Weight loss abstract
Animal feed or human food which contains added conjugated linoleic
acids (CLA) can enhance growth and prevent anorexia and weight loss
due to immune stimulation (e.g., endotoxin exposure) and the adverse
effects of catabolic hormones (i.e., IL-1). Methods of treatment
using CLA also are disclosed.
Weight loss claims
1. A method of preventing weight loss, reduction in weight gain
or anorexia in an animal caused by immune stimulation of the animal
by endotoxin, said method comprising administering orally or parenterally
to said animal a safe amount of a member selected from a conjugated
linoleic acid, free linoleic acid, salts thereof and mixtures thereof,
said amount being effective to prevent the weight loss, reduction
in weight gain or anorexia caused by the immune stimulation.
2. A method of claim 1 in which the animal is a bird.
3. A method of claim 1 in which the conjugated linoleic acid is
selected from 9,11-octadecadienoic acid and 10,12-octadecadienoic
4. A method of alleviating the adverse catabolic effects produced
by a product of the immune system which is released after immune
stimulation of an animal by endotoxin, said method comprising orally
or parenterally administering to said animal a safe amount of a
member selected from a conjugated linoleic acid, free linoleic acid,
salts thereof and mixtures thereof, said amount being effective
to alleviate said adverse catabolic effects produced by a product
of the immune system.
5. A method of claim 4 in which the conjugated linoleic acid is
selected from 9,11-octadecadienoic acid and 10,12-octadecadienoic
6. A method of alleviating the adverse catabolic effects produced
by interleukin-1, said method comprising administering orally or
parenterally to an animal a safe amount of a member selected from
a conjugated linoleic acid, free linoleic acid, salts thereof and
mixtures thereof, said amount being effective to alleviate said
adverse catabolic effects.
7. A method for improving an animal food so as to prevent the weight
loss, the reduction in weight gain or the anorexia which can be
caused by immune stimulation of an animal by endotoxin, said method
comprising adding to an animal food a member selected from 9,11-octadecadienoic
acid; 10, 12-octadecadienoic acid; and mixtures thereof, so that
the food contains about 0.1% to about 2.0% by weight of the food,
said amount being effective when the food is fed to an animal to
prevent the weight loss, the reduction in weight gain or the anorexia
caused by immune stimulation.
Weight loss description
FIELD OF THE INVENTION
The present application generally relates to an animal feed additive
and a pharmacologic agent for use in humans. More particularly,
it relates to a feed additive/pharmacologic agent which prevents
weight loss or reduction in the rate of weight gain and to methods
relating to its use.
BACKGROUND OF THE INVENTION
Researchers have observed anorexia and weight loss or reduction
in weight gain in humans and animals that have been exposed to immune
stimulants, such as endotoxin (LPS). The intraperitoneal injection
of lipopolysaccharide (i.e. endotoxin) into chickens decreases food
intake and growth rate for 24 hours, alters nutrient metabolism,
and induces fever.
Recent studies (Klasing et al., 1987, J Nutr. 117:1629) have confirmed
that the vaccination of domestic fowl with several immune stimulants
also can result in a substantial reduction in feed intake and induce
weight loss or decreases in weight gain. In a study recently conducted
with white Pekin ducks, two vaccinations reduced final carcass weight
by as much as 0.4 lbs./bird and breast meat by 0.075 lbs./bird.
Broilers and Single Comb White Leghorns (egg laying chickens) also
have been observed to have reduced weight gains following immune
stimulation. The potential losses due to immune stimulation costs
the poultry industry millions of dollars per year. At the present
time, antibiotics are used to prevent such weight loss but the use
of antibiotics for this purpose is expensive and not without disadvantages.
In a similar manner anorexia, weight loss, and reduced growth of
humans that are subjected to chronic immune stimulation because
of infections, surgery, or exposure to immune stimulants is devastating
to health and well being.
