Note: Descriptions are shown in the official language in which they were submitted.
2~3438o
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8 P E C I F I C A T I O N
"COMPO8ITION BA8FD ON A INO ACID8 INTENDED FOR T~E `~ ~
TR~AT~EN$ OF 8FP8I8 OR OF AN ATTAC~ BRINGING ABOUT -i ~ y
aN INFLANMATORY RFACTION, IN ANIMAL8 aND MaN"
BACKGROUND OF THE INVENTION i i
The present invention relates to compositions based ~,?"~
on amino acids for preventing and/or reducing tissue
damage brought about by multiple metabolic dysfunctions
which appear, especially as a result of a sepsis. ~ ~`
Infection may be independent of any other pathology,
but infection most commonly occurs in man after a
surgical operation or is associated with a trauma, a ~-
burn, diabetes, a cirrhosis, a neoplasm, or the like.
Infection may also occur during treatment with
immunosuppression, cytolytic or cytostatic agents.
Septic illnesses are also strongly correlated with a
state of malnutrition, very especially in young children
and in elderly people. Such illnesses are also found in ;
animals such as domestic animals and especially in
industrial stockraising (pigs, chickens, and the like).
The metabolic response to infection is complex and,
up to the present, very many issues still remain
unexplained. This complexity results in particular from
the participation of many factors: modification in the
supplies of the substrates to the various organs and in
their use, variation in the sensitivity and the
reactivity of the tissues to the hormones, for example ;
resistance to insulin, change in blood flow rates,
participation of many mediators such as PAF, or cytokines
(interleukins, TNF, and the like), the pharmacological
effects of which may be in conflict according to the
tissue under consideration.
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The response to infection is dynamic, with several
pha~es whose intensity and duration depend on the
severity of the attack and on the ti~e at which infection
occurs with respect to the attack. Three periods are
usually distinguished (Cuthbertson, 1942). The "ebb
phase" - the 24 hours after the attack which is
characterized by a rapid mobilization of the energetic
substrates and a reduced metabolic activity. The ebb
phase is followed by the "flow phase", the duration of
which varies from a few days to 2 to 3 weeks. This
period sees a metabolic activity increase with the result
of a general catabolism of the tissues, in particular of
the muscle. The last phase, in survivors, corresponds
to the convalescence, which is anabolic.
The present invention is more particularly targeted
at treating or preventing by nutritional compositions the
dysfunctions which take place in the first two phases.
These phases are characterized by the existence of an
anorexia and a hypermetabolic response which is reflected
clinically by the weight loss and especially a wasting
away in muscle proteins, by an inflammatory state, the
existence of a tachycardia, a hyperventilation, an
increased oxygen consumption, a disfunction of the immune
system, and the like.
Accelerated loss in proteins from the muscle is used
to deal with~
- the increased requirements for glucose of the body
by means of hepatic neoglucogenesis and for glutamine,
an essential energy source for the cells of the
intestinal mucous membrane or for the rapid
multiplication cells of the immune system,
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- the amino acid requirements for the increased
protein syntheses of several organs, in particular of
inflammatory proteins in the liver.
The actions of the hormones and of certain
mediators, such as a-TNF, have been the subject and still
form the subject of many evaluations. Although certain
mechanisms are beginning to be better explained, with
respect to the specific nutritional requirements and more
particularly those which concern amino acids, very little
is known in the case of sepsis or of post-attack
inflammatory reactions.
SUMMARY OF THE INVENTION
The present invention provides a method and
composition for treating sepsis.
To this end, the present invention provides, in an
embodiment, a composition comprising a biologically and
nutritionally acceptable medium and including at least
one component for providing cysteine chosen from the
group consisting of free cysteine, cysteine precursor,
cysteine prodrug, protein including cysteine and peptide
hydrolysate containing cysteine, the component for
providing cysteine being present in a proportion so that
the pharmacologically active cysteine that is provided
to an individual that ingest the composition is greater
than the proportion of cysteine present in a nutritional
composition that corresponds to the requirements of a
healthy man, the proportion of cysteine being determined
with respect to all the amino acids present in the
composition.
