OF THE INVENTION
One embodiment of the present invention relates to a pharmaceutical composition for treatment of a patient that has or is at risk of developing hepatic steatosis or steatohepatitis, the composition consisting essentially of: (a) soluble vitamin E in an amount of between about 10 international units per kilogram body weight of the patient per day (IU/kg/day) and about 100 IU/kg/day; (b) m
Pryor Alton N.
The Regents of The University of Colorado
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