U.S. patent application number 09/726688 was filed with the patent office on 2001-03-15 for composition and method for treating nonalcoholic steatohepatitis.
Invention is credited to Fan, David, Hsia, Houn Simon.
Application Number | 20010000028 09/726688 |
Document ID | / |
Family ID | 22760725 |
Filed Date | 2001-03-15 |
United States Patent
Application |
20010000028 |
Kind Code |
A1 |
Hsia, Houn Simon ; et
al. |
March 15, 2001 |
Composition and method for treating nonalcoholic
steatohepatitis
Abstract
Nonalcoholic steatohepatitis (NASH) is a disease of the liver
characterized by inflammation and damage to the liver cells.
Typically, steatohepatitis involves inflammation of the liver
related to fat accumulation, and mimics alcoholic hepatitis but is
observed in patients who seldom or never consume alcohol.
Nonalcoholic steatohepatitis can lead to serious liver damage, and
ultimately cirrhosis. The present invention provides methods and
compositions useful for the treatment or alleviation of
nonalcoholic steatohepatitis and the pharmaceutical formulations
for their administration to a human. Specifically, compositions
comprised of lecithin, antioxidants and vitamin B complex are
administered parenterally, most preferably by oral administration.
Specific therapeutic formulations include admixtures of these
compounds and specific dosage formulations include daily oral
administrations of these compounds in tablet or powder forms.
Inventors: |
Hsia, Houn Simon; (Irvine,
CA) ; Fan, David; (Newport Beach, CA) |
Correspondence
Address: |
LYON & LYON LLP
SUITE 4700
633 WEST FIFTH STREET
LOS ANGELES
CA
90071-2066
US
|
Family ID: |
22760725 |
Appl. No.: |
09/726688 |
Filed: |
November 29, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09726688 |
Nov 29, 2000 |
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09205082 |
Dec 4, 1998 |
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6180139 |
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Current U.S.
Class: |
424/439 ;
424/464; 426/662; 426/72; 426/73; 544/251; 544/327; 546/301;
549/315; 549/408; 554/80; 568/824 |
Current CPC
Class: |
A61K 31/355 20130101;
A61K 31/685 20130101; A61K 31/685 20130101; A61K 2300/00 20130101;
A61K 31/355 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/439 ; 426/72;
424/464; 426/73; 426/662; 554/80; 544/327; 568/824; 544/251;
546/301; 549/315; 549/408 |
International
Class: |
A23L 001/30 |
Claims
What is claimed is:
1. A composition for the treatment of nonalcoholic steatohepatitis
comprising lecithin, a vitamin B complex, and antioxidants.
2. The composition of claim 1 wherein the lecithin is a dietary
supplement.
3. The composition of claim 2 wherein the antioxidants are
comprised of vitamin C.
4. The composition of claim 2 wherein the antioxidants are
comprised of vitamin E.
5. The composition of claim 2 wherein the antioxidants are
comprised of vitamin C or E and selenium.
6. The composition of claim 5 further comprising vitamin A.
7. The composition of claim 1 wherein the dosage of dietary
lecithin is between approximately 15 to 50 grams.
8. The composition of claim 1 wherein the dosage of antioxidants
and B vitamin complex is between approximately 675 to 4050
milligrams.
9. The composition of claim 1 prepared as a daily dosage of
approximately 20 grams of lecithin and 1350 milligrams of
antioxidants and B vitamin complex.
10. The composition of claim 2 wherein the lecithin dietary
supplement is enriched with phosphatidylcholine.
Description
CROSS REFERENCE TO RELATED APPLICATION
1. This is a divisional of co-pending application Ser. No.
09/205,082, filed on Dec. 4, 1998. The priority of the prior
application is expressly claimed, and the disclosure of each of
this prior application is hereby incorporated by reference in its
entirety.