In an embodiment, the cysteine in the
pharmacologically active form is present in a proportion
equal to or greater than 3% with respect to all the amino
acids present in the composition.
.... ; . . . ~ . ~. .. , . .. , ... . .. .. . - -
213~380
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In an embodiment, the amount of nitrogen from the ;;~
cysteine is greater than or equal to 2.15% with respect ;;
to the total amount of nitrogen.
In an embodiment, the composition includes threonine
in proportions equal to or greater than 5% by weight with
respect to the other amino acids that are present in the
composition.
In an embodiment, the composition includes serine ~;
in proportions equal to or greater than 12% by weight
with respect to the other amino acids that are present
in the composition. -
In an embodiment, the composition includes at least
aspartic acid in proportions greater than or equal to
10%, these proportions being determined with respect to
the amount of amino acid present in the composition.
In an embodiment, the composition includes at least ~ i
asparagine in proportions greater than or equal to 10%, ~ -~
these proportions being determined with respect to the
amount of amino acid present in the composition. ;; ~;
In an embodiment, the composition includes leucine, ~ ~;
isoleucine, valine, tryptophan, phenylalanine, lysine, ;- :
methionine and threonine. .
In an embodiment, the composition includes glycine.
In an embodiment, the composition includes arginine
In an embodiment, the composition includes taurine
In an embodiment, the composition includes ~ ~-
glutamine.
- In an embodiment, the amino acids are present in a
free form.
In an embodiment, the composition contains, per one ~ ~ `
liter~
Leucine 5 to 12 g/l
Isoleucine 3 to 10 g/l ~ ~;
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Valine 5 to 10 g/l
Tryptophan 1.0 to 3 g/l -~
Phenylalanine 1.5 to 7 g~
Lysine 2 to 7 g/l
Methionine 1.5 to 5 g/l
Threonine 3.0 to 7 g/l.
In an embodiment, cystine is present in the form of
a prodrug.
In an embodiment, the composition includes L-
oxothiazolidine-carboxylic acid.
In an embodiment, the composition includes salts of
L-oxothiazolidine-carboxylic acid. ;
In an embodiment, the composition is in the form of
a solution.
In an embodiment, the composition is provided as a
complete nutritional composition intended for parenteral
administration and includes a carbohydrate calorie
source, a lipid calorie source, electrolytes, trace
elements and vitamins.
In an embodiment, the composition is provided in the
form of a nutritional enteral composition a calorie
source, a carbohydrate, a lipid calorie source,
electrolytes, trace elements and vitamins.
In an embodiment, the composition is provided in the ~ ~
form of a powder which can be rehydrated at the time of ~ ~;
administration.
The present invention also provides a method for ;~
preventing or decreasing tissue damage brought about by
metabolic dysfunctions.
The present invention also provides a method of
treating sepsis or to an attack bringing about an
inflammatory reaction.
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Additional features and advantages of the present
invention are described in, and will be apparent from,
the detailed description of the presently preferred
embodiments.
DETAILED DESCRIPTION
OF THE PRESENTLY PREFERRED EMBODIMENTS
The inventors have determined that the sudden
stimulation of the syntheses of a large number of
inflammatorv and defensive proteins, vital for the body,
secreted in low amounts in the normal physiological
situation, rich in certain amino acids is required in
particular, in the case of sepsis. During this acute
phase, in view of the state of anorexia of the patients
or the animals, the synthesis of these proteins implies
that the body degrades significant amounts of muscle
proteins or other proteins, in order to have available
a sufficient amount of these amino acids. The increased
consumption of glutamine, as an energy source, by the
digestive system during various attacks, is an
illustration thereof.
The hepatic proteins of inflammation, such as C~
reactive protein, ~1-l-antichymotrypsin, ~1-acid
glycoprotein, fibrinogen,haptoglobulin,~2-macroglobulin
(in rats) or metallothioneins, contain a high percentage
of cysteine, serine, aspartic acid, asparagine and
threonine compared with those of muscle proteins.
Threonine, aspartic acid and asparagine are amino acids
to which are bonded the constituent carbohydrate units
of these various glycoproteins.
