U.S. patent application number 10/002179 was filed with the patent office on 2002-07-25 for method for the prevention and treatment of cachexia and anorexia.
Invention is credited to Abbruzzese, Bonnie Chandler, Cope, Frederick Oliver, Demichele, Stephen Joseph, McCamish, Mark Anthony.
Application Number | 20020099020 10/002179 |
Document ID | / |
Family ID | 27092312 |
Filed Date | 2002-07-25 |
United States Patent
Application |
20020099020 |
Kind Code |
A1 |
Abbruzzese, Bonnie Chandler ;
et al. |
July 25, 2002 |
Method for the prevention and treatment of cachexia and
anorexia
Abstract
The present invention relates to methods and nutritional
compositions for the prevention and treatment of cachexia and
anorexia. The methods of the invention comprise administering a
composition comprising effective amounts of .omega.-3 fatty acids
such as alpha-linolenic acid, stearidonic acid, eicosapentaenoic
acid, docosapentaenoic acid, docosahexaenoic acid or mixtures
thereof; of branched-chain amino acids valine, leucine, isoleucin
or mixtures thereof; with or without reduced levels of tryptophan
and 5-hydroxytryptophan; and of antioxidant system selected from
the group comprising beta-carotene, vitamin C, vitamin E, selenium,
or mixtures thereof.
Inventors: |
Abbruzzese, Bonnie Chandler;
(Dubin, OH) ; McCamish, Mark Anthony;
(Worthington, OH) ; Cope, Frederick Oliver;
(Worthington, OH) ; Demichele, Stephen Joseph;
(Dublin, OH) |
Correspondence
Address: |
ROSS PRODUCTS DIVISION OF ABBOTT LABORATORIES
DEPARTMENT 108140-DS/1
625 CLEVELAND AVENUE
COLUMBUS
OH
43215-1724
US
|
Family ID: |
27092312 |
Appl. No.: |
10/002179 |
Filed: |
December 5, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10002179 |
Dec 5, 2001 |
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09642630 |
Aug 18, 2000 |
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09642630 |
Aug 18, 2000 |
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09479550 |
Jan 7, 2000 |
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09479550 |
Jan 7, 2000 |
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08842454 |
Apr 24, 1997 |
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08842454 |
Apr 24, 1997 |
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08635179 |
Apr 25, 1996 |
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Current U.S.
Class: |
424/278.1 ;
424/702; 514/1.2; 514/19.3; 514/458; 514/474; 514/5.5; 514/560;
514/763 |
Current CPC
Class: |
A23V 2002/00 20130101;
A23V 2002/00 20130101; A61P 35/00 20180101; Y10S 426/801 20130101;
A23L 33/175 20160801; A23L 33/12 20160801; A61K 31/202 20130101;
A23V 2250/211 20130101; A23V 2250/187 20130101; A23V 2250/712
20130101; A23V 2200/02 20130101; A23V 2250/1868 20130101; A23V
2250/712 20130101; A23V 2250/187 20130101; A23V 2250/1626 20130101;
A61K 31/70 20130101; A23V 2250/708 20130101; A61P 43/00 20180101;
A23V 2250/708 20130101; A23V 2200/308 20130101; A23V 2200/30
20130101; A23V 2250/1626 20130101; A23V 2250/5046 20130101; A23V
2002/00 20130101; Y10S 426/80 20130101; A61K 47/12 20130101; A23L
33/16 20160801; A61P 37/04 20180101; A61P 3/00 20180101; A61P 3/02
20180101; A61K 47/183 20130101; A61K 9/0029 20130101; A61P 3/04
20180101; A61P 7/00 20180101; A23L 33/40 20160801 |
Class at
Publication: |
514/21 ; 514/458;
514/474; 514/560; 514/763; 424/702 |
International
Class: |
A61K 038/00; A61K
031/355; A61K 031/375; A61K 031/015; A61K 033/04 |
Claims
We claim:
1. A method of preventing the onset of cachexia and/or anorexia or
treating existing cachexia and/or anorexia in a human, said method
comprising enterally administering to the human on a daily basis at
least: (a) an oil blend containing .omega.-6 fatty acids and at
least 450 mg of .omega.-3 fatty acids, the weight ratio of
.omega.-6 fatty acids to .omega.-3 fatty acids being from about 0.1
to about 3.0; and (b) a source of amino-nitrogen wherein 15% to 50%
by weight of the amino acids of said source of amino-nitrogen are
branched-chain amino acids; and (c) an antioxidant component
comprising at least one nutrient selected from the group comprising
beta-carotene, vitamin C, vitamin E, selenium, and mixtures
thereof; wherein at least said oil blend and said antioxidant are
present in a liquid nutritional matrix.
2. The method according to claim 1, further comprising
administering to the human a source of amino-nitrogen wherein
tryptophan is present in an amount of less than about 5.0% by
weight of the total amount of the amino acids present in said
source of amino-nitrogen.
3. The method according to claim 1, further comprising
administering to the human a source of amino-nitrogen wherein 15%
to 25% by weight of the amino acids of said source of
amino-nitrogen are branched-chain amino acids.
4. The method according to claim 1 which further comprises daily
administering to the human: (a) an oil blend containing .omega.-6
fatty acids and at least 1000 mg of .omega.-3 fatty acids, the
weight ratio of .omega.-6 fatty acids to .omega.-3 fatty acids
being from 0.1 to 1.0; and (b) a source of amino-nitrogen wherein
15% to 25% by weight of the amino acids are branched-chain amino
acids, and wherein tryptophan is present in an amount of less than
3.0% by weight of the total amount of the amino acids present in
said source of amino-nitrogen; and (c) an antioxidant mixture
comprising beta-carotene, vitamin C, vitamin E and selenium.
5. The method of claim 4 wherein the antioxidant system of
component (c) comprises about 2,500 to about 6,500 micrograms
beta-carotene, about 250 to about 1,000 milligrams vitamin C, about
100 to about 500 I.U. vitamin E and about 75 to about 125
micrograms selenium per liter.
6. The method of claim 1 in which the .omega.-3 fatty acids
comprise from about 15 to about 30% by weight of the total fatty
acids and are selected from the group consisting of alpha-linolenic
acid, stearidonic acid, eicosapentaenoic acid, docosapentaenoic
acid and docosahexaenoic acid.
7. The method of claim 6 in which the .omega.-3 fatty acids
comprise from about 15 to about 40% by weight of the total fatty
acids and are selected from the group consisting of
eicosapentaenoic acid and docosahexaenoic acid.
8. The method of claim 7 in which at least about 15% by weight of
the total fatty acids is eicosapentaenoic acid.
9. The method of claim 1 wherein the weight ratio of .omega.-6
fatty acids to .omega.-3 fatty acids in said oil blend is from
about 0.1 to about 1.0; about 15% to about 25% by weight of the
amino acids of said source of amino-nitrogen are branched-chain
amino acids; and said antioxidant component comprises a mixture of
beta-carotene, vitamin C, vitamin E and selenium.
10. The method according to claim 1 which further comprises daily
administering to the human: (a) an oil blend containing .omega.-6
fatty acids and at least 1000 mg of .omega.-3 fatty acids, the
weight ratio of .omega.-6 fatty acids to .omega.-3 fatty acids
being from 0.1 to 1.0; and (b) a source of amino-nitrogen wherein
15% to 25% by weight of the amino acids are branched-chain amino
acids, and wherein tryptophan is present in an amount of less than
5.0% by weight of the total amount of the amino acids present in
said source of amino-nitrogen.
11. The method of claim 10 comprising feeding eicosapentaneoic acid
as the .omega.-3 fatty acid.