FIELD OF THE INVENTION
2. The present invention generally relates to dietary supplements
containing lecithin, antioxidants and/or a vitamin B complex to
treat liver disease. A preferred embodiment is a composition and
the use thereof of a dietary supplement comprising lecithin, at
least one antioxidant, and a vitamin B complex administered orally
to treat or alleviate nonalcoholic steatohepatitis.
BACKGROUND OF THE INVENTION
3. The liver is the largest organ in the human body, located in the
superior portion of the right upper abdomen. This organ is highly
complex and specialized and performs many crucial biochemical
functions. The liver is critically involved in the removal of
toxins from the body and in the manufacture of proteins including
energy storage and blood clotting factors. The liver is also
involved in storing minerals, vitamins and glucose in the form of
glycogen, which is metabolized in large quantities to provide
energy. The liver also plays a role in red blood cell metabolism
and the break-down of certain metabolic byproducts in the blood
stream.
4. Nonalcoholic steatohepatitis (NASH) is a liver disease that is
frequently reported in both men and women, although it most often
appears in women and is especially prevalent in the obese. Although
the disease has been observed to be accompanied by several other
pathological conditions, including diabetes mellitus,
hyperlipidemia and hyperglycemia, the cause and progression of the
disease, as well as the causal or temporal relation to these
conditions, is not well understood. However, in patients suffering
from NASH, certain characteristics of liver tissue and
abnormalities of function are typical. Specifically, fatty
deposits, tissue degeneration, inflammation, cell degeneration,
cirrhosis, elevation of free fatty acids and other such
abnormalities have come to be associated with nonalcoholic
steatohepatitis and are frequently seen in patients suffering from
NASH.
5. Steatohepatitis, excess fat in the liver, is a condition often
observed in cases of starvation, overloading of carbohydrates,
absence of energy in the form of proteins, obesity, and cortico
steroid therapy. It has been hypothesized that the accumulation of
fat in the liver may be the result of increased accumulation of
free-fatty acids, increased manufacture of fatty acids in the
liver, decreased oxidation of free fatty acids, or the synthesis or
secretion of LDL cholesterol. The increased level of free fatty
acids in some cases of steatohepatitis may implicate the reactivity
of free fatty acids with biological membranes. NASH patients
exhibit increased asparate aminotransferase and/or alanine
aminotransferase activity, characteristically at least 150% of
normal. To confirm the clinical diagnosis of NASH, evidence of zero
to low alcohol consumption is required and confirmation of the
absence of a previous infection with hepatitis B virus or hepatitis
C. The specific diagnosis of nonalcoholic steatohepatitis may also
depend on detailed analysis of liver biopsy specimens. The
histological features identified may include macrovesicular fat,
cirrhosis, inflammation of the parenchyma and the presence of
Mallory hyaline bodies.
6. Approximately 8% of patients who undergo liver biopsies will
show histological evidence of NASH. The physiological condition
that most commonly accompanies NASH is obesity, with approximately
70% and above of NASH sufferers also displaying clinically
diagnosed obesity. NASH is particularly prevalent in obese patients
who have undergone jejunal bypass to treat the obesity. In NASH
patients, the extent of obesity tends to be generally correlated
with the amount of steatosis and to be unrelated to
non-insulin-dependent diabetes mellitis. However,
non-insulin-dependent diabetes mellitis increases the prevalence of
steatohepatitis especially in patients requiring insulin. Weight
loss in patients before death does not appear to alleviate the
steatosis and, somewhat paradoxically, obese patients who lost
weight before death may actually have a higher incidence of
steatohepatitis. The disease rarely occurs in any patient under the
age of 30, but is particularly prevalent in patients in their 50s
and 60s.
7. Even in NASH patients who do not consume any alcohol at all,
liver biopsy specimens tend to mimic those seen in patients
suffering from alcoholic hepatitis. However, a comparison of the
two conditions reveals a higher incidence of vacuolation
(indicative of diabetes) and steatosis in NASH as compared to
alcoholic hepatitis. Patients suffering from alcoholic hepatitis
also have a higher incidence of periportal and pericellular
fibrosis and proliferation of the bioduct. Overall, the symptoms
and histological damage observed in alcoholic hepatitis patients
are more severe than in NASH.