During the defensive reactions, as a result of the
state of anorexia, the body, in order to synthesize these
various vital proteins, must significantly degrade its
muscle proteins in order to cover these specific
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requirements. This is all the more true since myofibril
proteins, the proteins of the inflammatory reaction,
generally have short half-lives. ~ ~-
By providing for the amino acid requirements not
only makes it possible for the body to improve the
syntheses of vital proteins but also makes it possible
to avoid the loss of muscle proteins. As the body does
not have reserve proteins, any amount of lost proteins
corresponds to a loss of function. The reduction in the
muscle proteins not only leads to a detrimental change
in the respiratory capacities of the patient but also in
his motor capacities. There follows a long period of
convalescence, given that the regeneration of myofibril
proteins is slow. By providing the necessary ~ ~
requirements this leads to a shorter sickness time and ~ ',;
makes it possible to shorten the period of
hospitalization. It also makes possible a better
protection return for domestic animals.
It has also been determined that, during the period ;~
of shock due to sepsis, with the existence of a
persistent hypermetabolism, there exists an abundant -~
production of free radicals. The harmful effects of free
radicals have been widely described. To control these
oxidizing processes, the body has available antioxidizing
substances and "radical traps." Glutathione, a
tripeptide composed of glycine, glutamic acid and
cysteine, is one of the most abundant of these
substances. The increased requirement for this
derivative involves, for the body, having available for
its synthesis a sufficient amount of the three amino
acids which constitute glutathione.
The loss of glutathione, at the cell level, has
deleterious metabolic consequences for the body: in
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~ 2~3~380 ~
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- 8 -
addition to its role as a free radical captor,
glutathione is involved in many reactions of the
metabolism (coenzyme of enzymatic ~eactions, synthesis
of deoxyribonucleotides, metabolism of xenobiotics,
intracellular reducing agent) and it is itself a cysteine
reserve, directly available for protein synthesis.
The inventors have discovered, after developing a
sepsis model in rats, consisting of a single injection
of living bacteria (E. coli) which keeps the animals in
a catabolic situation lasting several days, that the
requirement for certain amino acids had increased.
It was determined that, during the induced sepsis,
there is observed in the septic animals, as compared to
"pair-fed" animals, a significant loss in weight. This
weight lost, lasted two or three days, with the
institution of a severe anorexia. It was also found in
the septic animals that there was a high level of
circulating ~-TNF greater than 10 ng/ml, a plasma content
of acid ~1-glycoprotein multiplied by 20 to 60, a
hyperglycaemia (1.82 g/l) and a hyperinsulinaemia (34.7
~u/ml)-
Measurements of protein synthesis, estimated by the
large dose technique, have shown, still with respect to
"pair-fed" animals, that, in the liver, the rate of
synthesis had increased from 1.8 to 2.7 times whereas,
in the muscle, it had decreased by 30%. In the latter
tissue, an increase in proteolysis is observed.
The protein synthesis of the whole body, less that
of the liver, is increased despite a large decrease in
muscle syntheses. This implies that, in other organs,
the syntheses are stimulated. It was possible, in
particular, to observe an increase in protein synthesis
in the spleen and lungs.
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The study of the fixation and oxidation balances of
the amino acids during this infection model has made it
possible, in fact, to determine an ihcreased requirement
for a number of essential and nonessential amino acids,
and more particularly in the liver. The protein content
of the liver of the infected rats increases by 42%
compared with the pair-fed controls. The inventors were
able to observe more particularly an increase in the
concentration of cysteine of the order of 74%.
The analysis of the amino acids content of the whole
body showed a large decrease in the infected animals,
except for the cysteine/cystine combination which
increases significantly by 9% with respect to the pair-
fed controls and for certain amino acids (threonine and
arginine), which are maintained at the same level. This
indicates a saving of these amino acids, since the
infected rats catabolize 3.7 and 54% less threonine and
cysteine respectively than the pair-fed controls, in
contrast to all the other indispensable amino acids which
show increased oxidations of 10 to 30% during the
infection.