12. A liquid nutritional composition comprising per liter: (a) at
least 450 mg of .omega.-3 fatty acids and wherein the weight ratio
of .omega.-6 fatty acids to .omega.-3 fatty acids is from about 0.1
to about 3.0; (b) at least 50 grams of a source of amino-nitrogen
wherein 15 to 50% by weight of the amino-nitrogen is branched-chain
amino acids and wherein tryptophan is present in an amount less
than about 5.0% by weight of the total amino-nitrogen; and (c) at
least 1 gram of an antioxidant system comprising beta-carotene,
vitamin C, vitamin E and selenium.
13. The composition according to claim 12, wherein the weight ratio
of .omega.-6 fatty acids to .omega.-3 fatty acids is from about 0.1
to about 1.0, and wherein 15 to 25% by weight of the amino-nitrogen
is branched-chain amino acids.
14. The composition according to claim 13, further comprising at
least 1000 mg of .omega.-3 fatty acids per liter.
15. A liquid nutritional composition according to claim 12 wherein:
(a) at least 500 mg of .omega.-3 fatty acids are present and the
weight ratio of .omega.-6 fatty acids to .omega.-3 fatty acids is
from 0.2 to 2.0; (b) tryptophan is present in an amount of less
than 3.0% by weight of the total amino-nitrogen; and (c) at least
2.0 grams of said antioxidant system is present per liter.
16. A method of preventing the onset of anorexia or of treating
existing anorexia in a human comprising administering to the human
a nutritional composition comprising amino acids wherein about 5 to
25 grams of branched-chain amino acids selected from valine,
leucine, isoleucine, or mixtures thereof are present in an amount
from about 15% to about 50% by weight of the total amount of amino
acids present in said composition, and wherein tryptophan in an
amount not greater than about 5.0 % by weight of the total amount
of amino acids is present in said composition and wherein .omega.-6
and .omega.-3 fatty acids are present at a weight ratio of from
about 0.1 to about 3.0 and at least one antioxidant is present in
the nutritional composition.
17. A method for preventing immunosuppression in a human comprising
administering to the human a liquid nutritional composition
comprising: (a) an oil blend containing .omega.-6 and .omega.-3
fatty acids, the weight ratio .omega.-6 fatty acids to .omega.-3
fatty acids being about from 0.1 to about 3.0; and (b) an
antioxidant component comprising about 2,500 to about 6,500
micrograms per liter beta-carotene, about 250 to about 1,000
milligrams per liter vitamin C, about 100 to about 500 I.U. per
liter vitamin E, and about 75 to about 125 microgram per liter
selenium.
18. The method of claim 17 in which at least 400 mL of said liquid
nutritional composition are administered to said human per day.
19. A method for enhancing the transport and efficacy of anticancer
drugs in a human having a cancerous condition comprising
administering to the human a nutritional composition comprising an
oil blend containing .omega.-6 and .omega.-3 fatty acids, the
weight ratio of total .omega.-6 fatty acids to .omega.-3 fatty
acids being from about 0.1 to about 3.0.
Description
[0001] This application is a continuation-in-part of prior
application Ser. No. 08/635,179 filed Apr. 25, 1996, which is
hereby incorporated by reference.
[0002] The present invention relates to methods and nutritional
compositions for the prevention and treatment of cancer cachexia
and anorexia. In the practice of the present invention patients are
enterally administered .omega.-3 fatty acids including, but not
limited to alpha-linolenic (18:3 .omega.-3), stearidonic (18:4
.omega.-3), eicosapentaenoic (20:5 .omega.-3), docosapentaenoic
(22:5 .omega.-3), and docosahexaenoic (22:6 .omega.-3), in
combination with antioxidants including, but not limited to,
beta-carotene, vitamin C, vitamin E, selenium, or mixtures thereof;
a source of amino-nitrogen with high levels of branched-chain amino
acids including valine, leucine, isoleucine, and with or without
reduced levels of tryptophan and 5-hydroxytryptophan.
BACKGROUND
[0003] Cancer cachexia is a syndrome characterized by anorexia,
weight loss, premature satiety, asthenia, loss of lean body mass,
and multiple organ dysfunction. The majority of patients with
cancer whose disease progresses to metastatic disease develop
cachexia during their treatment program and the cachexia
contributes to their deaths. The frequency of weight loss in cancer
patients ranges from 40% for patients with breast cancer, acute
myelocytic leukemia, and sarcoma to more than 80% in patients with
carcinoma of the pancreas and stomach. About 60% of patients with
carcinomas of the lung, colon or prostate have experienced weight
loss prior to beginning chemotherapy. Although the relationship
between pretreatment malnutrition (weight loss) and adverse outcome
is established, no consistent relationship has been demonstrated
between the development of cachexia and tumor size, disease stage,
and type or duration of the malignancy. Development of cachexia in
the cancer patient is not caused simply by increased energy
expenditure by the host or by the tumor. The malignant cachexia is
partially related to reduced caloric intake.
[0004] Cancer cachexia is not simply a local effect of the tumor.
Alterations in protein, fat, and carbohyrate metabolism occur
commonly. For example, abnormalities in carbohydrate metabolism
include increased rates of total glucose turnover, increased
hepatic gluconeogenesis, glucose intolerance and elevated glucose
levels. Increased lipolysis, increased free fatty acid and glycerol
turnover, hyperlipidemia, and reduced lipoprotein lipase activity
are frequently noted. The weight loss associated with cancer
cachexia is caused not only by a reduction in body fat stores but
also by a reduction in total body protein mass, with extensive
skeletal muscle wasting. Increased protein turnover and poorly
regulated amino acid oxidation may also be important. Presence of
host-derived factors produced in response to the cancer have been
implicated as causative agents of cachexia, e.g., tumor necrosis
factor-.alpha. (TNF) or cachectin, interleukin-1 (IL-1), IL-6,
gamma-interferon (IFN), and prostaglandins (PGs) (e.g.,
PGE.sub.2).
[0005] Anorexia, with progressive depletion of body stores leading
to the cachectic state, is observed in 50% of cancer-bearing
patients. Different mechanisms proposed to explain the pathogenesis
of anorexia include: (i) increased production of cytokines such as
TNF and IL-1, and (ii) increased serotoninergic activity within the
central nervous system secondary to enhanced availability to the
brain of its precursor, tryptophan. Dickerson, J. W. T. et al.,
1976, J. Neurochem 27: 1245-1247 have suggested that diets should
be selected to keep the ratio of plasma tryptophan to the sum of
neutral amino acids constant. Cangiano, C., et al., 1994,
Anticancer Res. 14: 1451-1456 has also disclosed that a close
relationship between plasma free tryptophan concentration and
anorexia in cancer patients supports the serotoninergic system
activity in the pathogenesis of cancer anorexia.
[0006] Cancer is characterized primarily by an increase in the
number of abnormal cells derived from a given normal tissue,
invasion of adjacent tissues by these abnormal cells, and lymphatic
or blood-borne spread of malignant cells to regional lymph nodes
and to distant metastatic sites. Clinical data and molecular
biologic studies indicate that cancer is a multi-step process that
begins with minor preneoplastic changes, which may under certain
conditions progress to neoplasia causing metabolic effects such as
cachexia.
[0007] Tumor cells differ from normal cells in their metabolism of
fat in that tumor cells consume short-chain and medium-chain fatty
acids poorly. For example, tumor-bearing mice fed a diet rich in
medium-chain triglycerides had less weight loss with a marked
reduction in tumor size compared with animals fed long-chain
triglycerides. Moreover, there have been problems reported with the
use of high levels of medium-chain triglycerides and use of
structured lipids has been suggested in some total parenteral
nutrition formulas. Moreover, these structured lipids do not
provide the same benefits if administered enterally. U.S. Pat. Nos.