8. Many experimental studies have been conducted to better
understand NASH. For example, Susumu Itoh et al. studied 16
nonalcoholic steatohepatitis patients and 22 alcoholic hepatitis
patients and discovered various differences between these two
similar liver diseases. Susumu Itoh et al., Comparison between
Nonalcoholic Steatohepatitis and Alcoholic Hepatitis, 82 The
American Journal of Gastroenterology 650 (July 1987). Other
examples include Ian R. Wanless & John S. Lentz, Fatty Liver
Hepatitis (Steatohepatitis) and Obesity: An Autopsy Study with
Analysis of Risk Factors, 12 Hepatology 5:1106 (1990)(concluding
that fatty acids have a role in the hepatocellular necrosis found
in some obese individuals) and Bruce R. Bacon et al., Nonalcoholic
Steatohepatitis: An Expanded Clinical Entity, 107 Gastroenterology
1103 (1994)(concluding that NASH should not only be considered as a
disease predominantly seen in obese women with diabetes).
9. Choline deficiency has been known to cause fatty infiltration of
the liver in animals such as rats, hamsters, pigs and dogs. Thus, a
deficiency in choline may result in the inability of the liver to
transport fatty acids such as triglycerides. Indeed, one recent
study has shown that hepatic steatosis in many long-term total
parenteral nutrition patients may be caused by a deficiency in
plasma-free choline, and that such deficiency may be reversed with
lecithin (phosphatidylcholine) supplementation. Alan Buchman et
al., Lecithin Increases Plasma Free Choline and Decreases Hepatic
Steatosis in Long-Term Total Parenteral Nutrition Patients, 102
Gastroenterology 1363 (1992).
10. Although nonalcoholic steatohepatitis is generally viewed as a
progressive liver disease, the condition tends to be stable over at
least a few years in patients exhibiting the most common clinical
manifestations of the disease. A majority of patients who have
undergone repeated biopsies over a multi-year period have, for the
most part, revealed no significant morphological changes over this
period. To date, scientists have not discovered any biochemical,
clinical or histological measurements that can distinguish between
patients that will suffer comparatively stable NASH with those for
whom NASH is a precursor to a more serious liver ailment, and even
death.
11. Currently, an established therapy for patients suffering from
NASH does not exist. Weight loss is a common prescription, simply
because obesity is frequently found in patients suffering from
NASH. The effect of a reduction in weight loss on NASH cannot be
determined with certainty, however, because obese patients seldom
maintain significant weight reduction.
SUMMARY OF THE INVENTION
12. The present invention is comprised of methods and compositions
for the treatment or alleviation of nonalcoholic steatohepatitis,
specifically, pharmaceutical formulations and methods for their
administration to a human suffering from NASH as part of a
treatment regimen to alleviate, or at least manage, the disease.
Preferably, the composition is comprised of a dietary lecithin,
antioxidant compounds, and/or B vitamin complexes. The
pharmaceutical compositions are preferably formulated for oral
administration in a dosage range that results in a decrease in
hepatic steatosis indicated by increased liver density. In a
preferred clinical application of the invention, a well-tolerated
oral dosage is taken regularly by NASH patients whose liver
function and histology is monitored for response to the
formulation.
DETAILED DESCRIPTION OF THE INVENTION
13. The present invention is a pharmaceutically acceptable
composition, usually administered as a dietary supplement, to treat
or alleviate nonalcoholic steatohepatitis, with a principal aim to
reduce hepatic steatosis. In a preferred embodiment, the
composition comprises of a dietary lecithin supplement and a
dietary supplement containing antioxidants and a vitamin B complex.