Analysis of the distribution of radioactivity in the
different tissues after injection of L-[35S] cysteine
into rats in the above-mentioned model of infection
revealed an increased utilization of cysteine to
synthesize the proteins of the inflammatory reaction and
glutathione. In effect, the radioactivity incorporated
per gram of protein in the spleen and in the plasma
proteins minus albumin increases by 70% in infected
animals relative to their pair-fed controls. The
percentage of the injected dose occurring in a fraction
mainly containing cysteine and glutathione is,
respectively, 1.9 and 4 times as high in the liver and
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the spleen of infected animals compared with pair-fed
controls. ~-
The effect on weight loss of supplementing diets -
with amino acids confirmed the inventors' belief for an ~:
increased requirement for certain amino acids during an
infection. Three groups of animals receiving diets with ` ;``~
equal nitrogen contents were compared: a contxol group
(group C), a group receiving a diet supplemented with
threonine, serine, aspartic acid, asparagine and arginine
(group AA) and a group receiving a diet supplemented with
threonine, serine, aspartic acid, asparagine, arginine
and cysteine (group Cys). These supplementations enabled
the weight 108s to be limited and the resumption of
growth of the infected animals to be accelerated. Ten i~
days after infection, the animals' weight was 15%, 8% and
, . ::
2.5% lower than their initial weight in groups C, AA and
Cys, respectively. Increasing the cysteine content of
the diet from 0.8% to 6.7% led to an approximately 35%
reduction in the nitrogen excretion of the infected
animals relative to their pair-fed controls in the days
following infection. In this same study, supplementation
of the diet with cysteine enabled the glutathione
concentration in the liver to be normalized, the latter
concentration being decreased by a factor of the order
of 25% with the diet containing only 0.8~ of cysteine.
These results have made it possible for the
inventors to establish that, during sepsis in particular
and more generally during the triggering of highly
catabolic and hypermetabolic situations, the requirements
for cysteine and, on a lesser scale, for threonine,
serine, aspartic acid and asparagine, are markedly
increased.
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--` 213~3~0 :
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-- 11 --
The present invention provides compositions of amino
acids present in proportions such that they provide the
specific requirements for amino acids and make it
possible to avoid or to prevent the loss of significant
S mass of muscle proteins.
The present invention provides an amino acids
composition, intended to be administered orally,
enterally or parenterally, which makes it possible to
solve the above-identified problems.
In another embodiment, the invention provides the
use of a composition of amino acids, for the purpose of
treating tissue damage brought about by metabolic
dysfunctions which appear in particular as a result of
sepsis.
In another embodiment, the invention provides a
method for treatment and prevention of tissue damage
brought about by metabolic dysfunctions which appear
especially as a result of a sepsis.
The composition based on amino acids intended to be
administered orally, enterally or parenterally, in
accordance with the invention, contains, in a
biologically and nutritionally acceptable medium, at
least free cysteine or cysteine in the form of a prodrug
or proteins or hydrolysates which are rich in cysteine,
in a proportion of pharmacologically active cysteine
greater than the proportion of cysteine present in a
nutritional composition corresponding to the requirements
of a healthy man. The proportion of cysteine is
determined with respect to all the amino acids present
in the composition.
In a preferred embodiment of the invention,
cysteine, in the pharmacologically active form, is
present in a proportion equal to or greater than 3~ with
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respect to all the amino acids present in the
composition.
In an embodiment of the present invention, the
composition of amino acids in accordance with the
invention additionally contains at least threonine in
proportions equal to or greater than 5% and/or at least
serine in proportions equal to or greater than 12% and/or ;~
at least aspartic acid or asparagine in proportions equal
to or greater than 10%, these proportions being
determined with respect to the amount of amino acids `~
present in the composition.
In a preferred embodiment, the present invention
provides compositions as defined above containing the 8 ~:
essential amino acids, namely leucine, isoleucine,
valine, tryptophan, phenylalanine, lysine, methionine and
threonine.
According to another embodiment of the invention the
composition also contains glycine and/or arginine.