4,906,664 and 5,081,105 disclose the use of certain structured
lipids in the treatment of cancer. Preparations for enteral
nourishment including varying ratios of .omega.-6 to .omega.-3
(2.1:1-3.0:1) have also been used in oncologic patients. However,
these preparations used proportionately larger amounts of .omega.-6
to .omega.-3 fatty acids. Furthermore, these preparations did not
include additional amounts of branched-chain amino acids and
antioxidants as set forth in the present invention. The use of the
polyunsaturated fatty acid eicosapentaenoic acid is suggested for
the treatment of cachexia by inhibiting lipolytic activity of
lipolytic agents in body fluids and the activity of the enzyme
guanidino-benzoatase. See Tisdale, M. J., and Beck, A., U.S. Pat.
No. 5,457,130, issued Oct. 10, 1995; and Tisdale, et al. Cancer
Research 50: 5022-5026 (August 1990). However, the product taught
by Tisdale was in a solid dosage form, requiring an already ill
patient to swallow 12-16 capsules per day. This method had serious
drawbacks, including difficulty in swallowing, belching, and bad
odor.
[0008] Thus, the prevention and/or treatment of cachexia and
anorexia remain a frustrating problem. Both animal and human
studies suggest that nutritional support is largely ineffective in
repleting lean body mass in the cancer-bearing host. Randomized
trials exploring the usefulness of total parenteral nutrition (TPN)
support as an adjunct to cytotoxic antineoplastic therapy have
demonstrated little improvement in treatment results. See for
example Brennan, M. F., and Burt, M. E., 1981, Cancer Treatment
Reports 65 (Suppl. 5): 67-68. This, along with a clear
demonstration that TPN can stimulate tumor growth in animals
suggests the routine use of TPN in cancer treatment is not
justified. Kisner, D. L., 1981, Cancer Treatment Reports 65 (Suppl.
5): 1-2.
[0009] Long chain fatty acid bio-pathways and physiological actions
are discussed in U.S. Pat. No. 5,223,285 to DeMichele, et al., the
entirely of which is incorporated herein by reference.
[0010] Also of interest is U.S. Pat. No. 5,444,054 to Garleb, et
al. and a related U.S. Pat. No.______ (allowed application Ser. No.
08/221,349). These documents describe compositions and methods
useful in the treatment of ulcerative colitis. Such compositions
include a protein source that can be intact or hydrolyzed proteins
of high biological value (col. 21); an indigestible oligosaccharide
such as fructooligosaccharide; and a lipid blend containing a
relatively high proportion of eicosapentaneoic acid, which
contributes to a relatively high .omega.-3 to .omega.-6 fatty acid
ratio.
SUMMARY OF THE INVENTION
[0011] The methods of the invention generally comprise inhibiting
metabolic and cytokine associated features of cachexia in an
individual by administering a nutritional composition comprising an
effective amount of .omega.-3 fatty acids including, but not
limited to alpha-linolenic acid, stearidonic acid, eicosapentaenoic
acid, docosapentaenoic acid and docosahexaenoic acid, alone or in
combination with each other. The invention also relates to
administering a nutritional composition comprising effective
amounts of branched-chain amino acids, valine, leucine, isoleucine,
or mixtures thereof, and with or without a reduced amount of
tryptophan and hydroxytryptophan. The invention further provides a
method of reducing oxidative damage and anti-cancer drug-induced
immunosuppression in a cancer patient by administering a
nutritional composition comprising effective amounts of
antioxidants including, but not limited to beta-carotene, vitamin
C, vitamin E, selenium, or mixtures thereof.
[0012] In one aspect, the invention provides a method of preventing
the onset of cachexia and/or anorexia, or treating existing
cachexia and/or anorexia in a human comprising enterally
administering to the human at least:
[0013] (a) an oil blend containing .omega.-6 fatty acids and at
least 450 mg of .omega.-3 fatty acids, the weight ratio of
.omega.-6 fatty acids to .omega.-3 fatty acids being from about 0.1
to about 3.0; and
[0014] (b) a source of amino-nitrogen wherein 15% to 50% by weight
of the amino acids of said source of amino-nitrogen are
branched-chain amino acids; and
[0015] (c) an antioxidant component comprised of at least one
nutrient selected from the group comprising beta-carotene, vitamin
C, vitamin E, selenium, or mixtures thereof.
[0016] These components may be administered in a single composition
or in separate vehicles. Preferably, about 15% to about 25% of the
amino-nitrogen is provided by branched-chain amino acids; most
preferably, about 20%. It is also preferred that the source of
amino nitrogen provides tryptophan in an amount of less than about
5.0% by weight of the total amount of the amino acids of said
source of amino-nitrogen; more preferably at a level of less than
3% by weight.
[0017] In another aspect, the invention provides a method of
preventing the onset of anorexia or of treating existing anorexia
in a human comprising administering to the human a nutritional
composition comprising amino-nitrogen wherein about 5 to 25 grams
of branched-chain amino acids selected from valine, leucine,
isoleucine, or mixtures thereof are present in an amount from about
15% to about 50% by weight, preferably about 15-25%, of the total
amount of amino-nitrogen present in said nutritional composition,
and wherein tryptophan in an amount not greater than about 5.0% by
weight of the total amount of amino acids is present in said
composition and wherein .omega.-6 and .omega.-3 fatty acids are
present at a weight ratio of from about 0.1 to about 3.0 and at
least one antioxidant is present in the nutritional
composition.
[0018] There is further disclosed a method for preventing
immunosuppression in a human comprising administering to the human
a liquid nutritional composition comprising:
[0019] (a) an oil blend containing .omega.-6 and .omega.-3 fatty
acids, the weight ratio .omega.-6 fatty acids to .omega.-3 fatty
acids being about from 0.1 to about 3.0; and
[0020] (b) an antioxidant component comprising about 2,500 to about
6,500 micrograms per liter beta-carotene, about 250 to about 1,000
milligrams per liter vitamin C, about 100 to about 500 I.U. per
liter vitamin E, and about 75 to about 125 mcg per liter
selenium.
[0021] There is also disclosed a method of enhancing the transport
and efficacy of anticancer drugs in a human having a cancerous
condition comprising administering to the human a nutritional
composition comprising an oil blend containing .omega.-6 and
.omega.-3 fatty acids, the weight ratio of total .omega.-6 fatty
acids to .omega.-3 fatty acids being from about 0.1 to about
3.0.
[0022] In another aspect, the invention provides a liquid
nutritional composition comprising per liter:
[0023] (a) at least 0.45 gm (450 mg) of .omega.-3 fatty acids and
wherein the weight ratio of .omega.-6 fatty acids to .omega.-3
fatty acids is from about 0.1 to about 3.0;
[0024] (b) at least 50 grams of a source of amino-nitrogen wherein
15 to 50% by weight of the amino-nitrogen is branched-chain amino
acids and wherein tryptophan is present in an amount less than
about 5.0% by weight of the total amino-nitrogen; and
[0025] (c) at least 1 gram of an antioxidant system comprising
beta-carotene, vitamin C, vitamin E and selenium.
[0026] Generally, such compositions provide much higher levels of
the .omega.-3 fatty acids: preferably from about 1.0 gm to about
100 gm per liter; more preferably, from about 5.0 gm to about 10 gm
per liter. Similarly, it is preferred that about 15-25% (typically
about 20%) by weight of the source of amino-nitrogen is
branched-chain amino acids.
[0027] The various methods according to the present invention may
be accomplished by feeding a single composition that contains all
the components of the invention .omega.-6 to .omega.-3 oil,
branched-chain amino acids and antioxidant system) or each
component may be fed individually. Further, these methods may be
accomplished through the consumption of pills or capsules that
contain the elements of the claimed invention. In one embodiment of
the invention, a nutritional liquid formulation containing all the
elements of the invention is contemplated except for the
branched-chain amino acids which may be consumed in the form of a
pill or tablet.