The dietary lecithin supplement is preferably prepared in powder
form. The antioxidant compounds and vitamin B complex may be
combined into a single dosage and are preferably prepared together
in tablet form. Preferably, a dosage in the range of 15 to 50 grams
of the dietary lecithin supplement and 675 to 4050 milligrams (1 to
6 tablets) of the antioxidant/vitamin B complex supplement should
be administered daily. Most preferably, however, 20 grams of the
dietary lecithin supplement and 1350 milligrams (2 tablets) of the
antioxidant/vitamin B complex supplement should be taken twice
daily.
14. As used herein, the term "lecithin" includes choline and
choline phospholipids such as phosphatidylcholine, and naturally
occurring choline containing compounds in general, including
derivatives of lecithin such as phosphatidylserine. "Lecithin" is
primarily comprised of choline and inositol, two compounds that are
used by the body in the break-down of cholesterol and dietary fats.
Once lecithin is reduced to these two components, choline is
converted into acetyl choline, a compound used in neurological
activity including brain and muscle function. Lecithin may also
function to help the body absorb Vitamin A, Vitamin D, and Thiamin
in the digestive tract. Typically, dietary lecithin supplements
contain lecithin/phosphatidylcholine/choline in a ratio of
1.1:10:50 and are sometimes ingested to reduce triglycerides and
serum cholesterol. Additionally, lecithin has been investigated as
an agent for the treatment of a wide variety of liver ailments,
ranging from alcoholism to radiation exposure to exposure to toxic
chemicals.
15. Phosphatidylserine is a phosphylipid that is implicated in the
structural integrity and chemical function of cell membranes.
Phosphatidylserine may also be taken as a supplement and is
indicated in patients suffering from a deficiency of methyl donors,
i.e., folic acid, Vitamin B12, and essential fatty acids that
reduce the capacity of the brain to synthesize this compound.
16. Although, as noted above, dietary lecithin has been
investigated as a remedy for certain liver ailments, sources of
lecithin in the diet tend to be found in high-fat, high-cholesterol
foods such as meat, liver and eggs which should be avoided by the
typical NASH patient who tends to be obese. Therefore, pursuant to
the present invention, dietary lecithin is preferably ingested
orally as a supplement. The dietary lecithin supplement is
available from commercial sources or may be manufactured by
techniques known in the art. In the preferred embodiment, a
granulated phospholipid fraction from soya lecithin enriched with
phosphatidylcholine is used. This supplement comprises of
phosphatidylcholine (minimum 50%), phosphatidylethanolamine
(maximum 30%), lyso-phosphatidylcholine (maximum 5%), and other
phospholipids (maximum 9%).
17. The "vitamin B complex" of the invention is a combination of
two or more of the compounds that form the group of water soluble
vitamins generally recognized as B vitamins, including vitamin B-1,
B-2, B-3, B-5, B-6, B-7, B-12, and folic acid. As will be readily
appreciated by those in the art, the invention also includes
analogues, precursors, pro-drugs and functional metabolic
by-products of these compounds. In addition, these vitamins
contained in natural extracts, yeast compounds, and concentrations
of natural products may be administered pursuant to the
invention.
18. Like all vitamins, B vitamins are essential to metabolism and
other necessary biological functioning in higher organisms. As
noted, B vitamins are water soluble and typically function as
co-enzymes that interact with metabolic enzymes to complete
certain, specific biochemical functions. Vitamin B-1, thiamine,
functions to release energy from carbohydrates, alcohol, and fat. A
biochemically active form of B-1, thiamine pyrophosphate, is a
co-enzyme in certain metabolic processes including the citric acid
cycle and the conversion of alanine to acetyl co-enzyme. Thiamine
forms a co-enzyme following phosphorolation by ATP-dependent
pyrophosphorylase. Thiamine pyrophosphate contains a substituted
pyrimidine nitrogen heterocyclic ring and a thiazole
nitrogen-sulfur heterocycle. The thiazole moitey provides the
activity in the metabolism of pyruvate to provide a non-oxidative
decarboxylation.