The mechanism by which immune stimulation causes anorexia, weight
loss and reduced growth is known to be mediated by catabolic hormones
released following immune stimulation (i.e., macrophage cytokine
known as interleukin-1 or IL-1). The production of IL-1 from macrophages
simultaneously stimulates T-cells to release IL-2, an anticarcinogenic
compound which is desirable, but the release of IL-1 and other catabolic
hormones from stimulated macrophages and possibly other immune-regulated
cells induces an undesirable systemic reduction in skeletal muscle
synthesis and increased muscle degradation resulting in weight loss
or a decline in weight gain. Thus, while IL-1 and related immune
hormones are essential cytokines for immune function, their systemic
hormonal effects are devastating and have prevented its acceptance
for immune therapy.
There is a need for feed additives, pharmacologic agents, and methods
which can enhance growth and prevent the weight loss and anorexia
that follows immune stimulation. There also is a need for a feed
additive, pharmacologic agent, and method that can counteract the
adverse effects of IL-1 and other hormones that induce tissue catabolism.
BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to disclose a feed additive,
pharmacologic agent, and methods of using the feed additive and
pharmacologic agent which prevent the weight loss and anorexia following
It also is an object to disclose a method to counteract the adverse
effects of catabolic hormones, such as IL-1.
We have discovered that the conjugated linoleic acids 9,11-octadecadienoic
acid and 10,12-octadecadienoic acid (CLA) are valuable animal feed
additives and potential pharmacologic agents which can enhance growth
and prevent the weight loss that follows immune stimulation in animals,
including humans..We also have discovered that the administration
of safe and effective amounts of CLA to an animal can prevent the
adverse effects of immune stimulation.
It will be apparent to those skilled in the art that the forementioned
objects and other advantages may be achieved by the practice of
the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
In a preferred embodiment of the invention a safe and effective
amount of CLA is added to the food of an animal or human which has
been or may be subjected to vaccination or other exposure to immune
stimulants. The amount of CLA to be used as a feed or food additive
is an amount which is safe and effective under conditions of use
to prevent weight loss and/or enhance the growth of the animal to
which it is administered. Because of the difference in size and
susceptibility of animals and humans to the adverse effects of immune
stimulation the amounts which are safe and effective will vary considerably.
However, since CLA is a natural food ingredient and it is relatively
non-toxic, the amount which can be administered is not critical
as long as it is enough to be effective.
The practice of the present invention is further illustrated by
the examples which follow:
Four pens of 10 chicks were fed a standard poultry ration with
0.5% lard (controls) or with 0.5% CLA mixed daily (2 pens per treatment).
When the chicks were 3 weeks of age, they were weighed, inoculated
with 100 .mu.g of E. Coli 0111:B4 endotoxin i.p. to stimulate the
immune system. Chicks were again weighed 24 h later. While the chicks
feed the unsupplemented diet failed to gain body weight following
endotoxin exposure, the chicks fed CLA gained 10 grams (p<0.07)
(Table I). Antibody responses to sheep red blood cells demonstrated
that CLA had no effect on antibody synthesis.
TABLE 1 ______________________________________ Av. Wt. Av. 24h
post Av. initial % with no or Treatment Initial Wt. endotoxin 24h
negative gain ______________________________________ Control 311
.+-. 12 311 .+-. 12 0 .+-. 3 53 .5% CLA 305 .+-. 9 315 .+-. 9 10
.+-. 4 27 ______________________________________
Another group of chicks were fed a diet containing 0.5% CLA which
was mixed with the feed daily. At 3 weeks of age the chicks were
inoculated i.p. with 750 .mu.g E. Coli 055:B5 endotoxin to stimulate
immunity or phosphate buffered saline (PBS) as a control. The control
chicks injected with PBS gained 9 g over the following 24 h period,
and the CLA fed, PBS injected chicks gained 13.5 g. When chicks
fed the control diet were injected with endotoxin, they lost 1.3
g of body weight over the following 24 h period. However, the CLA
fed chicks even after endotoxin injection continued to gain an average
of 6.6 g.
The results of the examples demonstrate that a lower proportion
of chicks lose weight, within 24 hours of being injected with endotoxin,
when the chicks ingest an animal feed which contains CLA. In fact,
the results show that not only do a fewer number of birds lose weight
but that those birds that are fed CLA actually gain considerably
more weight than the control birds. In addition, the loss of body
weight in rats following stimulation was 50% of those not fed CLA.