[0028] In yet another co-embodiment of the invention, a liquid
nutritional product contains all the elements of the composition,
wherein the branched-chain amino acids are dispersed within the
liquid in the form of microcapsuies. This administration of the
branched-chain amino acids in the form of capsules, tablets, pills
and/or microcapsules is advantageous since the organoleptic or
taste properties of the amino acids are very objectionable.
[0029] In contrast to the prior art, the nutritional composition of
the present invention is not restricted to correcting metabolism of
just one nutrient class at a time, such as lipids or amino acids.
Instead, a preferred nutritional multinutrient composition
comprises a balanced formulation containing .omega.-3 fatty acids,
antioxidants, branched-chain amino acids, and with or without a
reduced level of tryptophan and 5-hydroxytryptophan. Such a
composition can demonstrate strong inhibition of cachexia and
anorexia associated with a variety of different cancers (disease
states).
[0030] In yet another embodiment, the methods further optionally
comprise administering the nutritional composition in combination
with cancer chemotherapeutic agents, including but not limited to,
5-fluorouracil, mitomycin-C, adriamycin, chloroethyl nitrosoureas
and methotrexate, to improve the transport of the drug into the
target cancer cells and ultimately the efficacy of the anticancer
agent.
[0031] The Examples presented below exemplify the use according to
the methods of the invention of .omega.-3 fatty acids,
antioxidants, branched-chain amino acids with or without a reduced
level of tryptophan in nutritional therapy of cachexia and anorexia
in human patients suffering from different cancers, including, but
not limited to, liver, breast, lung, prostate, gastrointestinal and
pancreatic cancer.
DETAILED DESCRIPTION OF THE INVENTION
[0032] "Cachexia" refers to a state of general ill health and
malnutrition. It is often associated with and induced by malignant
cancer, and is characterized by loss of appetite, loss of body
mass, especially lean body mass, and muscle wasting.
[0033] "Anorexia" refers simply to a loss of appetite, whether
brought on by medical or psychological factors. Anorexia is often
closely associated with, and generally contributes to, the cachexia
seen in patients with advanced cancers.
[0034] "Fatty acids" refer to a family of carboxylic acids having a
hydrocarbon chain, generally from about 12 to 24 carbons long. When
unsaturated (having a double bond) at least one point in the
hydrocarbon chain, such fatty acids are designated by the position
of the first double bond. .omega.-3 fatty acids have a first double
bond at the third carbon from the methyl end of the chain; and
include, but are not limited to, .alpha.-linolenic acid,
stearidonic acid, eicosapentaenoic acid ("EPA"), docosapentaenoic
acid and docosahexaenoic acid ("DHA") and the like. .omega.-6 fatty
acids have a first double bond at the sixth carbon from the methyl
end of the chain; and include, but are not limited to, linoleic
acid, .gamma.-linolenic acid, arachidonic acid ("AA"), and the
like. The ratio of .omega.-6 fatty acids to .omega.-3 fatty acids
is simply the ratio of the total amounts (usually expressed as
weight) of each type.
[0035] Branched-chain amino acids are amino acids that have a fork
or branch in the side chain. These include primarily those having a
carbon-carbon branch, i.e. valine, leucine and isoleucine; but may
also include other types of branches.
[0036] "Nutritional matrix" as used herein refers to a delivery
vehicle that contains fats, amino nitrogen and carbohydrates and
provides some or all of the nutritional support for a patient in
the recommended daily amounts. Frequently a nutritional matrix will
contain vitamins, minerals, trace minerals and the like to provide
balanced nutrition.
[0037] "Cytokines" as used herein refer to the causative agents of
cachexia in the cancer patient, produced by the individual in
response to the presence of cancer, and include, but are not
limited to, tumor necrosis factor (TNF) or cachectin, interleukin-1
(IL-1), IL-6 and gamma-interferon (IFN). TNF is produced by the
macrophages in response to nonspecific stimuli including cancer,
infection, trauma and stress. The mechanism of action in cancer
cachexia involves an immune response to the tumor with the
production of cytokines, which not only mediate tumor lysis but
also the metabolic changes seen in cancer cachexia through specific
TNF receptors and/or via the induction of other cytokine
receptors.
[0038] While not intending the invention to be limited to any
particular theory of operation, applicants describe below a
probable mechanism. A mode of action of cytokines is mediated via
interactions with receptors on the plasma membrane. This is
typically defined as a "signal transduction event." In general, a
cytokine receptor consists of an extracellular domain, a
transmembrane region spanning the phospholipid bilayer of the
plasma membrane, and an intracellular domain having either
enzymatic activity or binding other molecules, so that a signal is
delivered inside the cell in response to the cytokine ligand
interaction. The signal transduction mechanisms involve second
messengers, including phospholipases, adenylate cyclase and cyclic
AMP, inositol phosphates, diacylglycerols and protein kinase C.
More particularly, phospholipase A2 generates arachidonic acid, a
precursor of dienoic prostaglandins, thromboxanes, prostacyclin and
leukotrienes of the 4 series.
[0039] Cytokines such as TNF and IL-1 stimulate production of
arachidonic acid metabolites which are important to their
inflammatory and tissue damaging actions and are responsible for
immunosuppression in general, and in exacerbating some
paraneoplastic conditions including metabolic changes seen in
cancer cachexia.
[0040] The invention is based, in part, on a method of inhibiting
signal transduction and cytokine activity using nutritional
compositions comprising high levels of .omega.-3 fatty acids, in
particular, of the long chain (e.g. 20 or more carbons) .omega.-3
fatty acids, eicosapentaenoic (EPA) and docosahexaenoic (DHA).
[0041] Since administration of EPA and DHA results in a reduction
of arachidonic acid in membrane phospholipids, such an effect not
only diminishes the supply of arachidonic acid as a precursor for
the dienoic eicosanoids but also inhibits their production through
competitive inhibition by EPA. The cyclooxygenase and lipoxygenase
metabolites of EPA have attenuated activity. Furthermore, .omega.-3
fatty acids, alpha-linolenic and stearidonic can be converted
through elongation/desaturation to EPA; and similarly, DHA can be
retroconverted to EPA. Thus, the methods of invention comprise
methods of inhibiting cytokine activity (e.g., TNF, IL-1) and
cancer cachexia by interfering with signal transduction at the
receptor level and inhibiting arachidonic acid metabolism.
[0042] Incorporation of .omega.-3 fatty acids in membrane
phospholipids not only alters the activity of membrane-associated
enzymes (e.g., phospholipase A2) but also alters the balance
between constituent saturated and unsaturated fatty acids and
regulation of membrane fluidity, facilitates the transport of
anticancer drugs into the cancer cells and thus enhances the
efficacy of the drugs. Alberts, A. W., et al., 1978, Biochim.
Biophys. Acta 509:239-250. In addition, the inhibition of
arachidonic acid metabolism results in prevention and/or reversal
of immunosuppression by reducing the production of prostaglandins
and leukotrienes (PGE2 and LTB4), which are immunosuppressive.
[0043] The invention also provides a method of reducing the
concentration of brain tryptophan and serotonin to prevent or
inhibit premature satiety and cancer cachexia and/or anorexia in a
cancer patient in whom the prevention and treatment of cancer
anorexia is desired by administering effective amounts of
branched-chain amino acids, valine, leucine, isoleucine, or
mixtures thereof, and with or without a reduced amount of
tryptophan.
[0044] The methods and compositions of the invention provide a
method of manipulating the concentration of brain tryptophan by:
(i) increasing the branched-chain amino acids, which provide
competition for tryptophan for penetration across the blood-brain
barrier; and (ii) reduced levels of tryptophan and
5-hydroxytryptophan in relation to branched-chain amino acids in
the nutritional composition of the invention. Such an intervention
can increase appetite and thus prevent and/or treat cancer
anorexia.