19. Vitamin B-2, riboflavin, is metabolized to form the flavin
adenine dinucleotide (FAD) and flavin mononucleotide (FMN)
co-enzymes. Both co-enzymes have an isoalooxazine ring that accepts
two electrons in enzymatic reactions. Biochemically, vitamin B-2
releases energy from protein, fats, and carbohydrates. Vitamin B-3,
niacin or nicotinamide, is involved in the synthesis of pyridine
nucleotides. Niacin reacts with adenosine to form nicotinamide
adenine dinucleotide (NAD), which performs a critical function as
an electron carrier in certain biochemical processes. Niacin is
also reported to play an important role in digestive functions and
in maintaining serum cholesterol levels. Biochemically, vitamin B-3
is involved in the oxidative metabolism of ingested food and
appears to play a role in maintaining the circulatory system.
Vitamin B-6, pyridoxine, is structurally similar to pyridine but
features a hydroxymethyl group in the para position. Biochemically,
the para-hydroxymethyl group is oxidized to form an aldehyde and
the hydroxymethyl group in the meta position undergoes
phosphorylation to yield a pyridoxal phosphate. Vitamin B-6 is
metabolically involved in transaminations, decarboxylations, and
chemical modifications to amino acids. Vitamin B-6 also appears to
promote blood cell and hemoglobin formation and assists in
carbohydrate protein and fat metabolism.
20. Vitamin B-12, cyanocobalamin, contains a monovilent cobalt
metal centrally located in a porphyrin-like structure of
tetrapyrrole rings. Biochemically, vitamin B-12 contributes a
methyl group to the synthesis of certain compounds in numerous
biochemical reactions, including specifically, a synthesis of
choline and methionine. Vitamin B-9, folic acid, functions as a
methyl donor following enzymatic reduction to tetrahydrofolate by
reaction with the enzyme dihydrofolate reductase. Vitamin B-9 is
reported to promote the formation of erythrocytes and to play a
role in the maintenance of the neurological system.
21. The antioxidants of the present invention include at least one
of vitamins C or E and preferably include other known antioxidants
such as vitamin A and certain forms of selenium. Selenium is
preferably administered in a selenium yeast composition that
improves the bioavailability of the selenium. Such compositions are
commercially available (Viva America Marketing, Inc., Costa Mesa,
Calif.). As with the B vitamin complex, analogues, precursors,
functional metabolics, concentrations of natural products and other
substitutes for the isolated vitamin composition may be used. In
the preferred embodiment of the invention, wherein the compositions
are administered orally, the compositions may be administered in
pill or liquid form. The pill form may be comprised of traditional
pharmaceutically acceptable carriers and formulations such as
preservatives, fillers, gums, stabilizers, and other functionally
inert substances, such as sodium or calcium carbonate, calcium
phosphate, lactose, and solidifying or binding agents such as
gelatin, acacia, and pharmaceutically acceptable lubricants. A
pharmaceutically acceptable formulation pursuant to the present
invention meets the pharmaceutical industry standards for toxicity,
mutagenicity, sterility, non-pyrogenicity, shelf-life stability,
and overall standards of biocompatibility.
22. Pursuant to the present invention, antioxidants and a vitamin B
complex are preferably administered together as part of a dietary
supplement also containing lecithin. The contents of a suitable
composition containing a combined antioxidant/vitamin B complex
supplement are shown below in Table 1.