The composition in accordance with the invention can
also contain taurine and/or glutamine. ~;~
The compositions in accordance with the invention ;
are in an embodiment provided in a solution form, which
i8 a mixture of amino acids. In an embodiment, the
compositions can optionally be used in the form of their
pharmaceutically acceptable salts, in a medium consisting -
generally of distilled water. `~
The compositions in accordance with the invention ~''`'~A':~
can, in an embodiment, contain, per 1 liter of amino :
acids solutions, the following constituents in the
following amounts~
Leucine 5 to 12 g/l
Isoleucine 3 to 10 g/l ~ ~c
Valine 5 to 10 g/l
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213~3~0
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- 13 -
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Tryptophan 1.0 to 3 g/l
Phenylalanine 1.5 to 7 g/1
Lysine 2 to 7 g/l
Methionine 1.5 to 5 g/l
Threonine 3.0 to 7 g/l
This composition can optionally contain serine in
proportions from 2.5 to 6 g/l, aspartic acid in
proportions from 1.5 to 4 g/1, glycine in proportions
from 3 to 7 g/l, arginine in proportions between 5 and
10 g/l, taurine in proportions between 1 and 4 g/l, and
glutamine in proportions greater than or equal to 4 g/l.
Pursuant to the present invention, cysteine is
present in this composition in proportions equal to or
greater than 3% with respect to the total amount of amino
acids present. Preferably, the cysteine is present in
the composition at a level of between 3 to about 10% of
the total amino acids present.
According to another preferred embodiment of the
invention, threonine, as already ~hown above, is present
in proportions equal to or greater than 5% and is
preferably present at a level of between 5 to about 12%
with respect to the total amount of amino acids present.
Serine, when it is present, is preferentially
present in proportions equal to or greater than 12% and
preferably between 12 to about 16% with respect to the
total weight of amino acids present. Aspartic acid or
asparagine, when they are present, are preferably present
in proportions equal to or greater than 10% to about
preferably between 10 and 15% with resp~ct to the total
weight of amino acids present.
Cysteine, used in accordance with the invention, can
be used in a prodrug form or in the form of a
pharmaceutically acceptable salt, such as in the L~
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- 14
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oxothiazolidinecarboxylic acid form, especially when it ~ J,~
is desired to avoid maintaining high cysteine plasma
levels. It is well understood that it is possible to use ~ -
other cysteine precursors or derivatives which can be
converted to cysteine inside cells. Cysteine can be used ~ -
in the combined form with other amino acids such as in
the protein or peptide form. ;
The amounts of prodrug or cysteine precursors,
peptide or protein are determined on the basis of the ;
cysteine which is capable of being released from these ;
derivatives. ;
, .~
It is also possible to use the other amino acids
mentioned above in the form of precursors or prodrugs, ~ ;
such as, for example, in the dipeptide form, especially
in the case of aspartic acid and/or of asparagine.
The compositions in accordance with the invention
can be provided not only in an aqueous solution form but
also in other forms. Thus it is that cysteine can be
administered simply by modifying existing enteral oral
formula by introducing therein the amount of cysteine
compatible with the proportions in accordance with the
invention. `
The supplementation of cysteine can also be carried ~ i:
out in preparations intended for oral or enteral
nutrition. It can be carried out, in this case, by the
use of proteins or peptide hydrolysates which are : ~ ,"'r"'"
naturally rich in cysteine/cystine. i~
The cysteine level must, in this case, also be : -
present in amounts greater than the proportion of
cysteine present in a composition intended for a healthy
man; this amount is determined with respect to all the
amino acids present in the free or combined form. It is
also possible to express the necessary amount by taking
::: ~ : ::: :
---`` 2~3~380 -
- 15 -
account of the nitrogen content contained in the cysteine
or of these precursors and that of the total amount of
nitrogen in the composition. The percentage represents
in this case the amount of nitrogen from the cysteine
with respect to the total nitrogen present.
Cysteine bonded in a protein or a peptide
hydrolysate is preferably present in proportions equal
to or greater than 3% with respect to all the amino acids
present in the free or bonded form in the composition.