In addition to using CLA as an animal feed additive (e.g. poultry
feed) to enhance growth and prevent weight loss by diminishing the
effects of immune stimulation, CLA is useful as an immune modulator
(e.g. IL-1 inhibitor). The adverse or harmful catabolic effects
of systemic IL-1 may be alleviated by adding CLA to the food of
animals, including humans, experiencing weight loss associated with
acute or chronic diseases.
A group of seven rats was fed a semi-purified diet to which CLA
was not added; a second group was fed the same diet containing 0.5%
CLA. Three weeks later the animals were weighed. Four animals from
each group were inoculated with endotoxin (1 mg/kg body weight);
the remaining three animals from each group were inoculated with
PBS. Rats fed the control diet and injected with PBS gained 7.4
g. Rats fed the CLA-containing diet and injected with PBS gained
5.4 g. Rats fed control diet and injected with endotoxin lost 21.05
g. Rats fed CLA-containing diet and injected with endotoxin lost
only 11.9 g.
In another embodiment of the invention a fatty acid that is converted
into CLA or which modulates the level of CLA in the body of an animal
or a human is fed. Specifically, we have found that linoleic acid
is converted to CLA in the bodies of rats, probably by microorganisms
in the gastrointestinal system (S. F. Chin, W. Liu, K. Albright,
and M. W. Pariza, 1992, FASEB J. 6:Abstract #2665).
A group of seven rats was fed a semi-purified diet containing 5%
corn oil; a second group was fed the same diet with corn oil but
also containing added free linoleic acid (0.5%). Three weeks later
the animals were weighed. Four animals from each group were inoculated
with endotoxin (1 mg/kg body weight); the remaining three animals
from each group were inoculated with PBS. Rats fed the control diet
and injected with PBS gained 7.4 g. Rats fed the diet to which linoleic
acid had been added, and injected with PBS, gained 7.2 g. Rats fed
control diet and injected with endotoxin lost 21.05 g. Rats fed
diet to which linoleic acid had been added, and injected with endotoxin,
lost only 11.4 g. We believe these results are due to the conversion
of added linoleic acid to CLA within the body of rats as discussed
The methods of the present invention may take several embodiments.
In one embodiment, the CLA is added to an animal's feed or to a
human's food. In another embodiment, the CLA can be administered
to an animal in a pharmaceutical or veterinary composition containing
a safe and effective dose of the CLA. In a third embodiment, the
animal can be fed a safe amount of the reactants which will form
the CLA in situ in the animal or human.
The novel animal feeds and pharmaceutical preparations of the present
invention are those containing the free conjugated linoleic acids
(CLA) 9,11-octadecadienoic acid and 10,12-octadecadienoic acid in
combination with a conventional animal feed (e.g. poultry feed),
human food supplement, or approved pharmaceutical diluent. Active
forms of CLA also include compositions containing the active isomers
of CLA; non-toxic salts thereof; active esters and other active
chemical derivatives thereof; and mixtures thereof. Animals and
humans may also be given a substance such as linoleic acid which
is converted to CLA within the body, or which may modulate intracellular
levels of CLA or otherwise mimic the beneficial effects of CLA in
mitigating anorexia, weight loss, and reduced growth resulting from
The free conjugated linoleic acids (CLA) have been previously isolated
from fried meats and described as anticarcinogens by Y. L. Ha, N.
K. Grimm and M. W. Pariza, in Carcinogenesis Vol. 8, No. 12, pp.
1881-1887 (1987). Since then, they have been found in some processed
cheese products. Y. L. Ha, N. K. Grimm and M. W. Pariza, in J. Agric.
Food Chem., Vol. 37, No. 1, pp. 75-81 (1987). However, animal feeds
containing CLA, or its non-toxic derivatives, such as the sodium
and potassium salts, as an additive in combination with conventional
animal feeds or human foods are novel.