[0045] The methods and compositions of the invention also provide a
method of reducing the risk or progression of certain symptoms of
cancer, such as cancer cachexia and anorexia by administering
antioxidant nutrients including, but not limited to, beta-carotene,
vitamin C, vitamin E, selenium, or mixtures thereof.
Epidemiological evidence indicates that a combination of
beta-carotene, vitamin E and selenium can effect a reduction in
cancer risk in some populations. Blot, N. J. et al., 1993, J. Natl.
Cancer Inst. 85: 1483-1492. Furthermore, vitamin E is added to
satisfy any additional requirements as a result of a higher intake
of .omega.-3 polyunsaturated fatty acids. By the administration of
the antioxidant nutrients of the invention to cancer patients
having cachexia and whose immune system has been depressed on
account of chemotherapy and/or oxidative burden, improvements in
the nutritional status, as well as prevention and treatment of
immunosuppression and cachexia can be achieved.
[0046] Nutritional support in the cancer patient can be categorized
as (i) supportive, in which nutrition support is instituted to
prevent nutrition deterioration in the adequately nourished patient
or to rehabilitate the depleted patient before definitive therapy;
(ii) adjunctive, in which nutrition support plays an integral role
in the therapeutic plan; and (iii) definitive, in which aggressive
nutrition support is required for the patient's existence. The
routes for providing nutrition support include an oral diet, tube
feeding and peripheral or total parenteral nutrition. The preferred
embodiment for nutritional methods and compositions of the
invention is by the oral route.
[0047] An alternate to oral feeding is tube feeding by means of
nasogastric, nasoduodenal, esophagostomy, gastrostomy, or
jejunostomy tubes.
[0048] A typical nutritional composition useful in the method of
this invention will have a caloric distribution as follows: about
12 to 24% (target 21%) from a source of amino-nitrogen, about 40 to
65% (target 61%) from carbohydrate and about 10 to 35% (target 18%)
from fat. More particularly, the oil blend may comprise
approximately 30% of .omega.-3 fatty acids, preferably largely
consisting of eicosapentaenoic acid and docosahexaenoic acid.
Dietary oils used in the preparation of the nutritional composition
generally contain .omega.-3 fatty acids in the triglyceride form
and include, but are not limited to canola, medium chain
triglycerides, fish, soybean, soy lecithin, corn, safflower,
sunflower, high-oleic sunflower, high-oleic safflower, olive,
borage, black currant, evening primrose and flaxseed oil. Table 1
sets forth both preferred amounts and ranges for an oil blend
useful in the invention. Specifically, the weight ratio of
.omega.-6 fatty acids to .omega.-3 fatty acids in the lipid blend
according to the invention is about 0.1 to 3.0. The daily delivery
of .omega.-3 fatty acids should be at least 450 mg and may vary
depending on body weight, sex, age and medical condition of the
individual. As mentioned, higher levels are desired for adult human
consumption: for example, from about 0.5 to 50 gm daily, more
preferably from about 2.5 to 5 gm daily.
1TABLE 1 OIL BLEND (% total weight of lipid blend) OIL PREFERRED
RANGE Canola 9.3% 5.0-40.0% MCT 16.2% 10.0-50.0% Fish 65.0%
25.0-80.0% Soybean 5.5% 3.0-30.0% Soy lecithin 4.0% 2.0-6.0%
[0049] Table 2 presents the fatty acid profile of an exemplary oil
blend useful in the present invention. The weight ratio of the
total .omega.-6 fatty acids to the total .omega.-3 fatty acids in
this embodiment is 0.26 to 1 which is within the claimed range for
this invention.
2TABLE 2 FATTY ACID PROFILE (% of total fatty acids by weight) OIL
% Caproic (6:0) 0.53 Capyrlic (8:0) 10.35 Capric (10:0) 7.16 Lauric
(12:0) 0.29 Myristic (14:0) 3.53 Palmitic (16:0) 7.41 Palmitoleic
(16:1.omega.7) 5.73 Stearic (18:0) 1.39 Oleic (18:1.omega.9) 15.23
Linoleic (18:2.omega.6) 7.21 Gamma-linoleic (18:3.omega.6) 0.21
Alpha-linoleic (18:3.omega.3) 2.21 Stearidonic (18:4.omega.3) 2.40
Arachidic (20:0) 0.13 Eicosenoic (20:1.omega.9) 0.74 Arachidonic
(20:4.omega.6) 0.87 Eicosapentaenoic (20:5.omega.3) 17.14 Erucic
(22:1.omega.9) 0.17 Docosapentaenoic (22:5.omega.3) 2.08
Docosahexaenoic (22:6.omega.3) 7.73 Nervonic (24:1.omega.9) 0.14
Others 7.35 Total 100.00
[0050]
3TABLE 3 LIPID BLEND CHARACTERISTICS % .omega.-3 fatty acids 30.51
% .omega.-6 fatty acids 9.67 % .omega.-9 fatty acids 15.28 %
saturated fatty acids 27.07 % monounsaturated fatty acids 19.33 %
polyunsaturated fatty acids 40.17 .omega.-6/.omega.-3 ratio 0.32
18:2.omega.6/18:3.omega.3 ratio 4.26 18:3.omega.3, % total energy
0.33 18:2.omega.6, % total energy 1.41 18:1.omega.9, % total energy
2.42 PUFAs, % total calories 7.23 saturated fatty acids, % total
calories 4.87 EPA (20:5.omega.3) per 8 oz container, g 1.09 DHA
(22:6.omega.3) per 8 oz container, g 0.46
[0051] Table 3 (above) sets forth selected characteristics of an
oil blend useful in the method of this invention. However, it will
be realized that the characteristics may vary among other formulas
useful for this invention, depending on the specific oils added and
the ratios in which they are used.
[0052] An amino acid profile for a nutritional composition useful
in the invention is presented in Table 4.
4TABLE 4 AMINO ACID PROFILE Amino Acid g/100 g Protein Aspartic
Acid 7.08 Threonine 4.34 Serine 5.68 Glutamic Acid 20.58 Proline
10.55 Glycine 1.81 Alanine 3.04 Valine 5.90 Methionine 2.78
Isoleucine 4.77 Leucine 9.08 Tyrosine 4.79 Phenylalanine 4.96
Histidine 2.67 Lysine 7.27 Arginine 3.15 Tryptophan 0.99 Cystine
0.56 Total BCAA 19.75
[0053] The total amount of branched-chain amino acids ("BCAA")
useful in the present invention is about 15-50 g/100 g protein
(i.e. percent), preferably about 15-25 g/100 g. Thus, an 8 oz
container of the nutritional composition would contain up to about
8 g BCAAs per 16 grams of total protein. The daily delivery of
BCAAs is about 5-26 g. In order to deliver such a high amount of
the BCAAs, and because the BCAAs impart an unpleasant taste, the
nutritional composition may be accompanied by 1-3 gelatin capsules
containing BCAAs to provide the additional amount required above
the inherent amount present in the liquid product. The preferred
BCAAs are, but are not limited to, leucine, isoleucine and valine,
and are predominantly bitter in taste. Therefore, administering the
additional BCAAs in encapsulated form avoids taste problems which
are encountered with the use of quantities greater than 20 g/100 g
protein of BCAAs in the liquid product. The microencapsulated BCAAs
may also be mixed with taste masking compounds including, but not
limited to, polyphosphates, cyclodextrin (a cyclic glucose
oligomer) and Thaumatin (a proteinaceous intense sweetener).
[0054] A representative antioxidant profile useful in the method of
the invention is presented in Table 5 with range values and a
preferred embodiment.