When it is expressed as nitrogen content, the amount
of nitrogen from free cysteine or cysteine in the form
of one of its precursors, prodrug, protein or peptide
hydrolysate is greater than or equal to 2.15% with
respect to the total nitrogen. ~ '
The compositions of the present invention can be
provided in the form of a complete nutritional
composition intended for parenteral administration. Such
preparations can contain, besides the amino acids or ~ :
their derivates (peptides~, carbohydrate (glucose, - ~ i
fructose, sorbitol, and the like) and/or lipid (fatty ~ ;
acid triglycerides) calorie sources. The lipids can
contain long chains, medium chains, or short chains,
triglycerides. The composition can also contain ii~;
electrolytes, trace elements and vitamins. In these
nutritional compositions, cysteine or its precursors will
be present in proportions greater than 3% with respect
to the amount of amino acids present in the nutritive
composition. ~ -
The parenteral composition can be provided in the
form of an aqueous solution or non-aqueous solution,
suspension or emulsion.
When the composition is provided in the form of a
nutritional composition intended for the oral or enteral ~ ;
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- 16 -
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route cysteine will be present in proportions greater
than 3% with respect to the amount of amino acids present
in the nutritive composition. The supplementation of
cysteine or of other amino acids mentioned above is
obtained either with the amino acid itself, with a
prodrug or with proteins or peptide hydrolysates which
are particularly rich in the amino acid under
consideration (for example cysteine). This composition,
besides proteins, amino acids and peptides, can contain
carbohydrate (in the form of various hydrochlorides)
and/or lipid (triglycerides of fatty acids containing
long or medium chains, introduced in the form of oils of
various origins) calorie sources, electrolytes, trace
elements and vitamins.
Cysteine can also be premixed with the other amino
acids which can be used in the compositions in accordance
with the invention. The cysteine can also be provided
in the form of an aseptic powder which can be rehydrated
at the time of administration or can be stored in the
form of a frozen or refrigerated concentrate which is
defrosted and mixed to the suitable concentration at the
time of use.
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These compositions can be administered by devices
known in the methods of oral, parenteral or enteral
administration.
Another subject of the invention consists of a
method for preventing or decreasing tissue damage brought
about by metabolic dysfunctions. The treatment is
carried out using the compositions set forth above
parenterally or enterally. -
Another subject of the invention is the treatment
of tissue damage brought about by metabolic dysfunctions
which appear in particular as a result of sepsis, by
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213~380
- 17
administering, parenterally and enterally, to man or ;~
animals a sufficient amount of cysteine or of a ~- ~:``;;~.`
functional analogue as a defined above, in amounts which
are pharmacologically active and greater than the amount
of cysteine present in a nutritional composition ..
corresponding to the requirements of a healthy man or ..
animal.
The administration is more particularly carried out
orally, parenterally or enterally. The amount of .~
cysteine administered is equal to or greater than 3% with ~.. :; :.
respect to the total amount of amino acids administered - .
and is preferably between 3% and 10%. .
By way of example, and not limitation, the following . ~ ~
examples are provided. ." . , .~G
Examples 1 and 2 - The following amino acid solutions are ",.",,.. ,,~,.,'j:.,.,,!:,, ,"',
prepared~
Leu 7.2 g/l 7.2 g/l ;~
Ile 5.6 g/l 5.6 g/l :, :~
Val 5.6 g/l 5.6 g/l
Trp 1.2 g/l 1.2 g/l .
Phe 3.2 g/l 3-2 g/l
Lys 3.2 g/l 3.2 g/l
Met 2 g/l 2 g/l
Thr 4 g/l 6 g/l ~ 'h' ,j
Asp 8 g/l 8.5 g/l :~
Glu 2.4 g/l 2.4 g/l :
Ser 9.8 g/l 9.8 g/l
Gly 5-9 g/l 5 g/l
Ala 6.2 g/l 5.8 g/l .
Cys 2.5 g/l 4 g/l
Orn 2.4 g/l
~. ' '
2134380
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- 18 -
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Tyr 0.4 g/l 0.4 g/l
His 3.2 g/l 3 g/1
Arg 4.6 g/l ' 4.6 g/l ``... '`.!~.".'`',".'''',
Pro 3.2 g/l 3.2 g/l
Distilled water q.s. for 1 1
AAT 80.2 g/l 80.7 g/l .:~
Example 3 - The following amino acid solution is ..
prepared~
Leu 6 g/l .