The free acid forms of the CLA may be prepared by isomerizing linoleic
acid. The non-toxic salts of the free CLA acids may be made by reacting
the free acids with a non-toxic base. Natural CLA may also be prepared
from linoleic acid by the action of .DELTA..sup.12 -cis, .DELTA..sup.11
-transisomerase from a harmless microorganism such as the Rumen
bacterium Butyrivibrio fibrisolvens. Harmless microorganisms in
the intestinal tracts of rats and other monogastric animals may
also convert linoleic acid to CLA (S. F. Chin, W. Liu, K. Albright
and M. W. Pariza, 1992, FASEB J.6:Abstract #2665).
The CLA obtained by the practice of the described methods of preparation
contains one or more of the 9,11-octadecadienoic acids and/or 10,12-octadecadienoic
acids and active isomers thereof. It may be free or bound chemically
through ester linkages. The CLA is heat stable and can be used as
is, or dried and powdered. The CLA is readily converted into a non-toxic
salt, such as the sodium or potassium salt, by reacting chemically
equivalent amounts of the free acid with an alkali hydroxide at
a pH of about 8 to 9.
Theoretically, 8 possible geometric isomers of 9,11- and 10,12-octadecadienoic
acid (c9,c11; c9,t11; t9,c11; t9,t11; c10,c12; c10,t12; t10,c12
and t10,t12) would form from the isomerization of c9,c12-octadecadienoic
acid. As a result of the isomerization, only four isomers (c9,c11;
c9,t11; t10,c12; and c10,c12) would be expected. However, of the
four isomers, c9,t11- and t10,c12- isomers are predominantly produced
during the autoxidation or alkali-isomerization of c9,c12-linoleic
acid due to the co-planar characteristics of 5 carbon atoms around
a conjugated double-bond and spatial conflict of the resonance radical.
The remaining two c,c-isomers are minor contributors.
The relatively higher distribution of the t,t-isomers of 9,11-
or 10,12-octadecadienoic acid apparently results from the further
stabilization of c9,t11- or t10,c12-geometric isomers, which is
thermodynamically preferred, during an extended processing time
or long aging period. Additionally the t,t-isomer of 9,11- or 10,12-octadecadienoic
acid that was predominantly formed during the isomerization of linoleic
acid geometrical isomers (t9,t12-, c9,t12- and t9,c12-octadecadienoic
acid) may influence the final ratio of the isomers or the final
CLA content in the samples.
Linoleic acid geometrical isomers also influence the distribution
of minor contributors (c,c-isomers of 9,11- and 10,12-, t9,c11-
and c11,t12-octadecadienoic acids). The 11,13-isomer might be produced
as a minor product from c9,c12-octadecadienoic acid or from its
isomeric forms during processing.
To enhance growth, prevent weight loss or counteract the adverse
effects of catabolic hormones, the CLA and its non-toxic derivatives,
such as the non-toxic salts, in addition to being added to an animal's
feed or human food or formed in situ can be administered in the
form of pharmaceutical or veterinary compositions, such as tablets,
capsules, solutions or emulsions to the animal or the humans. The
exact amount to be administered, of course, depends upon the form
of CLA employed, the route of administration, and the nature of
the animal's or human's condition or disease. Generally, the amount
employed of CLA and its non-toxic salts employed as a pharmaceutical
will range from about one part per million (ppm) to about 10,000
ppm of CLA in the animal's or human's diet. However, the upper limit
of the amount to be employed is not critical because CLA is relatively
non-toxic and it is a normal constituent of the human diet (including
human breast milk). The amounts to be added to a conventional animal
feed or human's food as an additive can range from 0.01% to 2.0%
or more by weight of the animal's or human's food.
The preferred pharmaceutical and veterinary compositions of CLA
contain the non-toxic sodium or potassium salt of CLA in combination
with a pharmaceutical diluent. When the compositions are solutions
or suspensions intended for oral administration the diluent will
be one or more diluents, such as lactose or starch, and the product
will be a tablet, capsule or liquid. When the compositions are solutions
or suspensions intended for parenteral administration the preferred
diluent will be Sterile Water for Injection U.S.P.
It will be readily apparent to those skilled in the art that a
number of modifications or changes may be made without departing
from the spirit and scope of the present invention. Therefore, the
invention is only to be limited by the claims.