5TABLE 5 ANTIOXIDANT PROFILE Antioxidant Preferred Range
Beta-carotene 5,000 .mu.g/L 2,500-6,500 .mu.g/L Vitamin E 300 IU/L
100-500 IU/L Vitamin C 650 mg/L 250-1,000 mg/L Selenium 90 .mu.g/L
78.8-125 .mu.g/L
[0055] The overall nutrient profile of this example is set forth in
Table 6. In a specific embodiment of this invention, the
nutritional product provides at least 100% of the U.S. RDA for
vitamins and minerals in 1184 mL (five 8 fluid ounce servings),
which would provide 1184 kcal per day.
[0056] If used as a sole source of nutrition, and assuming a 2000
kcal diet, between 8 and 9 servings (237 mL; 8 fluid ounces) of
this illustrative formulation would be required. However, as seen
from example IV below, there is benefit derived from
supplementation with as few as two servings per day. Thus a minimum
daily amount of long chain .omega.-3 fatty acids is preferably
about 3 grams, calculated as (1.06 g EPA+0.46 g DHA) times 2 8 oz
servings. Of course, if more servings are consumed to provide
additional calories, more .omega.-3 fatty acids will be
administered, up to a practical maximum of about 14 grams per day
(about 9 servings at same fatty acid levels). Levels of the fatty
acids, antioxidants and/or source of amino nitrogen on a per liter
basis are not crucial, except to the extent that a reasonable
volume of fluid should supply the recommended daily amounts
consistent with the invention. Determination of a reasonable volume
is easily within the ambit of those skilled in the art, especially
in view of the specific guidance found in the examples.
6TABLE 6 NUTRIENT PROFILE Nutrient Qty/Liter Protein, g 67.40 Fat,
g 27.20 Carbohydrate, g 207.00 Total Dietary Fiber, g 10.70
Indigestible Oligosaccharide (FOS), g 12.40 Gum Arabic, g 9.10 Soy
Polysaccharide, g 1.60 Beta-carotene, .mu.g 5000 Vitamin A, IU 5500
Vitamin D, IU 800.00 *Vitamin E, IU 300.00 Vitamin K, .mu.g 135.00
Vitamin C, mg 650.00 Folic Acid .mu.g 1900 Thiamine, mg 6.50
Riboflavin, mg 5.00 Vitamin B.sub.6, mg 5.00 Vitamin B.sub.12,
.mu.g 18.00 Niacin, mg 40.00 Choline, mg 525.00 Biotin, .mu.g
750.00 Pantothenic Acid, mg 24.00 Sodium, mg 1500 Potassium, mg
2000 Chloride, mg 1519 Calcium, mg 1800 Phosphorous, mg 1250
Magnesium, mg 450.00 Iodine, .mu.g 175.00 Copper, mg 2.61 Zinc, mg
29.20 Iron, mg 22.20 Selenium, .mu.g 90.00 Chromium, .mu.g 125.00
Molybdenum, .mu.g 206.00 Carnitine, mg 150.00 Taurine, mg 275.00
Kcal/mL 1 *d-alpha-tocopherol (all natural form) or
dl-alpha-tocopherol acetate, or a combination of the two.
[0057] The following specific examples are set forth to illustrate
various preferred embodiments of the invention but the scope of the
invention is defined by the appended claims.
EXAMPLE I
[0058] The specific list of materials for manufacturing the
nutritional cancer product of this Example I is presented in Table
7. Of course, various changes in specific ingredients and
quantities may be made without departing from the scope of the
invention.
7TABLE 7 LIST OF MATERIALS INGREDIENT AMOUNT WATER 31,605.21 kg GUM
ARABIC 437.84 kg ULTRATRACE/TRACE MINERAL PREMIX 14.50 kg ZINC
SULFATE 2969.89 gm FERROUS SULFATE 2856.50 gm MANGANESE SULFATE
784.60 gm CUPRIC SULFATE 423.11 gm SODIUM MOLYBDATE 21.39 gm
CHROMIUM CHLORIDE 20.80 gm SODIUM SELENITE 8.11 gm CITRIC ACID
894.94 gm SUCROSE (Carrier) 6520.67 gm POTASSIUM CITRATE 50.00 kg
SODIUM CITRATE 95.00 kg POTASSIUM IODIDE 9.00 gm POTASSIUM CHLORIDE
91.00 kg CORN SYRUP SOLIDS 5630.96 kg MALTODEXTRIN 1407.52 kg
MAGNESIUM PHOSPHATE DIBASIC 131.00 kg CALCIUM PHOSPHATE TRIBASIC
47.50 kg (PREFERABLY MICRONIZED) CALCIUM CARBONATE 122.50 kg SUGAR
(SUCROSE) 852.77 kg FRUCTOOLIGOSACCHARIDE 509.96 kg MEDIUM CHAIN
TRIGLYCERIDES 172.69 kg (FRACTIONATED COCONUT OIL) CANOLA OIL 99.13
kg SOY OIL 58.63 kg 57% VITAMIN A PALMITATE 250.00 gm 2.5% VITAMIN
D 35.00 gm D-ALPHA-TOCOPHEROL ACETATE (R,R,R) 10.65 kg
PHYLLOQUINONE 6.50 gm 30% BETA-CAROTENE 824.00 gm SOY LECITHIN
42.64 kg SODIUM CASEINATE 1427.04 kg PARTIALLY HYDROLYZED SODIUM
CASEINATE 1427.04 kg SOY POLYSACCHARIDE 85.28 kg 75% WHEY PROTEIN
CONCENTRATE 184.46 kg REFINED DEODORIZED SARDINE OIL 692.87 kg
ASCORBIC ACID 37.08 kg 45% POTASSIUM HYDROXIDE 25.96 kg TAURINE
12.00 kg WATER SOLUBLE VITAMIN PREMIX 4.50 kg NIACINAMIDE 1688.60
gm CALCIUM PANTOTHENATE 1092.24 gm THIAMINE CHLORIDE HYDROCHLORIDE
278.78 gm PYRIDOXINE HYDROCHLORIDE 268.34 gm RIBOFLAVIN 217.87 gm
FOLIO ACID 37.82 gm BIOTIN 32.87 gm CYANOCOBALAMIN 0.75 gm DEXTROSE
(Carrier) 882.74 gm FOLIO ACID 43.50 gm CHOLINE CHLORIDE 25.00 kg
L-CARNITINE 7.00 kg ARTIFICIAL STRAWBERRY FLAVOR 31.75 kg
ARTIFICIAL CREAM FLAVOR 18.14 kg FD & C Red Dye No.3 1,220.16
gm
[0059] The liquid nutritional product of the present invention was
manufactured by preparing three slurries which are blended
together, combined with refined deodorized sardine oil, heat
treated, standardized, packaged and sterilized. The process for
manufacturing 45,360 kg (100,000 pounds) of the liquid nutritional
product, using the List of Materials from Table 7, is described in
detail below.
[0060] A carbohydrate/mineral slurry is prepared by first heating
about 6,260 kg of water to a temperature in the range of about
71.degree. C. to 77.degree. C. with agitation. The gum arabic is
then added to the water using a mixing apparatus. Next the
ultratrace/trace mineral premix is added to the water and dissolved
by agitating the resultant solution for at least one minute. The
following minerals are then added, in the order listed, with high
agitation: potassium citrate, sodium citrate, potassium iodide and
potassium chloride. The corn syrup solids (Grain Processing
Corporation, Muscatine, Iowa, U.S.A. under the trade designation
"Maltrin M-200") and maltodextrin (Grain Processing Corporation,
trade designation "Maltrin M-100") are then added to the slurry and
the temperature of the slurry is maintained at about 71.degree. C.
with high agitation for at least about 20 minutes.