Ile 4.5 g/l ;. '-';~
Val 4.5 g/l
Trp 1.2 g/l .,
Phe 3 g/l `~
Lys 3 g/l
Met 2 g/l .
Thr 6 g/l
Asp 8.5 g/l
Gln 8 g/l
Ser 9.8 g/l
Gly 4.8 g/l
Ala 4 g/l
Cys 4 g/l ~:. :;;
orn --
Tyr 0.4 g/l .
His 3 g/l .
".
Arg 4 g/l
Pro 3 g/l :~
Water q.s. for 1 1 .:
. AAT 81.1 g/l :~
Example 4 - The following amino acid solution is
prepared: ~:
" ~:
... . .
213~380
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.. ... . ~ . .... ~ .
, .. ...; .. ..
. . .. ~
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Leu 12 g/l .. :~;
Ile 9.3 g/l .
Val 9.3 g/l .. ~
Trp 2 g/l ~.
Phe 5.33 g/l
Lys 5.33 g/l .
Met 3.33 g/l . .. ,.`
Thr 10 g/l .,~
Asp 14.16 g/l
Glu 4 g/l
Ala 10 g/l ....
Cys 6.66 g/l . .;,j~'
Orn
Tyr 0.5 g/l
Aig 7.6 g/l
Pro 5.18 g/l
Water q.s. for 1 1
AAT 134.17 g/l
Examples 5 and 6 - The following amino acid solutions are
prepared~
Leu 7.2 g/l 7.2 g/l
Ile 5.6 g/l 5.6 g/l ; ~ ;
Val 5.6 g/l 5.6 g/l
Trp 1.2 g/l 1.2 g/l ~.
Phe 3.2 g/l 3.2 g/l
Lys 3.2 g/l 3.2 g/l
Met 2 g/l 2 g/l : ~ `
Thr 4 g/l 6 g/l
;, ~"`'~' :
213~38o . ~ :.,.. `~,.i.
-- 20 ~ j"i~
" '. '. ` ..., ~ .,,
:., . ., ^;.;,. ":
., ,. ~ ,' .'~! ~
Asp 8 g/l 8.5 g/l
Glu 2 . 4 g/l 2.4 g/l .~ .. ?.i.
Ser 9.8 g/l ~ 9.8 g/l . ;~
Gly 5.6 g/l 5 g
Ala 6 g/l 5.8 g/l -"
OTC 2.6 g/l 4 g/l
Orn 2. 4 g/l ~ G~,
Tyr 0. 4 g/l o.i g/l
His 3.2 g/l 3 g/l `f
Arg 4 . 8 g/l 4 . 6 g/l ''~
Pro 3.2 g/l 3.2 g/l ~``"`''"';:i~'~;~
Water q.s. for 1 1 :~: .,
AAT 80.4 g/l 80.7 g/l
4-Oxothiazolidinecarboxylic acid or in the salt .
form.
Example 7 - The following amino acid solution is
prepared~
Leu 6 g/l
Ile 4.5 g/l
Val 4.5 g/l
Trp 1.2 g/l
Phe 3 g/l
Lys 3 g/l ~ ~i
Met 2 g/l
Thr 6 g/l
Asp 8.5 g/l ; ~
Gln 7.8 g/l i ~s.. `
Ser 9.8 g/l
Gly 5 g/l
Ala 4 g/l
OTC 4 g/l
2 1 3 ~ 3 8 0
' .': ''",'.."..`'',
., . . .~ :.,
Orn ~~ ; `~
Tyr 0.4 g/l ,;.`~: ,
His 3 g/l ' .,~
Arg 4 g/l ',,!,',,.",~".',',',.. ','',,,;,"~",,,
Water q.s. for 1 1
AAT 81.1 g/l
4-Oxothiazolidinecarboxylic acid or in the salt
form.