1 TABLE 1 Description Unit (mg) per tablet Thiamine Mononitrate
(Vitamin B-1) 1.500 Riboflavin (Vitamin B-2) 1.753 Niacinamide
(Vitamin B-3) 20.101 Pyridoxine HCL (Vitamin B-6) 2.062
Cyanocobalamin (Vitamin B-12) 0.600 D-Calcium Pantothenate 10.870
Folic Acid (Vitamin B-9) 0.408 D-Biotin (Vitamin H) 30.000 Barley
Juice Powder 215.154 Wheat Spout Powder 100.000 Beta Carotene 5.000
Ascorbic Acid 50.000 Vitamin E Acetate 71.429 Selenium Yeast 1,600
MCG/GM 15.625 Stearic Acid Powder 3.250 Sylox (Silicon dioxide)
9.750 Magnesium Stearate 6.500 MCC (Methyl crystalline cellulose)
Total 675.200
23.
24. All of the other components of the antioxidant/vitamin B
complex compositions are available from commercial sources.
25. Having generally described the present invention, a further
understanding may be acquired by reference to the following
Example, an experimental study conducted to investigate the effects
of dietary supplementation with lecithin, antioxidants and a
vitamin B complex in NASH patients.
EXAMPLE I
26. Four patients, one male and three female, were recruited who
had increased aspartate aminotransferase (AST) and/or alanine
aminotransferase (ALT), at least one and a half times the upper
limits of normal, and a liver biopsy which demonstrated NASH within
three months prior to entering the study. These patients did not
have other chronic liver disease, and were not on total parenteral
nutrition or lipid lowering agents. Each patient was given 20 grams
of dietary lecithin supplement with antioxidants (vitamins A, C,
and E and selenium) and vitamin B complex 300 percent of the RDA
daily level twice a day for a total of 12 weeks.
27. Serum levels of AST, ALT, GGT (gamma-glutamyltranspeptidase),
alkaline phospatase, total bilirubin, lipid profile, free choline
and phospholipid bound choline of plasma and red blood cell were
measured at entry, week 4, week 8, and week 12. A computed
tomography (CT) scan of liver was obtained at entry and week 12.
Another liver biopsy was performed after the treatment to confirm
the change of fatty infiltration measured by the CT scan. Portal
inflammation, lobular activity, steatosis, and fibrosis were graded
from 0 to 4. The Average CT tissue density in Hounsfield Units (HU)
for liver and spleen was generated from multiple representative
sections. Liver density was determined by the liver-spleen
differential, with 0 to 8 HU representing borderline fatty changes
and negative HU values corresponding to marked fatty
infiltration.
28. The study was completed by all four patients without adverse
drug reaction. Furthermore, all four patients showed a
statistically significant decrease in hepatic steatosis indicated
by increased liver density as measured by CT scans (4.97.+-.4.65 HU
before treatment vs. -5.21.+-.8.07 HU after treatment; p<0.05).
On histology, two out of four patients had a reduction in
steatosis. No change in portal inflammation was observed, however,
two out of four patients had mildly increased lobular activity.
Although a small increase in fibrosis was observed, it cannot be
concluded whether this is a positive or negative effect. Increased
fibrosis may result from focal sampling bias, moreover, fibrosis
has been observed to correlate with a degree of obesity and the
existence or development of fibrosis is not known to be directly
correlated with the development or progression of NASH. Detailed
biopsy results are shown below in TABLE 2.
2TABLE 2 Patent Portal Lobular Glycogenated Number Inflammation
Activity Steatosis Fibrosis Iron Nuclei #1 Pre- 1 0 2 2 1 1
treatment Post- 1 1 1 3 1 1 treatment #2 Pre- 2 1 2 2 0 0 treatment
Post- 2 2 1 2 0 0 treatment #3 Pre- 0 2 3 0 0 0 treatment Post- 0 2
3 2 0 0 treatment #4 Pre- 0 1 1 0 0 1 treatment Post- 0 1 1 1 0 0
treatment
29.
30. There will be various modifications, improvements, and
applications of the disclosed invention that will be apparent to
those of skill in the art, and the present application encompasses
such embodiments to the extent allowed by law. Although the present
invention has been described in the context of certain preferred
embodiments, the full scope of the invention is not so limited, but
is in accord with the scope of the following claims.
* * * * *