[0061] Add magnesium phosphate dibasic, calcium phosphate tribasic,
and calcium carbonate to the slurry. Sugar (sucrose), and
fructooligosaccharide (Golden Technologies Company, Golden, Colo.,
U.S.A. under the trade designation "Nutriflora-P-
Fructo-oligosaccharide Powder (96%)") are added to the slurry. The
completed carbohydrate/mineral slurry is held with high agitation
at a temperature in the range of about 60-66.degree. C. for not
longer than 12 hours until it is blended with the other
slurries.
[0062] An oil slurry is prepared by combining and heating the
medium chain triglycerides (fractionated coconut oil), canola oil
and soy oil to a temperature in the range of about 32-43.degree. C.
with agitation. The 57% vitamin A palmitate, 2.5% vitamin D.sub.3,
D-alpha-tocopherol acetate (R,R,R form; Distillation Products
Industries, a division of Eastman Kodak Chemicat Company,
Rochester, N.Y. U.S.A. under the trade designation "Eastman Vitamin
E 6-81 D-Alpha Tocopherol Acetate Concentrate"), phylloquinone and
30% beta-carotene are added to the slurry with agitation. The soy
lecithin is then added to the slurry with agitation. The completed
oil slurry is held under moderate agitation at a temperature in the
range of about 32-43.degree. C. for not longer than 12 hours until
it is blended with the other slurries.
[0063] A protein-and-fiber-in-water slurry is prepared by first
heating about 19,678 kg of water to a temperature in the range of
about 60-63.degree. C. with agitation. Sodium caseinate, partially
hydrolyzed sodium caseinate (distributed by New Zealand Milk
Products, Santa Rosa, Calif., U.S.A. under the trade name Alanate
167) and soy polysaccharide are blended into the slurry using a
mixing apparatus. The temperature of the slurry is lowered to about
57-60.degree. C. and then the 75% whey protein concentrate is added
to the slurry using a mixing apparatus. The completed
protein-and-fiber-in-water slurry is held under agitation at a
temperature in the range of about 54-60.degree. C. for not longer
than 2 hours before being blended with the other slurries.
[0064] The oil slurry and the protein-and-fiber-in-water slurry are
blended together with agitation and the resultant blended slurry is
maintained at a temperature in the range of about 54-66.degree. C.
After waiting for at least one minute the carbohydrate/mineral
slurry is added to the blended slurry from the preceding step with
agitation and the resultant blended slurry is maintained at a
temperature in the range of about 54-66.degree. C. The vessel which
contained the carbohydrate/mineral slurry should be rinsed with
about 220 kg of water and the rinse water should be added to the
blended slurry. The refined deodorized sardine oil (distributed by
Mochida International Company, Limited, Shinjuku-ku, Tokyo, Japan
under the trade designation "50% Omega-3 marine oil EPA:DHA 28:12
with 0.8% mixed tocopherol as antioxidant") is then added to the
slurry with agitation. (In a most preferred method of manufacture
the sardine oil would be slowly metered into the product as the
blend passes through a conduit at a constant rate.) Preferably
after at least 5 minutes the pH of the blended slurry is
determined. If the pH of the blended slurry is below 6.55, it is
adjusted with dilute potassium hydroxide to a pH of 6.55 to
6.8.
[0065] After waiting a period of not less than one minute nor
greater than two 45 hours the blended slurry is subjected to
deaeration, Ultra-High-Temperature (UHT) treatment, and
homogenization, as described below:
[0066] A. Use a positive pump for supplying the blended slurry for
this procedure.
[0067] B. Heat the blended slurry to a temperature in the range of
about 66-71.degree. C.
[0068] C. Deaerate the blended slurry to 25.4-38.1 cm of Hg.
[0069] D. Emulsify the blended slurry at 61-75 Atmospheres.
[0070] E. Heat the blended slurry to a temperature in the range of
about 120-122.degree. C. by passing it through a plate/coil heat
exchanger with a hold time of approximately 10 seconds.
[0071] F. UHT heat the blended slurry to a temperature in the range
of about 144-147.degree. C. with a hold time of approximately 5
seconds.
[0072] G. Reduce the temperature of the blended slurry to be in the
range of about 120-122.degree. C. by passing it through a flash
cooler.
[0073] H. Reduce the temperature of the blended slurry to be in the
range of about 71-82 .degree. C. by passing it through a plate/coil
heat exchanger.
[0074] I. Homogenize the blended slurry at about 265 to 266
Atmospheres.
[0075] J. Pass the blended slurry through a hold tube for at least
16 seconds at a temperature in the range of about 74-85.degree.
C.
[0076] K. Cool the blended slurry to a temperature in the range of
about 1-70.degree. C. by passing it through a large heat
exchanger.
[0077] Store the blended slurry at a temperature in the range of
about 1- 7.degree. C., preferably with agitation.
[0078] Preferably at this time appropriate analytical testing for
quality control is conducted. Based on the test results an
appropriate amount of dilution water (10-38.degree. C.) is added to
the blended slurry with agitation.
[0079] A vitamin solution, a flavor and a color solution are
prepared separately and then added to the blended slurry.
[0080] The vitamin solution is prepared by heating about 394 kg of
water to a temperature in the range of about 43-66.degree. C. with
agitation, and thereafter adding the following ingredients, in the
order listed: Ascorbic Acid, 45% Potassium Hydroxide, Taurine,
Water Soluble Vitamin Premix, Folic Acid, Choline Chloride, and
L-Carnitine. The vitamin solution is then added to the blended
slurry with agitation.
[0081] The flavor solution is prepared by adding the artificial
strawberry flavor and artificial cream flavor to about 794 kg of
water with agitation. A nutritional product according to the
present invention has been manufactured using an artificial
strawberry flavor distributed by Firmenich Inc., Princeton, N.J.,
U.S.A. under the trade designation "Art. strawberry 57.883/A" and
an artificial cream flavor distributed by Firmenich Inc. under the
trade designation "Art Cream 59.200/A". The flavor solution is then
added to the blended slurry with agitation.
[0082] A color solution is prepared by adding the FD&C Red Dye
No. 3 to about 121 kg of water with agitation. The color solution
is then added to the blended slurry with agitation.
[0083] If necessary, diluted potassium hydroxide is added to the
blended slurry such that the product will have a pH in the range of
6.4 to 7.0 after sterilization. The completed product is then
placed in suitable containers and subjected to sterilization. Of
course, if desired aseptic processing could be employed.
[0084] The product made according to the procedure of this example
contains the oil blend of Table 8, below, the the fatty acid
properties of Tables 2 and 3, and the amino acid profile of Table
4, all set forth above.
8TABLE 8 OIL BLEND (% total weight of lipid blend) OIL Percent
Total Lipids Canola 9.3% MCT 16.2% Fish 65.0% Soybean 5.5% Soy
lecithin 4.0%
EXAMPLE II
[0085] The objective of this experiment was to evaluate the
organoleptic characteristics of nutritional composition of the
invention fortified by the addition of branched-chain amino acids
incorporated at two different levels. To measure organoleptic
properties, three taste standards, described in Table 9, were
prepared to rank the bitter and sour intensity of the test
compositions containing branched-chain amino acids.
9TABLE 9 TASTE INTENSITY SCALE Basic Concentration* Representative
Standard Taste Intensity by Weight Products 1 Sour 1 0.05% Citric
Acid Milk Chocolate, Coffee Whole Peanuts 2 Bitter 1 0.05% Caffeine
Milk Chocolate 3 Bitter 2 0.10% Caffeine Beer *Aqueous
solutions
[0086] Two test compositions (designated "high" and "low") were
prepared by adding selected branched-chain amino acids ("BCAA") to
the liquid nutritional composition of Example I. A control
composition of Example I that did not contain the supplemental
branched-chain amino acids was also evaluated for flavor
characteristics. The specific amino acids and amounts added are
given in Table 10. In both test compositions the branched-chain
amino acids did not completely disperse in the nutritional
composition due to their hydrophobic nature, and small clumps of
branched-chain amino acids were visible in the matrix. The test
compositions were evaluated and the results of the organoleptic
test scoring are also set forth in Table 10.