Example 8 - The following amino acid solution is
prepared~
Leu 12 g/l
Ile 9.3 g/l
Val 9.3 g/l ~ i:
lS Trp 2 g/l
Phe 5.33 g/l
Lys 5.33 g/l
Met 3.33 g/l :~ ;
Thr 10 g/l
Asp 14.16 g/l ~ .;
Gln 4 g/l
Ser 16 g/l
Gly 8.33 g/l :
Ala 10 g/l
OTC 6.66 g/l .: ~ :
Orn --
Tyr 0.5 g/l .
His 5 g/l
Arg 7.6 g/l . .; ; :~
Pro- 5.33 g/l
Water q.s. for 1 1
- ' ' ~',' '~ ' `'
2 1 3 ~ 3 ~ 0
.. ;~.. ,;.
- 22 -
AAT 134.17 g/l ''''.
4-Oxothiazolidinecarboxylic acid or in the salt
Example 9 - The following amino acid solution is :~.";;.
prepared~
Leu 6 g/l '~' ' ~''. ',""''''',''.'~:.!.'
Ile 5 g/l
Val 5 g/l
Trp 1.2 g/l
Phe 3 g/l
Lys 3 g/l ~ ~ -
Met 2 g/l :~
Thr 6 g/l ;~:
Asp 8.S g/l ~ .:
Ser 9.6 g/l : : ~
Cys 5 g/l . ~:
Ala-Gln 15 g/l
Gly 5 g/l
Arg 4 g/l :
, . ., . :.; .
Water q.s. for 1 1 .
AAT 78.3 g/l
Example 10 - The following amino acid solution is
:. . . ;- ~ .
prepared: ..
Leu 6 g/l :~
Ile 5 g/l - -~.~f .~ r,
Val 5 g/l ;~
Trp 1.2 g/l :
Phe 3 g/l
Lys 3 g/l
Met 2 g/l
Thr 6 g/l
."'~ '''.
,:,., ,.. , . : : - . . , -
2 1 3 4 3 8 0
..... :~.,.
- 23 -
Asp 8.5 g/l .
Ser 9.6 g/l
OTC 5 g/l
Ala-Gln 15 g/l .
Gly 5 g/l
Arg 4 g/l ;
Water g.s. for 1 1
AAT 78.3 g/l
4-Oxothiazolidinecarboxylic acid or in the salt -~ . j,''''~J~1.
form.
Example 11 .;~,s,
Composition (for 1000 ml~ intended for oral or enteral .:~
administration
Proteins 58.2 g (in the form of ; ; ~a.
small casein and
whey peptides)
Cysteine 4.9 g
Lipids 52 g (medium chain .~
triglycerides, soya . ~. ~''r':.
oil, and the like) ~ !,;/,is
Glucides 158 g (maltodextrins and
starch) .. :~
Inorganics
Sodium 1000 mg
Potassium 1660 mg Z S~.,'~"'~',~',A~
Calcium 450 mg :~
Phosphorus 500 mg .. ,
Magnesium 330 mg ~','.;.... '~,a'`''.'~`'c~
Iron 13.3 mg
Zinc 13.3 mg
Manganese2.7 mg
Copper 1.3 mg
Chlorides2500 mg
,~ ', ,'~',.',.:.', "'',,
1 3 ~ 3 8 0 ;
............................. ........ .................. ................. . :` ` ,
- 24 -
Iodine 100 mg
Vitamins
A 1064 mg
E 20 mg
Bl 2 mg
B2 2 mg
B5 6.7 mg
B6 2.6 mg
C 133 mg
PP 26.6 mg
B12 3 mg
Folic acid 333 mg
Biotin 133 mg
. :. .~
Choline 266 mg ~;
The same proportion of cysteine can also be supplied
by a precursor, for example 4-oxothiazolidine-carboxylic ~ ,,
acid or peptides which are rich in cysteine.
It should be understood that various changes and
modifications to the presently preferred embodiments
described herein will be apparent to those skilled in the
art. Such changes and modifications can be made without
departing from the spirit and scope of the present
invention and without diminishing its attendant
advantages. It is therefore intended that such changes
and modifications be covered by the appended claims. ~ .
.'!,, ~, .,
,.'' " ~ :'
7~
."~