10TABLE 10 BRANCHED-CHAIN AMINO ACID FORTIFICATION "high" test
"low" test control BCAA in gm/237 mL serving valine 2.5 1.3 0
leucine 2.5 1.3 0 isoleucine 2.5 1.3 0 Total 7.5 3.9 0 TASTE TEST
SCORE bitter 1.5 to 2 1.5 none sour 0.5 0.5 none
[0087] Based on the results of this taste session, the evaluators
collectively agreed that the bitter and sour flavor notes
attributed to the branched-chain amino acids are less than ideal
for a ready-to-use oral nutritional composition. Thus, in one
embodiment of this invention, any additional branched-chain amino
acids are supplied to patient in the form of a pill or capsule
distinct from the liquid nutritional of the invention..
EXAMPLE III
[0088] The effect of nutritional intervention with .omega.-3 fatty
acids, branched-chain amino acids and antioxidants in the
nutritional compositions of the invention, on prevention and
treatment of cachexia can be monitored by any of the methods known
to one skilled in the art, including but not limited to measuring:
(i) food intake, body weight and anthropometric measurements; (ii)
serum levels of lipids, fatty acids, amino acids and antioxidants;
(iii) levels of serologic markers where appropriate, e.g.,
carcinoembryonic (CEA) antigens, serotonin, C-reactive protein, TNF
and IL-1; (iv) changes in the morphology of tumors using techniques
such as computed tomographic (CT) scan, ultrasonography, magnetic
resonance imaging (MRI) and position emission tomography (PET).
[0089] Patients with hepatocellular carcinoma showing symptoms of
cachexia are provided with the nutritional product of the invention
with small, frequent feedings after surgical resection if the liver
tumor is localized and small, or along with a regimen of
chemotherapy. The liver functions and characteristics of the
hepatic carcinomas are tested by procedures known in the art.
[0090] The daily nutritional management of liver cancer, therefore,
includes administration of 2 to 4 containers of 8 ounce servings
(237 mL) of the nutritional composition providing a daily amount
of: (i) combined EPA and DHA in the range of 3 to 6 g, with the
preferred dosage being about 3 g; (ii) branched-chain amino acids
in the range of 5 to 25 g, with the preferred dosage being about
10-15 g branched-chain amino acids; and (iii) vitamin C in the
range of 125 to 500 mg, with the preferred dosage being about 300
mg vitamin C; (iv) vitamin E in the range of 50 to 250 IU, with the
preferred dosage being about 150 IU vitamin E; (v) beta-carotene in
the range of 1250 to 3250 .mu.g, with the preferred dosage being
about 2500 beta-carotene .mu.g; (vi) selenium in the range of 40 to
60 .mu.g, with the preferred dosage being about 45 .mu.g selenium.
The effect of nutritional intervention on cancer cachexia and
anorexia are monitored at monthly intervals (or as recommended in
the clinical follow-up) as known in the art, and depending on the
results obtained, the therapeutic regimen is developed to maintain
andlor boost the weight gain by the patient, with the ultimate goal
of achieving tumor regression and complete eradication of cancer
cells.
[0091] For the underweight breast cancer patient on adjuvant
chemotherapy, administration of the nutritional composition of the
invention is started any time after surgery. The nutritional
composition used in breast cancer patients is designed to maintain
an adequate intake in spite of nausea, mucositis, and other side
effects of chemotherapy. Patients receiving radiation therapy for
breast cancer receive effective amounts of the nutritional
composition to promote maintenance and repair of body tissue. The
therapeutic and/or prophylactic regimens used in breast cancer
patients are the same as those described in Section 6 above for
patients recovering from hepatocellular carcinoma. The procedures
of monitoring the patient under clinical evaluation for prevention
and treatment of cachexia and anorexia in breast cancer are known
in the art.
EXAMPLE IV
[0092] A pilot study was conducted to assess the effectiveness of a
specific formula in ameliorating the cachexia of cancer patients.
The formula of Example I was prepared. In addition to other
nutrients, it contained (per two 237 mL servings) the long-chain
.omega.-3 fatty acids, the fructooligosaccharide ("FOS") and the
antioxidant system specified in Table 10.
11TABLE 10 TRIAL PRODUCT Ingredient Amount per 2 .times. 237 mL
servings EPA .omega.-3 2.0 gm DHA .omega.-3 0.92 gm
fructooligosaccharide 5.8 gm beta carotene 2.8 mg vitamin C 300. mg
vitamin E 150. IU selenium 58. mcg
[0093] In the pilot clinical trial of this example, ten patients
with pancreatic cancer were evaluated. These patients were
cachectic and losing weight at a mean rate of 0.86 kg per week over
an average of 22 weeks (range: 11 to 56 weeks) prior to the trial.
Over a three week trial period, patients consumed an average of two
237 mL (8 fluid ounces) servings per day as a supplement to their
diets. After the trial period the group demonstrated a mean
increase in weight of 2.1 kg (up from baseline), which translates
to a mean weekly weight gain of 0.7 kg (See Table 11).
12TABLE 11 Patients' Age, Gender and Weight Status Mean Weekly
Weight after Mean Weekly Patient Age Wt (kg) Change Baseline three
week Wt change Patient and Gender up to Baseline weight (kg) trial
(kg) during trial 1 56 f -0.4 51 51.75 0.25 2 64 m -1.2 67 na na 3
70 m -0.5 61 67.5 2.17 4 60 m -0.9 43 44 0.33 5 53 f -1.4 90 90.5
0.17 6 51 f -1.2 44.5 45.5 0.33 7 67 m -0.6 57 58 0.33 8 75 f -0.8
55 59 1.33 9 57 m -0.6 69 na na 10 53 f -1 57.5 na na Mean -0.86
0.7
[0094] In addition, much of the weight gained was lean body mass.
The group demonstrated a mean increase in lean body mass of 2.1%
and a decrease in C-reactive protein ("CRP") levels (See Table 12).
Serum CRP is a biochemical surrogate for the presence and progress
of cancer cachexia, and shows a strong positive correlation.
(Falconer, J. S. et al., Cancer 1995, 75:2077). Patients with serum
CRP levels >10 mg/L are frankly cachectic. The mean CRP level at
baseline was 31.5 and this dropped to about 10 after 3 weeks on the
experimental formula of the invention. Thus, the invention improves
cachexia in pancreatic cancer patients.
13TABLE 12 Patients' Lean Body Mass and CRP CRP after % Lean % Lean
Change in % Baseline 3 week Pa- Body Mass Body Mass Lean Body CRP
trial tient at Baseline after trial Mass mg/L mg/L 1 79.4 82.9 3.5
69 <10 2 85.6 na na 81 na 3 84 92.2 8.2 27 <10 4 85.6 86.3
0.7 <10 <10 5 73.7 75 1.3 <10 <10 6 79.7 80.7 1 63
<10 7 90.2 91.9 1.7 <10 10 8 81.4 80.1 -1.3 <10 <10 9
82.6 na na 25 na 10 86.9 na na <10 na Mean 82.9 84.2 2.1 31.5
10* *CRP values read as <10 are assumed to be 10 for calculation
of mean
[0095] The present invention is not to be limited to the scope by
the specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description. Such modifications are intended to fall
within the scope of the appended claims.
[0096] Various publications and patents are cited herein, the
disclosures of which are incorporated by reference in their
entireties.
* * * * *